instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6
values | meta_inputlicense stringclasses 6
values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
What was the outcome of reaction 'Protein urine present'? | Low-Vacuum Scanning Electron Microscopy to Assess Histopathological Resolution of Class V Lupus Nephritis: A Case Report.
Lupus nephritis (LN) is most frequently associated with poor outcomes in patients with systemic lupus erythematosus (SLE). LN manifests as histopathological changes in the kidney caused by immune complex formation and deposition. In particular, immunoglobulin G (IgG) deposits are frequently observed by immunofluorescence staining, which helps to establish the diagnosis of LN. In this case report, we describe a 57-year-old woman with SLE who had been undergoing treatment on an outpatient basis for 11 years. Her first and second renal biopsies revealed class V LN with a coarsely granular pattern of IgG deposition in the peripheral capillary walls. However, her third renal biopsy showed no IgG deposition, which indicated histopathological resolution of her class V LN. We used low-vacuum scanning electron microscopy (LV-SEM) to examine the three-dimensional structural alterations in her glomerular basement membranes. In this report, we describe findings that indicated resorption of epithelial deposits, that is, resolution of LN. The results of repeated kidney biopsies confirmed by LV-SEM suggested the possibility of a state unrelated to LN.
Introduction
Systemic lupus erythematosus (SLE) is a multiorgan, systemic autoimmune disease with clinical and serological heterogeneity [1]. Lupus nephritis (LN) is one of the most common and devastating manifestations of SLE. In approximately 50% of affected patients, SLE results in LN [2]. Although the overall mortality of patients with SLE has decreased remarkably in recent decades, renal disease remains the leading cause of death in these patients [3]. LN has histopathological diversity and is explained by immune complex deposition [4, 5]. Renal biopsy allows for evaluation of LN activity and determination of therapy based on histological features. Although individual patterns of immunofluorescence (IF) staining are highly variable, some general characteristics are applicable to all classes [4]. In more than 90% of patients with SLE, IF staining of the peripheral capillary wall or mesangial areas is seen microscopically. In particular, immunoglobulin G (IgG) deposits are observed using IF staining in almost every patient with LN [4, 6]. In most cases of LN, immune complexes in blood plasma are deposited on glomeruli, which can be seen using light microscopy (LM), IF, and transmission electron microscopy (TEM) [7].
In the present case, we performed three renal biopsies in 9 years. The first and second renal biopsies revealed IgG deposits in the peripheral capillary walls; however, the third renal biopsy showed no IgG deposits. Conventional renal biopsy paraffin sections stained with periodic acid methenamine silver (PAM) can be directly observed using low-vacuum scanning electron microscopy (LV-SEM). In conventional electron microscopy, only a small area can be viewed; however, LV-SEM enables scanning over broad areas of the specimen and in three dimensions under high magnification [8, 9]. We considered that evaluation using LV-SEM might be useful for the histopathological assessment of renal glomerular basement membrane (GBM) alterations. We therefore evaluated the two sides of the GBM using LV-SEM and examined the washout phenomenon of the membranous form of LN. We herein highlight the histopathological findings of this case.
Case Presentation
Clinical Information
A 57-year-old woman had presented with Raynaud's phenomenon and fever of unknown etiology at the age of 48 years. Laboratory analysis showed positive anti-nuclear autoantibody and renal insufficiency with proteinuria (1.33 g/g Cr). The titer of anti-double-stranded DNA autoantibody was slightly elevated (3.1 IU/mL). She was diagnosed with SLE in accordance with the Systemic Lupus International Collaborating Clinics criteria [10]. The patient's first renal biopsy was undertaken at this time. Examination of the biopsy specimen led to a diagnosis of class V LN in accordance with the World Health Organization classification [9]. According to this diagnosis, she was treated with oral prednisolone, and tacrolimus was added at the age of 49 years. These treatments were successful, and the urine protein level decreased remarkably 4 years after treatment was started (to around 0.3–0.4 g/g Cr). At the age of 53 years, she was treated with dose-reduced tacrolimus because the effectiveness of these treatments had been confirmed. Despite the slow improvement in her renal function, the severity of her proteinuria gradually increased during the 4 years since the first biopsy. We suspected recurrence, and she therefore underwent a second biopsy at the age of 54 years. This repeat biopsy also revealed class V LN. Based on these findings, mycophenolate mofetil at 1,250 mg/day was added to the treatment regimen.
At the age of 57 years, laboratory studies revealed low SLE activity with a normal complete blood count, normal complement protein levels, and an anti-double-stranded DNA antibody titer of 5.8 IU/mL; however, proteinuria was present (>2 g/g Cr) (Table 1). Therefore, she underwent a third renal biopsy at the age of 57 years. At this time, the patient's clinical course and immunological investigation indicated no progression of SLE. Because the pathological findings indicated negative conversion of IgG, we considered that the activity of LN had been lost. These pathological results could explain the decreased SLE activity, and the class V LN was presumed to have resolved.
The patient was subsequently treated with antihypertensive drugs with a focus on angiotensin II receptor antagonists. Following treatment, her proteinuria decreased to 0.5 g/g Cr.
Renal Biopsies
The patient's first renal biopsy was performed at the age of 48 years. Histopathological examination using LM revealed several foamy formations and a generalized diffuse thickening of the GBM, which manifested as prominent spikes on PAM silver staining (Fig. 1a1). On IF staining, coarsely granular deposits of IgG, C3, and C1q were evident in the capillary walls (Fig. 1a2). TEM revealed abundant subepithelial deposits lining all capillary loops (Fig. 1a3). The patient was diagnosed with LN class V according to the International Society of Nephrology/Renal Pathology Society classification.
The second biopsy at the age of 54 years revealed reduced spike formation and a bubbly appearance (stippling) under LM examination (Fig. 1b1). IF staining showed similar findings; coarsely granular deposits of IgG, C3, and C1q were evident in the capillary basement membrane (Fig. 1b2). On TEM, smaller electron-dense deposits than in the first renal biopsy suggested a resorptive process (Fig. 1b3). A well-developed GBM reaction surrounded the deposits with overlying foot process effacement. These findings also indicated type V LN.
The third biopsy at the age of 57 years revealed advanced glomerulosclerosis (5/25 glomeruli), and PAM silver staining exhibited a primarily bubbly appearance and dome patterns; the spikes had almost disappeared on LM examination (Fig. 1c1). Conversely, the IF findings showed a scattered distribution of the IgG deposits with negative C3 and C1q (Fig. 1c2). TEM also revealed a marked decrease in the electron density of the deposits that had been clearly seen in the previous two biopsies. Instead, GBM thickening and wrinkling were seen (Fig. 1c3). We doubted that the results of TEM and IF therefore differed from those of LM. Another remarkable finding on LM was arteriolar hyalinosis, which could be explained as arteriolopathy caused by calcineurin inhibitors. No evidence of calcineurin inhibitor toxicity such as striped interstitial fibrosis or tubular atrophy was observed. Tubular and interstitial lesions were attributed to the effect of renal sclerosis because of hypertension. The increase in urinary protein excretion could be explained by severe arterial sclerosis and calcineurin inhibitor-induced arteriolopathy rather than exacerbation of LN.
C4d is described as a byproduct of activation of the classical and lectin pathways. Because C4d acts as a positive marker for an immune complex-mediated mechanism in glomerular nephritis, C4d staining can be helpful in revealing immune complex deposition [11]. Unfortunately, we could not examine the C4d properties of the deposits using frozen sections because of a lack of additional tissue remaining in the block. Therefore, to confirm that LN was not the main cause of the clinical proteinuria, we investigated the GBM using a different method.
For further evaluation, we observed the GBM in all three biopsy specimens using LV-SEM (Hitachi Tabletop microscope TM4000; Hitachi High-Technologies Corp., Tokyo, Japan). In the first renal biopsy at the age of 48 years, LV-SEM of glomeruli retrieved from formalin-fixed paraffin-embedded tissue (PAM stain) revealed extensive and numerous subepithelial holes where deposits were thought to have been present. Additionally, well-developed GBM material formed spikes around the holes (Fig. 2a1). However, these holes were not found on the glomerular capillary luminal side (Fig. 2a2). This finding corresponded to Ehrenreich-Churg stage II membranous nephropathy (MN). The second renal biopsy at the age of 54 years showed a well-developed GBM reaction surrounding the holes where deposits might have been present; this finding was equivalent to Ehrenreich-Churg stage III MN (Fig. 2b1). Epithelium had formed and covered holes found in the first renal biopsy tissue, and it was difficult to see holes when looking down from the subepithelial side (Fig. 2b1). The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open (Fig. 2b2). The third renal biopsy at the age of 57 years exhibited epithelium covered by newly formed GBM material, with openings in the GBM inward toward the glomerular capillary lumen (Fig. 2c1, c2). We speculated that the holes in the glomerular capillary luminal side might emerge when immune complex deposits in the GBM wash out.
In studying the third renal biopsy specimen, we also drew a comparison between the IF findings of the scattered distribution of the deposits and the LV-SEM findings. We stained frozen sections for IF with PAM and examined them with LV-SEM. We compared and observed the same glomeruli (Fig. 3). No IgG staining was confirmed using IF, which suggested that no deposits were present in the GBM (Fig. 3a). However, many cavities were confirmed using LV-SEM (FIG. 3b). Therefore, it was considered that no deposit was present in the many holes, and it was presumed that washout of the immune complex deposits occurred in the membranous LN. Overall, further observation of the GBM with LV-SEM confirmed resolution of class V LN. This case was similar to stage IV MN according to the Ehrenreich-Churg staging criteria.
A case report by Nonaka et al. [12] described the conventional TEM assessment of subepithelial deposits in a patient with mild membranous LN. However, few cases of LN evaluated using LV-SEM in which the loss of immune complex deposits was discovered have been reported. Clinicians emphasize IgG deposition in the diagnosis of LN. Many clinicians tend to consider that LN is highly unlikely if IgG is negative using IF examination. In the present case, however, the diagnosis of LN was confirmed in the first and second renal biopsies.
This is our first experience of a case in which the pathological findings were presumed to indicate a state of resolution of class V LN, and we thought that this was a highly contradictory finding. We had doubts regarding whether the histopathological findings of LN disappear (as in common MN) as the disease activity of SLE decreases.
Discussion/Conclusion
In the present study, we found that membranous LN diminished or resolved over the course of the three renal biopsies. To help clarify this process, we evaluated the patient's kidney biopsy tissue using LV-SEM, which allows for observation of both sides of the GBM. By studying the three-dimensional structure of the GBM using LV-SEM, we confirmed the formation of holes on the glomerular capillary luminal side. From these findings, we suspected that the same pathology of the membrane washout phenomenon that occurs in MN occurred in our patient with LN.
LV-SEM sometimes outperforms the conventional technique, TEM. TEM is the superior technique for investigating cross-sectional images of various components in glomeruli; however, performing three-dimensional and whole/wide observations using ultrathin sections is difficult because of the limitation of the observable size. LV-SEM can be used to evaluate the three-dimensional ultrastructural changes of the glomerular extracellular matrices in the same specimen used for LM. It thus provides more detailed three-dimensional information [8, 9]. Therefore, to review the morphological alterations of the glomeruli in a three-dimensional, broad area, we examined the LM slides of the renal biopsy specimens using LV-SEM.
LV-SEM examination of the first biopsy revealed many openings or holes in the subepithelium, consistent with the LM, IF, and TEM findings. The second renal biopsy showed a well-developed GBM reaction surrounding the openings or holes with overlying foot process effacement. These LV-SEM results were almost identical to those of TEM. The third renal biopsy showed openings on the thickened GBM inward toward the glomerular capillary lumina and loss of the electron density of the deposits in TEM. We confirmed the findings of some openings or holes in the GBM on the luminal side of the vessel using LV-SEM. Thus, we suspected that the deposits were washed out through these holes. In other words, the findings we confirmed using LV-SEM might result from washout of the immune complexes (only the cavity remained after washout). This concept allows for the possibility of finding IgG positivity on IF, which can be said to be an essential marker of LN. IgG was negative using IF in the tissue from the third renal biopsy in this patient.
Furthermore, it is possible that LV-SEM might be useful for monitoring disease, in contrast to interpreting potentially challenging serological results. An example is M-type phospholipase A2 receptor (PLA2R)-negative MN. PLA2R-negative secondary MN is generally characterized by the irregular distribution and size of subepithelial deposits and the presence of irregular subendothelial and mesangial deposits in glomeruli. We believe that there may be some difference in the GBM of PRA2R-positive or -negative MN evaluated in detail using LV-SEM.
The Ehrenreich-Churg classification divides MN into four pathological stages according to the state of immune complex deposition and change in the GBM [13]. Stage IV MN is characterized by loss of the electron density of the deposits, transition to a “washout” state, and development of electron-lucent zones within an irregularly thickened GBM [13]. Furthermore, the GBM recovers to an almost normal morphology in stage V MN [14]. The GBM returns to its normal form without deposition or thickening in the state of washed-out MN. In the present case, however, LM did not show findings consistent with normalization of the GBM morphology, similar to the washout image seen in stage IV or V MN, and changes such as thickening and spike formation persisted. However, IgG and C3 deposits cannot be seen using IF staining. TEM also exhibited few deposits. This series of pathophysiological findings has been confirmed by observations on resolving glomerulopathy in serial allograft biopsies [15].
Based on these results, we postulated a pathological process beginning with LN that caused deposition of immune complexes on the GBM. A decrease in LN activity then led to loss of these deposits as the disease progressed to a state of stage V MN washout, which results in a bubbly appearance. That is, despite resolution of LN, LM showed a remarkable change in the GBM. When LM shows noticeable changes in the GBM and specific clinical findings are present (excessive urinary protein), clinicians will usually think that the cause is LN.
The opening on the GBM is normally covered by vascular endothelium. However, in MN, complement complexes might injure the GBM by inducing the production of reactive oxygen species, thus altering the membrane structure [16]. At that time, a large proportion of the immune complex might have passed through the GBM from the glomerular capillary luminal side toward the epithelial side and nephrosis developed. We suspected that in the present case, this backward event (from the epithelial side toward the glomerular capillary luminal side) could have occurred during the LN washout phase. In other words, we suspected the possibility that these holes observed on the glomerular capillary luminal side were formed when the immune complexes were washed out.
In conclusion, our patient exhibited a loss of LN activity and a change to a state of resolution of class V LN. Renal biopsy revealed negative conversion of IgG on IF, and spikes and domes were present in the GBM on LM. We believe that the evaluation of three-dimensional structural alterations in GBM using LV-SEM might be a useful approach for assessing variation in renal biopsies over time.
Statement of Ethics
This study was conducted according to the guidelines laid down in the World Medical Association Declaration of Helsinki. Informed consent was obtained from the patient described in this case report, and the consent allowed their data to be stored, as required by the Hiroshima University Hospital. Written consent to publish this information was obtained from the patient (images and publication).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not funded by any third party.
Author Contributions
M.Y., S.H., and T.D. contributed to the data collection. S.H. and T.M. designed the research. Y.M. and A.S. evaluated the pathological tissue. M.Y. and S.H. performed the primary manuscript preparation. M.Y., S.H., T.D., and T.M. wrote the paper. T.M. has primary responsibility for the final content. M.Y., S.H., T.D., Y.M., and A.S. reviewed the paper and revised it critically. All authors read and approved the final manuscript.
Acknowledgments
We thank Angela Morben, DVM, ELS, and Andrea Baird, MD, from Edanz Group (https://en-author-services.edanzgroup.com/), for editing drafts of the manuscript.
Fig. 1 Renal biopsy findings. a First renal biopsy. a1 LM revealed that the basement membrane was thickened and exhibited mainly spikes (red arrowheads) (PAM stain). Scale bar, 25 μm. a2 IF staining demonstrated coarsely granular deposits of IgG, C3, and C1q in the capillary walls (IF microscopy, IgG, C3, C1q; ×200). a3 TEM showed abundant subepithelial deposits. The pattern was equivalent to Ehrenreich-Churg stage II MN. Scale bar, 2 µm (TEM). b Second renal biopsy. b1 The basement membrane showed a global increase in thickening and a bubbly appearance on LM (red arrowheads). This appearance was comparable with Ehrenreich-Churg stage III MN (PAM stain). Scale bar, 50 μm. b2 IF exhibited coarsely granular deposits of IgG, C3, and C1q in the capillary basement membrane, as in the previous examination (IF microscopy, IgG, C3, C1q; ×200). b3 TEM examination showed that the dense deposits were smaller and had been partly resorbed. A well-developed basement membrane reaction surrounded the deposits with overlying foot process effacement. Scale bar, 2 µm (TEM). c Third renal biopsy. c1 The basement membrane was thickened and exhibited a general meandering-like wrinkling pattern as seen on LM. The bubbly appearance was the same as in the second biopsies (PAM stain). Scale bar, 50 μm. c2 IF showed almost negative conversion of IgG and negative C3 and C1q (IF microscopy, IgG, C3, C1q; ×200). c3 On TEM, the basement membrane showed global thickening, wrinkling, and podocyte foot process effacement. The electron density of the deposits was unclear. Scale bar, 2 µm (TEM). C, complement; IF, immunofluorescence; IgG, immunoglobulin G; LM, light microscopy; MN, membranous nephropathy; PAM, periodic acid methenamine silver; TEM, transmission electron microscopy.
Fig. 2 Renal biopsy findings using LV-SEM. a First renal biopsy. a1 An image from the epithelial side of the GBM. Basement membrane material accumulated between many holes (deposit-like appearance) and projected into the urinary space as “spikes” (red arrowheads). The holes were not covered with basement membrane. Scale bar, 2.5 μm. a2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary luminal side was covered by the material of the basement membrane, and no opening was seen (blue arrowheads). Scale bar, 2.5 μm. b Second renal biopsy. b1 An image from the epithelial side of the GBM. Intramembranous holes were observed. These holes (deposit-like appearance) were surrounded by well-developed basement membrane material (red arrowheads). In the subepithelium of the GBM, basement membrane material was newly formed on the holes, and the holes seen in a1 could not be confirmed from the epithelium side view. Scale bar, 5 μm. b2 An image from the glomerular capillary lumina. The GBM of the glomerular capillary lumina was almost covered by basement membrane material, and holes were still only partially open. Scale bar, 2.5 μm. c Third renal biopsy. c1 An image from the epithelial side of the GBM. Thickening of the basement membrane was still present. Vacuolation was present in potential spaces where the deposits might have been. The holes on the epithelium side shown in a1 were hardly observed. Scale bar, 2.5 μm. c2 An image from the glomerular capillary lumina. In contrast to c1, openings were present on the glomerular basement membrane inward toward the glomerular capillary lumina (blue arrowheads). Electron-lucent-like areas probably represented resorption of prior subepithelial immune complexes. Scale bar, 5 μm. GBM, glomerular basement membrane; LV-SEM, low-vacuum scanning electron microscopy.
Fig. 3 Comparison between IF microscopy and LV-SEM findings. a PAM stain of an IF-stained specimen. IF staining seemed to be almost nonexistent (red arrowhead and circle). b LV-SEM findings did not clearly confirm the immune complex deposition in the area (red arrowhead and circle). Examination of the site with LV-SEM indicated washout of the immune complex deposition. IF, immunofluorescence; LV-SEM, low-vacuum scanning electron microscopy; PAM, periodic acid methenamine silver.
Table 1 Patient's laboratory results upon admission at the age of 57 years
Parameter Value Reference range
Urine
pH 5.5 5.0–6.5
Red blood cells, /HPF 0–1 <5
Fatty casts, /WF 1–4 Negative
Epithelial casts, /WF 1–4 Negative
Urine protein/creatinine ratio, g/g 2.68 <0.15
N-acetyl-β-D-glucosaminidase, IU/L 13.2 0.7–11.2
β2-Microglobulin, µg/L 0.75 <230
Blood
Leukocyte count, /µL 4,750 4,500–9,000
Lymphocytes, /µL 940 1,200–3,690
Hemoglobin, g/dL 11.9 13.6–17.0
Platelet count, ×104/µL 20.7 14–36
Urea nitrogen, mg/dL 21.4 8.0–22.0
Creatinine, mg/dL 0.85 0.60–1.10
Estimated GFR, mL/min/1.73 m2 53 >90
Uric acid, mg/dL 6.0 3.6–7.0
Total protein, g/dL 6.2 6.7–8.3
Albumin, g/dL 3.7 4.0–5.0
Sodium, mEq/L 140 138–146
Potassium, mEq/L 5.3 3.6–4.9
Chloride, mEq/L 108 99–109
Corrected serum calcium, mg/dL 8.8 8.6–10.4
Phosphate, mg/dL 3.5 2.5–4.7
C-reactive protein, mg/dL 0.07 <0.30
CH50, CH50/mL 48.7 25–48
C3, mg/dL 98 65–135
C4, mg/dL 26 13–35
IgG, mg/dL 630 870–1,700
IgA, mg/dL 170 110–410
IgM, mg/dL 18 33–190
Anti-nuclear antibody ×320 <×40
(staining patterns) homologous, speckled
Anti-ssDNA antibody, IU/mL 2.8 <2.0
Anti-dsDNA antibody, IU/mL 5.8 <2.0
CH50, 50% hemolytic complement; dsDNA, double-stranded DNA; GFR, glomerular filtration rate; HPF, high-power field; Ig, immunoglobulin; ssDNA, single-stranded DNA; WF, whole field. | Recovering | ReactionOutcome | CC BY-NC | 33708798 | 19,404,881 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma.
The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS).
We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs).
The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4-3.4 months] and the median OS was 12.0 months (95% CI: 10.2-13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028).
In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.
pmcIntroduction
At present, there is still a lack of effective protocols for the treatment of advanced soft tissue sarcoma (STS), and patient prognosis is poor. The first-line treatment for most sarcoma subtypes is anthracycline-based chemotherapy, which can achieve an objective responsive rate (ORR) of 20–40% and disease control in 2.3 to 4.9 months (1-5). After failure of first-line chemotherapy, there is no standard recommended second-line treatment. Some new chemotherapeutic agents, including gemcitabine, trabectedin, and eribulin, have shown some benefit for certain subtypes of STS, but their significance for improving overall survival (OS) is still controversial (6-8). Some tyrosine kinase inhibitors (TKIs), including pazopanib, sunitinib, regorafenib, and anlotinib, amongst others, were reported to offer some benefit for disease control, but there are no large-scale randomized studies which demonstrate their effectiveness in improving OS (9-12). In the PALETTE study, the median progression-free survival (PFS) was 4.6 months for patients receiving pazopanib compared with 1.6 months for the placebo group (P<0.0001), but there was no significant difference in OS between the 2 groups (12.5 vs. 10.7 months, P=0.25) (9).
Recently, immune checkpoint inhibitors (ICIs), including pembrolizumab, have made great breakthroughs in cancer therapy, enabling some patients with advanced melanoma, lung cancer, and bladder cancer to achieve long-term disease control (13-15). However, except for some specific cancers, the response rate of solid tumors to immunotherapy is generally low. Therefore, how to screen for potential patients and how to improve the efficacy of ICIs through combination therapies are 2 promising research directions in the future. The molecular markers reported to be related to the therapeutic effect of ICIs include the expression of programmed death-ligand 1 (PD-L1) on tumor cells, tumor mutation burden, microsatellite instability, tumor infiltrating lymph node cells, and neoplastic antigen, among others (14-18). In addition, some clinical trials have shown that combining chemotherapy, targeted therapy, and radiotherapy can improve the response rate to ICIs (19-22).
Only a few studies have reported on the efficacy and safety of ICIs for STS (23,24). The results of the SARC028 trial showed that the ORR of pembrolizumab for the treatment of STS was 18%. The efficacy of pembrolizumab was reported to be related to the subtype of sarcomas, as it had a relatively high ORR in undifferentiated pleomorphic sarcoma (UPS) (23) and alveolar soft part sarcoma (ASPS) (24,25). Unfortunately, there is no evidence that most molecular markers, including PD-L1, are associated with the therapeutic effect of ICIs. The low incidence of STS and the high variance of responses make research into immunotherapies complex and difficult (26). This study retrospectively analyzed patients with advanced STS treated with pembrolizumab at our hospital, and investigated the potential factors related to its efficacy and safety.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-21-49).
Methods
Patient information
We examined 38 patients with pathologically confirmed STS who received pembrolizumab immunotherapy at Peking University Cancer Hospital & Institute from July 2017 to December 2018. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02). All patients had metastatic disease and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 standards (18). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores were 0–2. Pathological subtypes included leiomyosarcoma (LMS), UPS, ASPS, synovial sarcoma (SS), pleomorphic rhabdomyosarcoma (PRMS), clear cell sarcoma (CCS), dedifferentiated liposarcoma (DDLS), epithelioid sarcoma (ES), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma (AS), carcinosarcoma, exoskeletal chondrosarcoma (ESCS), and desmoplastic small round cell tumor (DSRCT). Based on previous systemic treatments, pembrolizumab was administered in 8 patients as first-line therapy, in 17 patients as second-line therapy, and in 13 patients as third- or further-line therapy. PD-L1 expression was evaluated if the tumor specimen can be obtained, using the proprietary Dako 22C3 IHC assay. PD-L1 expression was determined as positive if it was expressed in more than 1% of tumor cells.
Groups and therapy
Patients were divided into a pembrolizumab monotherapy group (A), combined chemotherapy group (B), and combined targeted therapy group (C), according to their medication strategy. Group A received pembrolizumab injections at 2 mg/kg for 21 days per cycle. In group B, the standard dose of anthracycline-based regimens (AIM, anthracycline, ifosfamide and mesna; or AD, anthracycline and dacarbazine), high dose ifosfamide, or gemcitabine combined with docetaxel or dacarbazine were used simultaneously with pembrolizumab injection. Chemotherapy was repeated for 4 to 6 cycles, or was discontinued if the disease progressed or intolerable adverse events (AEs) occurred. In group C, in addition to pembrolizumab, the patients were treated with either anlotinib (12 mg/day for 14 consecutive days, then discontinued for 7 days, in a 21-day cycle), pazopanib (400–600 mg/day), or lenvatinib (10–18 mg/m2) simultaneously. Target agents were consistently used until disease progression, intolerable toxicity, or complete tumor remission occurred. For all patients, pembrolizumab was continued for up to 2 years or until disease progression or unacceptable AEs occurred.
Treatment outcomes and adverse reactions
Radiographic tumor assessment, including magnetic resonance imaging or computed tomography, was performed at baseline and every 6 to 8 weeks during treatment. Safety assessments, including routine blood and biochemical tests, analysis of thyroid function and myocardial enzymes, and electrocardiograms, were performed at baseline and every 3 weeks before pembrolizumab administration. Special examinations were performed if the patient had suspicious AEs related symptoms. For example, lung CT scans were recommended if dyspnea and cough were present. The adverse reactions of patients were recorded and scored during follow-up. The primary endpoint was ORR, and the secondary endpoints included PFS, OS, and AEs. To further evaluate the effect of pembrolizumab alone, we assessed disease status 6 months after the withdrawal of chemotherapy and targeted therapy in groups B and C. ORR was defined as the ratio of complete response (CR) and partial response (PR) according to RECIST standards (18). PFS was defined as the time from the beginning of treatment to disease progression or death from cancer. OS was defined as the time from the beginning of treatment to patient death. AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (27).
Statistical analysis
SPSS 22.0 software was used for statistical analysis. Count data was expressed as frequency and percentage. The relationships between ORR and different therapeutic methods, treatment lines, and clinical characteristics were tested using Pearson’s chi-square test. Comparisons between PFS and OS were analyzed by Kaplan-Meier survival curves, and the Cox regression model was used to analyze related factors affecting PFS and OS. P<0.05 (two-tailed) was defined as statistically significant.
Results
Basic characteristics of patients
From July 2017 to December 2018, 38 patients with advanced STS received immunotherapy with pembrolizumab in our hospital. Among them, 17 were males and 21 were females, with an average age of 42.6 years (12–79 years). According to the ECOG PS assessments, 5 cases (13.2%) scored 0, 20 cases (52.6%) scored 1, and 13 cases (34.2%) scored 2. The number of cases of each pathological subtype were 9 LMS, 5 ASPS, 4 UPS, 4 PRMS, 4 CCS, 4 DDLS, 2 SS, 1 ES, 1 MPNST, 1 AS, 1 carcinosarcoma, 1 ESCS, and 1 DSRCT. Six cases received pembrolizumab monotherapy, including 2 cases receiving it as first-line treatment, 2 cases receiving it sequentially after chemotherapy, 1 case receiving it after TKI-targeted therapy, and 1 case with a history of both chemotherapy and targeted therapy. Another 16 cases received pembrolizumab combined with chemotherapy, including 7 cases with AD/AIM and 9 cases with other regimens, and 5 cases were treated with pembrolizumab combined with chemotherapy as first-line therapy, 8 cases were treated as second-line therapy, and 3 cases were treated as third- or further-line therapy. Of the 16 patients treated with pembrolizumab combined with targeted therapy, 8 patients received pazopanib, 6 received anlotinib, and 2 received lenvatinib. Only 1 of these patients was treated with pembrolizumab combined with targeted therapy as first-line therapy, while 7 cases were treated as second-line therapy, and 8 cases were treated as third- or further-line therapy.
Therapeutic response
All patients were treated with pembrolizumab for more than 2 cycles. Two patients died within 2 months without evaluation of treatment response. Of the remaining 36 patients, 3 patients survived less than 12 weeks and were evaluated at the 6th week, while the rest of the patients were evaluated every 6–8 weeks. One patient (2.8%) achieved CR, 6 patients (16.7%) achieved PR, 17 patients (47.2%) experienced stable disease (SD), and 12 patients (33.3%) experienced progressive disease (PD). The overall ORR was 19.4% (7/36). The ORRs of patients who received the treatments as first-line, second-line, or third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). However, there was no significant difference between different combination treatment groups (P=0.996), with an ORR of 20.0% (1/5), 18.8% (3/16), and 20.0% (3/15) in groups A, B, and C, respectively. Other clinical features, including sex, age, ECOG PS score, and lactate dehydrogenase (LDH) level, were also not associated with ORR (Table 1). PD-L1 was detected in 15 patients, among which 6 patients (40%) had positive PD-L1 expression. No significant correlation was found between treatment efficacy and PD-L1 expression levels (P=0.235, Table 1).
Table 1 The relationship between treatment response and clinical characteristics
Basic feature Case number ORR P value
Sex 0.418
M 15 4 (26.7%)
F 21 3 (14.3%)
Age 0.209
≤40 14 1 (7.1%)
>40 22 6 (27.3%)
ECOG performance 0.642
0 6 2 (33.3%)
1 18 3 (16.7%)
2 12 2 (16.7%)
LDH 0.652
Elevated 9 1 (11.1%)
Normal 27 6 (22.2%)
PD-L1 0.235
Negative 9 1 (11.1%)
Positive 6 3 (50%)
NA 21 3 (14.3%)
Treatment time 0.052
First-line 7 3 (42.9%)
Second-line 16 4 (25.0%)
Third-line or more 13 0 (0%)
Therapeutic methods 0.996
Monotherapy 5 1 (20.0%)
Chemotherapy combined 16 3 (18.8%)
Target therapy combined 15 3 (20.0%)
ECOG, Eastern Cooperative Oncology Group; ORR, objective responsive rate; LDH, lactate dehydrogenase; PD-L1, programmed cell death-ligand 1; NA, not available.
Four patients (11.1%) maintained CR or PR for at least 6 months with pembrolizumab monotherapy or after withdrawal of chemotherapy or targeted therapy regimens (Table 2), including 1 case each of ASPS, UPS, ESCS, and AS (Figure 1). However, none of the patients with LMS, the subtype with the highest number of cases (9), achieved long-term disease control. No factors were found to be associated with this indicator.
Table 2 Detailed information of the 4 patients who maintained PR or SD for at least 6 months with pembrolizumab
Sex Age Subtype ECOG score LDH Treatment time PD-L1 Treatment group Therapeutic response Time to progression
M 52 ASPS 2 0 Second-line NA Pembrolizumab alone PR Not reached
F 45 UPS 0 0 Second-line NA Combined AD PR Not reached
M 79 ESCS 2 1 Second-line Positive Combined lenvatinib PR 13 months
M 47 AS 1 0 First-line Positive Combined AD CR Not reached
ECOG, Eastern Cooperative Oncology Group; PR, partial response; CR, complete response; SD, stable disease; PD-L1, programmed cell death-ligand 1; LDH, lactate dehydrogenase; ASPS, alveolar soft part sarcoma; UPS, undifferentiated pleomorphic sarcoma; ESCS, exoskeletal chondrosarcoma; AS, angiosarcoma; NA, not available; AD, anthracycline and dacarbazine.
Figure 1 A patient with cardiac angiosarcoma achieved complete response (CR) after treatment with pembrolizumab combined with AD (anthracycline and dacarbazine) chemotherapy. (A) In a patient with cardiac angiosarcoma, pulmonary metastasis and hydrothorax were found after resection of the primary lesion. (B) When the patient started combined pembrolizumab and AD chemotherapy, the lung lesions were significantly reduced and the hydrothorax disappeared 6 cycles later on December 14, 2018. (C) The patient maintained clinical CR after maintenance with pembrolizumab monotherapy for 11.5 months through to November 29, 2019.
Survival conditions
All patients were followed for a median follow-up period of 11.9 months (range, 1.4–31.3 months). The median PFS was 2.9 months [95% confidence interval (CI): 2.4–3.4 months]. There were significant differences in PFS between patients with different lines of treatment, with a median PFS of 5.8 months (95% CI: 2.6–11.0 months), 3.5 months (95% CI: 2.0–5.0 months), and 2.8 months (95% CI: 2.4–3.1 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.005; Figure 2A). The median PFS of patients with normal LDH was 3.2 months (95% CI: 2.3–4.2 months), which was significantly higher than the PFS of 2.1 months (95% CI: 1.3–2.9 months) for patients with elevated LDH (P=0.025; Figure 2B). No significant difference in PFS was detected between treatment groups A, B, and C (P=0.160, 2.8 vs. 4.2 vs. 2.8 months, respectively; Figure 2C). Other clinical characteristics, including age, sex, ECOG PS score, and PD-L1 expression, did not significantly affect PFS.
Figure 2 Kaplan-Meier univariate analysis of progression-free survival (PFS). (A) Influence of treatment time on PFS. (B) Influence of serum lactate dehydrogenase (LDH) level on PFS. (C) Influence of combination strategies on PFS.
The median OS was 12.0 months (95% CI: 10.2–13.8 months). There were significant differences in OS between patients with different lines of treatment, with a median OS of 19.1 months (95% CI: 11.9–26.3 months), 15.4 months (95% CI: 12.8–19.8 months), and 7.0 months (95% CI: 4.1–9.9 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.002; Figure 3A). ECOG PS also significantly affected OS, with a median OS of 25.2 months (95% CI: 19.9–30.5 months), 12.5 months (95% CI: 7.7–17.3 months), and 7.5 months (95% CI: 4.8–10.2 months) in patients with a score of 0, 1, and 2, respectively (P=0.005; Figure 3B). The median OS of patients with normal serum LDH was significantly longer than those with elevated LDH (14.4 vs. 7.5 months, P=0.007). There were no significant differences in OS between the different treatment groups (P=0.185, Figure 3C). A Cox regression model of PFS was established by incorporating treatment line, therapeutic strategy, and LDH level (Table 3). The results showed that treatment time was the only independent factor affecting PFS. The risk of disease progression after treatment with ICIs as third- or further-line therapy was 3.94 times higher than that for first-line treatment (95% CI: 1.05–11.66, P=0.041). A Cox regression model of OS was established by incorporating treatment time, ECOG PS score, and LDH level (Table 3). The results showed that the ECOG PS score was the only independent factor affecting OS. The risk of death in patients with an ECOG PS score of 2 was 10.6 times greater than for those with a score of 0. The risk of death in patients treated with third- or further-line therapy was 2.75 times the risk for patients treated with first-line therapy, with a marginal statistical difference (95% CI: 0.88–8.59; P=0.057).
Figure 3 Kaplan-Meier univariate analysis of overall survival (OS). (A) Influence of treatment time on OS. (B) Influence of combination strategies on OS. (C) Influence of serum lactate dehydrogenase (LDH) level on OS.
Table 3 Cox regression model and multivariate analysis results
Parameters PFS OS
HR 95% CI P value HR 95% CI P value
Treatment time 0.033 0.057
First-line 1 1
Second-line 1.80 0.65–5.00 0.89 0.27–2.90
Third or more 3.94 1.36–11.51 2.75 0.88–8.59
LDH 0.071 0.434
Normal 1 1
High 2.16 0.94–4.97 1.44 0.58–3.57
ECOG performance status score
0 1 0.028
1 4.24 0.54–33.3
2 10.62 1.28–87.72
Therapeutic methods 0.407
Pembrolizumab 1
Pembro + chemo 0.77 0.27–2.20
Pembro + target 1.27 0.46–3.53
ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase.
Adverse events
The most common adverse reaction was fever, with an incidence of 68.4% (26/38), of which 6 cases (16.3%) had a temperature exceeding 38.5 °C. The other common adverse reactions were leukopenia (34.2%, 13/38), diarrhea (26.3%, 10/38), hypothyroidism (24.3%, 9/37), abnormal liver function (18.4%, 7/38), oral ulceration (18.4%, 7/38), and creatine kinase elevation (13.2%, 5/38). Six patients (15.8%) had severe AEs (SAEs), which led to treatment discontinuation (Table 4). In 1 patient with ASPS, platelets decreased to less than 1×109/L after 2 cycles of pazopanib combined with pembrolizumab. The patient died of gastrointestinal bleeding despite a large dose of glucocorticoids and platelet transfusion. Because it has not been reported that pazopanib can cause severe thrombocytopenia, which occurred in this patient very suddenly and rapidly, it was thought that the thrombocytopenia was related to the combination of pazopanib with pembrolizumab. In another case, a patient with PRMS developed very severe systemic skin bullae after using nonsteroidal anti-inflammatory drugs (NSAIDs) during the 4th cycle of pembrolizumab combined with AIM chemotherapy. We finally decided after discussion with dermatologists that the reaction was epidermolysis bullosa induced by the ICI, and after administration of a glucocorticoid and topical potassium permanganate, the skin bullae completely healed and only mild pigmentation remained. A patient with ASPS developed emergent blindness after 2 cycles of pembrolizumab combined with pazopanib. After discontinuation of both drugs and administration of glucocorticoids, symptoms improved completely within 2 days. Although no fundus examination was performed, the blindness was determined to be related to pembrolizumab. One patient had grade 4 bilirubin elevation, which returned to grade 2 after discontinuation of pembrolizumab and cortisol treatment. Unfortunately, the patient died of heart failure 2 months later due to old age and poor cardiopulmonary function. The other 2 cases of SAEs were pneumonia and liver function injury. After withdrawal of pembrolizumab and treatment with methylprednisolone, symptoms were relieved in both patients. All 6 SAEs occurred in patients receiving combination therapy, including 2 cases (10.5%) receiving pembrolizumab combined with chemotherapy and 4 cases (23.5%) receiving pembrolizumab combined with targeted therapy.
Table 4 Occurrence of severe adverse reactions
Sex Age Subtype Treatment time Treatment group Therapeutic
response Side effects Outcome of treatment
M 54 PRMS First-Line Combined with chemotherapy (AIM) PR Epidermolysis bullosa, G4 Recovered after cortisol treatment
M 79 Carcinosarcoma First-line Combined with anlotinib NA Elevated bilirubin, G4 Recovered and died of heart failure after 1.8 months
M 34 ASPS Second-line Combined with pazopanib NA Bone marrow depression, G4 Death after 1.2 months
F 41 CCS Second-line Combined with pazopanib PD Transaminase elevated, G3; elevated bilirubin, G2 Recovered after cortisol treatment
F 53 LMS Second-line Combined with chemotherapy (AIM) SD Pneumonia Recovered after cortisol treatment
F 38 ASPS Third-line Combined with pazopanib SD Blindness; elevated bilirubin, G2 Recovered after cortisol treatment
PRMS, pleomorphic rhabdomyosarcoma; ASPS, alveolar soft part sarcoma; CCS, clear cell sarcoma; LMS, leiomyosarcoma; NA, not available; AIM, doxorubicin + ifosfamide + mesna; AD, doxorubicin + dacarbazine; G, grade; SD, stable disease; PD, progressive disease; PR, partial response
Discussion
ICI immunotherapy has made breakthroughs in the treatment of advanced solid tumors. However, the response rate of single-drug immunotherapy is still low in individual tumors. The SARC028 study showed that the response rate to pembrolizumab in the treatment of STS was 18%, and the response of osteosarcoma was only 5% (2/40) (23). The overall response rate of the patients in the present study was 19.4%, but this was achieved by combination with chemotherapy or immunotherapy in most patients. The proportion of patients who remained stable or showed PR for more than 6 months after discontinuing combination agents was only 11.1%, which may be a better indicator of the real efficacy of pembrolizumab. This ratio was lower than in the SARC028 trial, and the PFS and OS of patients in our cohort were also relatively shorter. The most likely reason behind this finding may be that many patients had poor general health status and had received multiple lines of systemic therapy before administration of immunotherapy. It has been reported that the ECOG score can affect the effectiveness of pembrolizumab, and both ORR and survival in patients with high ECOG scores were lower than in those with low ECOG scores (28,29). In addition, the time of treatment also had a significant impact on the effectiveness of pembrolizumab. In non-small cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score ≥50%, the median OS of those who received pembrolizumab as first-line therapy in the KEYNOTE-024 study was 30.0 months, while the OS of patients treated with pembrolizumab as second-line therapy in KEYNOTE-010 was only 10.4 months (28,30). In the real world, most sarcoma patients do not use ICIs early when they develop metastasis because there are no indications. However, due to the lack of effective therapeutic methods, many patients have tried pembrolizumab at a later stage. In the present study, 33.3% of patients had an ECOG PS score of 2, 50.0% had an ECOG PS score of 1, and only 19.4% of patients received pembrolizumab as first-line therapy. Although the sample size was small, the chi-square test showed that time of treatment was a probable related factor affecting ORR, and the survival analysis indicated that it was also an independent factor affecting PFS and OS, while ECOG PS score mainly affected OS.
In this study, no factors were found to be associated with the effectiveness of pembrolizumab, including the expression of PD-L1 and different therapeutic combinations. In fact, no clear molecular marker associated with an immunotherapeutic effect on STS has been identified so far. It was reported that although PD-L1 was positive in 30–50% of STS, it was not found to be associated with the therapeutic effect of pembrolizumab (31,32). In a pooled analysis of a phase II trial with 384 sarcoma patients, the ORR and non-progression rates were similar in patients treated with anti-PD-1/PD-L1 as a single agent and those treated with a combination regimen (33). Different subtypes have different response rates to ICIs. Published studies have confirmed that ASPS and UPS have a high response rate to pembrolizumab (23,25), but only a few cases of other subtypes have been reported. In this study, we found 2 cases of AS and ESCS in which the efficacy lasted more than 6 months. Because the incidence of these 2 subtypes is very low, whether they have a high response rate to pembrolizumab needs to be confirmed in a multi-center clinical study with a large sample size. In addition, among the 9 cases of LMS in this study, there was no case with efficacy lasting more than half a year, suggesting that LMS may have a low response rate to ICIs. Given the inherent heterogeneity of sarcoma, future studies should examine histological subtypes to better understand the mechanisms of resistance and response.
The most common adverse reaction we observed in this study was fever (68.4%). The rates of other adverse reactions were all below 35%. However, 6 patients (15.8%) had SAEs which led to treatment discontinuation, but the organs involved showed no specific pattern, and included liver, lung, bone marrow, skin, and eyes. The incidence of SAEs in this study was higher than that reported in other studies, ranging from 5–8% (23,34,35). In a meta-analysis of immune-related AEs (irAEs), which included 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents, the overall incidence of irAEs was 26.82% in any grade and 6.10% for severe grade irAEs (34). The main reason for the increase in SAEs may be related to the combination strategies. All 6 cases of SAEs in this cohort occurred in the combination treatment groups, including 2 cases with combined chemotherapy and 4 cases with combined targeted agents, accounting for 10.5% and 23.5% of cases in each group, respectively. In patients with NSCLC, discontinuation of treatment due to AEs was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%) (36). Combinations with TKIs can also increase the incidence of SAEs, but the incidence of SAEs with different TKIs combined with pembrolizumab varies greatly. In a clinical trial of renal cell cancer, the percentage of AEs leading to treatment discontinuation reached as high as 80%, and the trial was subsequently terminated (37). However, pembrolizumab combined with axitinib or lenvatinib showed favorable safety, with only 9–21% of patients discontinuing study treatment because of treatment-related AEs (24,38). In the present study, there were 3 cases of SAEs which occurred after combined treatment with pazopanib, confirming the high risk of this combination. Because pazopanib is currently the only FDA-approved broad-spectrum TKI used for non-adipogenic STS, its safety should be strongly considered when combining with ICIs. The efficacy and safety of other TKIs combined with ICIs in the treatment of STS need to be confirmed in further clinical trials.
Our study was limited by its retrospective design and small sample size. In addition, 13 sarcoma subtypes were included in this study, which made it more difficult to analyze the efficacy and factors related to pembrolizumab. Therefore, we were careful when interpreting our findings. For example, in order to exclude the influence of other therapeutic factors on pembrolizumab, we assessed the disease status 6 months after withdrawal of chemotherapy and targeted agents in patients who received combination therapy. However, we did produce some interesting findings. For example, in addition to ASPS and UPS, pembrolizumab was effective in AS and ESCS, but not in LMS, which had the largest number of cases. Furthermore, we found that the major treatment-related SAEs occurred in patients receiving combination therapy, especially those receiving combinations with pazopanib. The low incidence of STS and the high variance of responses are the biggest obstacles to clinical research in this field. Although the results of this study were mostly descriptive, these data may be useful in optimizing future clinical trials of STS and guiding clinical practice.
Conclusions
In the real world, the effectiveness of pembrolizumab in the treatment of STS has been shown to be low. Some subtypes had a better response rate to pembrolizumab, including ASPS, UPS, ESCS, and AS, while the response of LMS was low. The PFS and OS of the patients in this group were poor, which was related to late treatment times and poor ECOG PS scores. Combination therapy with pembrolizumab may increase the risk of SAEs, especially when combined with pazopanib.
Supplementary
The article’s supplementary files as
10.21037/atm-21-49 10.21037/atm-21-49 10.21037/atm-21-49
Acknowledgments
Funding: China International Medical Foundation (No. Z-2014-06-15331).
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02).
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-21-49
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-21-49
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-49). The authors have no conflicts of interest to declare.
(English Language Editor: C. Betlazar-Maseh) | PAZOPANIB, PEMBROLIZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33708966 | 19,494,768 | 2021-02 |
What was the dosage of drug 'PAZOPANIB'? | Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma.
The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS).
We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs).
The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4-3.4 months] and the median OS was 12.0 months (95% CI: 10.2-13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028).
In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.
pmcIntroduction
At present, there is still a lack of effective protocols for the treatment of advanced soft tissue sarcoma (STS), and patient prognosis is poor. The first-line treatment for most sarcoma subtypes is anthracycline-based chemotherapy, which can achieve an objective responsive rate (ORR) of 20–40% and disease control in 2.3 to 4.9 months (1-5). After failure of first-line chemotherapy, there is no standard recommended second-line treatment. Some new chemotherapeutic agents, including gemcitabine, trabectedin, and eribulin, have shown some benefit for certain subtypes of STS, but their significance for improving overall survival (OS) is still controversial (6-8). Some tyrosine kinase inhibitors (TKIs), including pazopanib, sunitinib, regorafenib, and anlotinib, amongst others, were reported to offer some benefit for disease control, but there are no large-scale randomized studies which demonstrate their effectiveness in improving OS (9-12). In the PALETTE study, the median progression-free survival (PFS) was 4.6 months for patients receiving pazopanib compared with 1.6 months for the placebo group (P<0.0001), but there was no significant difference in OS between the 2 groups (12.5 vs. 10.7 months, P=0.25) (9).
Recently, immune checkpoint inhibitors (ICIs), including pembrolizumab, have made great breakthroughs in cancer therapy, enabling some patients with advanced melanoma, lung cancer, and bladder cancer to achieve long-term disease control (13-15). However, except for some specific cancers, the response rate of solid tumors to immunotherapy is generally low. Therefore, how to screen for potential patients and how to improve the efficacy of ICIs through combination therapies are 2 promising research directions in the future. The molecular markers reported to be related to the therapeutic effect of ICIs include the expression of programmed death-ligand 1 (PD-L1) on tumor cells, tumor mutation burden, microsatellite instability, tumor infiltrating lymph node cells, and neoplastic antigen, among others (14-18). In addition, some clinical trials have shown that combining chemotherapy, targeted therapy, and radiotherapy can improve the response rate to ICIs (19-22).
Only a few studies have reported on the efficacy and safety of ICIs for STS (23,24). The results of the SARC028 trial showed that the ORR of pembrolizumab for the treatment of STS was 18%. The efficacy of pembrolizumab was reported to be related to the subtype of sarcomas, as it had a relatively high ORR in undifferentiated pleomorphic sarcoma (UPS) (23) and alveolar soft part sarcoma (ASPS) (24,25). Unfortunately, there is no evidence that most molecular markers, including PD-L1, are associated with the therapeutic effect of ICIs. The low incidence of STS and the high variance of responses make research into immunotherapies complex and difficult (26). This study retrospectively analyzed patients with advanced STS treated with pembrolizumab at our hospital, and investigated the potential factors related to its efficacy and safety.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-21-49).
Methods
Patient information
We examined 38 patients with pathologically confirmed STS who received pembrolizumab immunotherapy at Peking University Cancer Hospital & Institute from July 2017 to December 2018. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02). All patients had metastatic disease and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 standards (18). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores were 0–2. Pathological subtypes included leiomyosarcoma (LMS), UPS, ASPS, synovial sarcoma (SS), pleomorphic rhabdomyosarcoma (PRMS), clear cell sarcoma (CCS), dedifferentiated liposarcoma (DDLS), epithelioid sarcoma (ES), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma (AS), carcinosarcoma, exoskeletal chondrosarcoma (ESCS), and desmoplastic small round cell tumor (DSRCT). Based on previous systemic treatments, pembrolizumab was administered in 8 patients as first-line therapy, in 17 patients as second-line therapy, and in 13 patients as third- or further-line therapy. PD-L1 expression was evaluated if the tumor specimen can be obtained, using the proprietary Dako 22C3 IHC assay. PD-L1 expression was determined as positive if it was expressed in more than 1% of tumor cells.
Groups and therapy
Patients were divided into a pembrolizumab monotherapy group (A), combined chemotherapy group (B), and combined targeted therapy group (C), according to their medication strategy. Group A received pembrolizumab injections at 2 mg/kg for 21 days per cycle. In group B, the standard dose of anthracycline-based regimens (AIM, anthracycline, ifosfamide and mesna; or AD, anthracycline and dacarbazine), high dose ifosfamide, or gemcitabine combined with docetaxel or dacarbazine were used simultaneously with pembrolizumab injection. Chemotherapy was repeated for 4 to 6 cycles, or was discontinued if the disease progressed or intolerable adverse events (AEs) occurred. In group C, in addition to pembrolizumab, the patients were treated with either anlotinib (12 mg/day for 14 consecutive days, then discontinued for 7 days, in a 21-day cycle), pazopanib (400–600 mg/day), or lenvatinib (10–18 mg/m2) simultaneously. Target agents were consistently used until disease progression, intolerable toxicity, or complete tumor remission occurred. For all patients, pembrolizumab was continued for up to 2 years or until disease progression or unacceptable AEs occurred.
Treatment outcomes and adverse reactions
Radiographic tumor assessment, including magnetic resonance imaging or computed tomography, was performed at baseline and every 6 to 8 weeks during treatment. Safety assessments, including routine blood and biochemical tests, analysis of thyroid function and myocardial enzymes, and electrocardiograms, were performed at baseline and every 3 weeks before pembrolizumab administration. Special examinations were performed if the patient had suspicious AEs related symptoms. For example, lung CT scans were recommended if dyspnea and cough were present. The adverse reactions of patients were recorded and scored during follow-up. The primary endpoint was ORR, and the secondary endpoints included PFS, OS, and AEs. To further evaluate the effect of pembrolizumab alone, we assessed disease status 6 months after the withdrawal of chemotherapy and targeted therapy in groups B and C. ORR was defined as the ratio of complete response (CR) and partial response (PR) according to RECIST standards (18). PFS was defined as the time from the beginning of treatment to disease progression or death from cancer. OS was defined as the time from the beginning of treatment to patient death. AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (27).
Statistical analysis
SPSS 22.0 software was used for statistical analysis. Count data was expressed as frequency and percentage. The relationships between ORR and different therapeutic methods, treatment lines, and clinical characteristics were tested using Pearson’s chi-square test. Comparisons between PFS and OS were analyzed by Kaplan-Meier survival curves, and the Cox regression model was used to analyze related factors affecting PFS and OS. P<0.05 (two-tailed) was defined as statistically significant.
Results
Basic characteristics of patients
From July 2017 to December 2018, 38 patients with advanced STS received immunotherapy with pembrolizumab in our hospital. Among them, 17 were males and 21 were females, with an average age of 42.6 years (12–79 years). According to the ECOG PS assessments, 5 cases (13.2%) scored 0, 20 cases (52.6%) scored 1, and 13 cases (34.2%) scored 2. The number of cases of each pathological subtype were 9 LMS, 5 ASPS, 4 UPS, 4 PRMS, 4 CCS, 4 DDLS, 2 SS, 1 ES, 1 MPNST, 1 AS, 1 carcinosarcoma, 1 ESCS, and 1 DSRCT. Six cases received pembrolizumab monotherapy, including 2 cases receiving it as first-line treatment, 2 cases receiving it sequentially after chemotherapy, 1 case receiving it after TKI-targeted therapy, and 1 case with a history of both chemotherapy and targeted therapy. Another 16 cases received pembrolizumab combined with chemotherapy, including 7 cases with AD/AIM and 9 cases with other regimens, and 5 cases were treated with pembrolizumab combined with chemotherapy as first-line therapy, 8 cases were treated as second-line therapy, and 3 cases were treated as third- or further-line therapy. Of the 16 patients treated with pembrolizumab combined with targeted therapy, 8 patients received pazopanib, 6 received anlotinib, and 2 received lenvatinib. Only 1 of these patients was treated with pembrolizumab combined with targeted therapy as first-line therapy, while 7 cases were treated as second-line therapy, and 8 cases were treated as third- or further-line therapy.
Therapeutic response
All patients were treated with pembrolizumab for more than 2 cycles. Two patients died within 2 months without evaluation of treatment response. Of the remaining 36 patients, 3 patients survived less than 12 weeks and were evaluated at the 6th week, while the rest of the patients were evaluated every 6–8 weeks. One patient (2.8%) achieved CR, 6 patients (16.7%) achieved PR, 17 patients (47.2%) experienced stable disease (SD), and 12 patients (33.3%) experienced progressive disease (PD). The overall ORR was 19.4% (7/36). The ORRs of patients who received the treatments as first-line, second-line, or third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). However, there was no significant difference between different combination treatment groups (P=0.996), with an ORR of 20.0% (1/5), 18.8% (3/16), and 20.0% (3/15) in groups A, B, and C, respectively. Other clinical features, including sex, age, ECOG PS score, and lactate dehydrogenase (LDH) level, were also not associated with ORR (Table 1). PD-L1 was detected in 15 patients, among which 6 patients (40%) had positive PD-L1 expression. No significant correlation was found between treatment efficacy and PD-L1 expression levels (P=0.235, Table 1).
Table 1 The relationship between treatment response and clinical characteristics
Basic feature Case number ORR P value
Sex 0.418
M 15 4 (26.7%)
F 21 3 (14.3%)
Age 0.209
≤40 14 1 (7.1%)
>40 22 6 (27.3%)
ECOG performance 0.642
0 6 2 (33.3%)
1 18 3 (16.7%)
2 12 2 (16.7%)
LDH 0.652
Elevated 9 1 (11.1%)
Normal 27 6 (22.2%)
PD-L1 0.235
Negative 9 1 (11.1%)
Positive 6 3 (50%)
NA 21 3 (14.3%)
Treatment time 0.052
First-line 7 3 (42.9%)
Second-line 16 4 (25.0%)
Third-line or more 13 0 (0%)
Therapeutic methods 0.996
Monotherapy 5 1 (20.0%)
Chemotherapy combined 16 3 (18.8%)
Target therapy combined 15 3 (20.0%)
ECOG, Eastern Cooperative Oncology Group; ORR, objective responsive rate; LDH, lactate dehydrogenase; PD-L1, programmed cell death-ligand 1; NA, not available.
Four patients (11.1%) maintained CR or PR for at least 6 months with pembrolizumab monotherapy or after withdrawal of chemotherapy or targeted therapy regimens (Table 2), including 1 case each of ASPS, UPS, ESCS, and AS (Figure 1). However, none of the patients with LMS, the subtype with the highest number of cases (9), achieved long-term disease control. No factors were found to be associated with this indicator.
Table 2 Detailed information of the 4 patients who maintained PR or SD for at least 6 months with pembrolizumab
Sex Age Subtype ECOG score LDH Treatment time PD-L1 Treatment group Therapeutic response Time to progression
M 52 ASPS 2 0 Second-line NA Pembrolizumab alone PR Not reached
F 45 UPS 0 0 Second-line NA Combined AD PR Not reached
M 79 ESCS 2 1 Second-line Positive Combined lenvatinib PR 13 months
M 47 AS 1 0 First-line Positive Combined AD CR Not reached
ECOG, Eastern Cooperative Oncology Group; PR, partial response; CR, complete response; SD, stable disease; PD-L1, programmed cell death-ligand 1; LDH, lactate dehydrogenase; ASPS, alveolar soft part sarcoma; UPS, undifferentiated pleomorphic sarcoma; ESCS, exoskeletal chondrosarcoma; AS, angiosarcoma; NA, not available; AD, anthracycline and dacarbazine.
Figure 1 A patient with cardiac angiosarcoma achieved complete response (CR) after treatment with pembrolizumab combined with AD (anthracycline and dacarbazine) chemotherapy. (A) In a patient with cardiac angiosarcoma, pulmonary metastasis and hydrothorax were found after resection of the primary lesion. (B) When the patient started combined pembrolizumab and AD chemotherapy, the lung lesions were significantly reduced and the hydrothorax disappeared 6 cycles later on December 14, 2018. (C) The patient maintained clinical CR after maintenance with pembrolizumab monotherapy for 11.5 months through to November 29, 2019.
Survival conditions
All patients were followed for a median follow-up period of 11.9 months (range, 1.4–31.3 months). The median PFS was 2.9 months [95% confidence interval (CI): 2.4–3.4 months]. There were significant differences in PFS between patients with different lines of treatment, with a median PFS of 5.8 months (95% CI: 2.6–11.0 months), 3.5 months (95% CI: 2.0–5.0 months), and 2.8 months (95% CI: 2.4–3.1 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.005; Figure 2A). The median PFS of patients with normal LDH was 3.2 months (95% CI: 2.3–4.2 months), which was significantly higher than the PFS of 2.1 months (95% CI: 1.3–2.9 months) for patients with elevated LDH (P=0.025; Figure 2B). No significant difference in PFS was detected between treatment groups A, B, and C (P=0.160, 2.8 vs. 4.2 vs. 2.8 months, respectively; Figure 2C). Other clinical characteristics, including age, sex, ECOG PS score, and PD-L1 expression, did not significantly affect PFS.
Figure 2 Kaplan-Meier univariate analysis of progression-free survival (PFS). (A) Influence of treatment time on PFS. (B) Influence of serum lactate dehydrogenase (LDH) level on PFS. (C) Influence of combination strategies on PFS.
The median OS was 12.0 months (95% CI: 10.2–13.8 months). There were significant differences in OS between patients with different lines of treatment, with a median OS of 19.1 months (95% CI: 11.9–26.3 months), 15.4 months (95% CI: 12.8–19.8 months), and 7.0 months (95% CI: 4.1–9.9 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.002; Figure 3A). ECOG PS also significantly affected OS, with a median OS of 25.2 months (95% CI: 19.9–30.5 months), 12.5 months (95% CI: 7.7–17.3 months), and 7.5 months (95% CI: 4.8–10.2 months) in patients with a score of 0, 1, and 2, respectively (P=0.005; Figure 3B). The median OS of patients with normal serum LDH was significantly longer than those with elevated LDH (14.4 vs. 7.5 months, P=0.007). There were no significant differences in OS between the different treatment groups (P=0.185, Figure 3C). A Cox regression model of PFS was established by incorporating treatment line, therapeutic strategy, and LDH level (Table 3). The results showed that treatment time was the only independent factor affecting PFS. The risk of disease progression after treatment with ICIs as third- or further-line therapy was 3.94 times higher than that for first-line treatment (95% CI: 1.05–11.66, P=0.041). A Cox regression model of OS was established by incorporating treatment time, ECOG PS score, and LDH level (Table 3). The results showed that the ECOG PS score was the only independent factor affecting OS. The risk of death in patients with an ECOG PS score of 2 was 10.6 times greater than for those with a score of 0. The risk of death in patients treated with third- or further-line therapy was 2.75 times the risk for patients treated with first-line therapy, with a marginal statistical difference (95% CI: 0.88–8.59; P=0.057).
Figure 3 Kaplan-Meier univariate analysis of overall survival (OS). (A) Influence of treatment time on OS. (B) Influence of combination strategies on OS. (C) Influence of serum lactate dehydrogenase (LDH) level on OS.
Table 3 Cox regression model and multivariate analysis results
Parameters PFS OS
HR 95% CI P value HR 95% CI P value
Treatment time 0.033 0.057
First-line 1 1
Second-line 1.80 0.65–5.00 0.89 0.27–2.90
Third or more 3.94 1.36–11.51 2.75 0.88–8.59
LDH 0.071 0.434
Normal 1 1
High 2.16 0.94–4.97 1.44 0.58–3.57
ECOG performance status score
0 1 0.028
1 4.24 0.54–33.3
2 10.62 1.28–87.72
Therapeutic methods 0.407
Pembrolizumab 1
Pembro + chemo 0.77 0.27–2.20
Pembro + target 1.27 0.46–3.53
ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase.
Adverse events
The most common adverse reaction was fever, with an incidence of 68.4% (26/38), of which 6 cases (16.3%) had a temperature exceeding 38.5 °C. The other common adverse reactions were leukopenia (34.2%, 13/38), diarrhea (26.3%, 10/38), hypothyroidism (24.3%, 9/37), abnormal liver function (18.4%, 7/38), oral ulceration (18.4%, 7/38), and creatine kinase elevation (13.2%, 5/38). Six patients (15.8%) had severe AEs (SAEs), which led to treatment discontinuation (Table 4). In 1 patient with ASPS, platelets decreased to less than 1×109/L after 2 cycles of pazopanib combined with pembrolizumab. The patient died of gastrointestinal bleeding despite a large dose of glucocorticoids and platelet transfusion. Because it has not been reported that pazopanib can cause severe thrombocytopenia, which occurred in this patient very suddenly and rapidly, it was thought that the thrombocytopenia was related to the combination of pazopanib with pembrolizumab. In another case, a patient with PRMS developed very severe systemic skin bullae after using nonsteroidal anti-inflammatory drugs (NSAIDs) during the 4th cycle of pembrolizumab combined with AIM chemotherapy. We finally decided after discussion with dermatologists that the reaction was epidermolysis bullosa induced by the ICI, and after administration of a glucocorticoid and topical potassium permanganate, the skin bullae completely healed and only mild pigmentation remained. A patient with ASPS developed emergent blindness after 2 cycles of pembrolizumab combined with pazopanib. After discontinuation of both drugs and administration of glucocorticoids, symptoms improved completely within 2 days. Although no fundus examination was performed, the blindness was determined to be related to pembrolizumab. One patient had grade 4 bilirubin elevation, which returned to grade 2 after discontinuation of pembrolizumab and cortisol treatment. Unfortunately, the patient died of heart failure 2 months later due to old age and poor cardiopulmonary function. The other 2 cases of SAEs were pneumonia and liver function injury. After withdrawal of pembrolizumab and treatment with methylprednisolone, symptoms were relieved in both patients. All 6 SAEs occurred in patients receiving combination therapy, including 2 cases (10.5%) receiving pembrolizumab combined with chemotherapy and 4 cases (23.5%) receiving pembrolizumab combined with targeted therapy.
Table 4 Occurrence of severe adverse reactions
Sex Age Subtype Treatment time Treatment group Therapeutic
response Side effects Outcome of treatment
M 54 PRMS First-Line Combined with chemotherapy (AIM) PR Epidermolysis bullosa, G4 Recovered after cortisol treatment
M 79 Carcinosarcoma First-line Combined with anlotinib NA Elevated bilirubin, G4 Recovered and died of heart failure after 1.8 months
M 34 ASPS Second-line Combined with pazopanib NA Bone marrow depression, G4 Death after 1.2 months
F 41 CCS Second-line Combined with pazopanib PD Transaminase elevated, G3; elevated bilirubin, G2 Recovered after cortisol treatment
F 53 LMS Second-line Combined with chemotherapy (AIM) SD Pneumonia Recovered after cortisol treatment
F 38 ASPS Third-line Combined with pazopanib SD Blindness; elevated bilirubin, G2 Recovered after cortisol treatment
PRMS, pleomorphic rhabdomyosarcoma; ASPS, alveolar soft part sarcoma; CCS, clear cell sarcoma; LMS, leiomyosarcoma; NA, not available; AIM, doxorubicin + ifosfamide + mesna; AD, doxorubicin + dacarbazine; G, grade; SD, stable disease; PD, progressive disease; PR, partial response
Discussion
ICI immunotherapy has made breakthroughs in the treatment of advanced solid tumors. However, the response rate of single-drug immunotherapy is still low in individual tumors. The SARC028 study showed that the response rate to pembrolizumab in the treatment of STS was 18%, and the response of osteosarcoma was only 5% (2/40) (23). The overall response rate of the patients in the present study was 19.4%, but this was achieved by combination with chemotherapy or immunotherapy in most patients. The proportion of patients who remained stable or showed PR for more than 6 months after discontinuing combination agents was only 11.1%, which may be a better indicator of the real efficacy of pembrolizumab. This ratio was lower than in the SARC028 trial, and the PFS and OS of patients in our cohort were also relatively shorter. The most likely reason behind this finding may be that many patients had poor general health status and had received multiple lines of systemic therapy before administration of immunotherapy. It has been reported that the ECOG score can affect the effectiveness of pembrolizumab, and both ORR and survival in patients with high ECOG scores were lower than in those with low ECOG scores (28,29). In addition, the time of treatment also had a significant impact on the effectiveness of pembrolizumab. In non-small cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score ≥50%, the median OS of those who received pembrolizumab as first-line therapy in the KEYNOTE-024 study was 30.0 months, while the OS of patients treated with pembrolizumab as second-line therapy in KEYNOTE-010 was only 10.4 months (28,30). In the real world, most sarcoma patients do not use ICIs early when they develop metastasis because there are no indications. However, due to the lack of effective therapeutic methods, many patients have tried pembrolizumab at a later stage. In the present study, 33.3% of patients had an ECOG PS score of 2, 50.0% had an ECOG PS score of 1, and only 19.4% of patients received pembrolizumab as first-line therapy. Although the sample size was small, the chi-square test showed that time of treatment was a probable related factor affecting ORR, and the survival analysis indicated that it was also an independent factor affecting PFS and OS, while ECOG PS score mainly affected OS.
In this study, no factors were found to be associated with the effectiveness of pembrolizumab, including the expression of PD-L1 and different therapeutic combinations. In fact, no clear molecular marker associated with an immunotherapeutic effect on STS has been identified so far. It was reported that although PD-L1 was positive in 30–50% of STS, it was not found to be associated with the therapeutic effect of pembrolizumab (31,32). In a pooled analysis of a phase II trial with 384 sarcoma patients, the ORR and non-progression rates were similar in patients treated with anti-PD-1/PD-L1 as a single agent and those treated with a combination regimen (33). Different subtypes have different response rates to ICIs. Published studies have confirmed that ASPS and UPS have a high response rate to pembrolizumab (23,25), but only a few cases of other subtypes have been reported. In this study, we found 2 cases of AS and ESCS in which the efficacy lasted more than 6 months. Because the incidence of these 2 subtypes is very low, whether they have a high response rate to pembrolizumab needs to be confirmed in a multi-center clinical study with a large sample size. In addition, among the 9 cases of LMS in this study, there was no case with efficacy lasting more than half a year, suggesting that LMS may have a low response rate to ICIs. Given the inherent heterogeneity of sarcoma, future studies should examine histological subtypes to better understand the mechanisms of resistance and response.
The most common adverse reaction we observed in this study was fever (68.4%). The rates of other adverse reactions were all below 35%. However, 6 patients (15.8%) had SAEs which led to treatment discontinuation, but the organs involved showed no specific pattern, and included liver, lung, bone marrow, skin, and eyes. The incidence of SAEs in this study was higher than that reported in other studies, ranging from 5–8% (23,34,35). In a meta-analysis of immune-related AEs (irAEs), which included 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents, the overall incidence of irAEs was 26.82% in any grade and 6.10% for severe grade irAEs (34). The main reason for the increase in SAEs may be related to the combination strategies. All 6 cases of SAEs in this cohort occurred in the combination treatment groups, including 2 cases with combined chemotherapy and 4 cases with combined targeted agents, accounting for 10.5% and 23.5% of cases in each group, respectively. In patients with NSCLC, discontinuation of treatment due to AEs was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%) (36). Combinations with TKIs can also increase the incidence of SAEs, but the incidence of SAEs with different TKIs combined with pembrolizumab varies greatly. In a clinical trial of renal cell cancer, the percentage of AEs leading to treatment discontinuation reached as high as 80%, and the trial was subsequently terminated (37). However, pembrolizumab combined with axitinib or lenvatinib showed favorable safety, with only 9–21% of patients discontinuing study treatment because of treatment-related AEs (24,38). In the present study, there were 3 cases of SAEs which occurred after combined treatment with pazopanib, confirming the high risk of this combination. Because pazopanib is currently the only FDA-approved broad-spectrum TKI used for non-adipogenic STS, its safety should be strongly considered when combining with ICIs. The efficacy and safety of other TKIs combined with ICIs in the treatment of STS need to be confirmed in further clinical trials.
Our study was limited by its retrospective design and small sample size. In addition, 13 sarcoma subtypes were included in this study, which made it more difficult to analyze the efficacy and factors related to pembrolizumab. Therefore, we were careful when interpreting our findings. For example, in order to exclude the influence of other therapeutic factors on pembrolizumab, we assessed the disease status 6 months after withdrawal of chemotherapy and targeted agents in patients who received combination therapy. However, we did produce some interesting findings. For example, in addition to ASPS and UPS, pembrolizumab was effective in AS and ESCS, but not in LMS, which had the largest number of cases. Furthermore, we found that the major treatment-related SAEs occurred in patients receiving combination therapy, especially those receiving combinations with pazopanib. The low incidence of STS and the high variance of responses are the biggest obstacles to clinical research in this field. Although the results of this study were mostly descriptive, these data may be useful in optimizing future clinical trials of STS and guiding clinical practice.
Conclusions
In the real world, the effectiveness of pembrolizumab in the treatment of STS has been shown to be low. Some subtypes had a better response rate to pembrolizumab, including ASPS, UPS, ESCS, and AS, while the response of LMS was low. The PFS and OS of the patients in this group were poor, which was related to late treatment times and poor ECOG PS scores. Combination therapy with pembrolizumab may increase the risk of SAEs, especially when combined with pazopanib.
Supplementary
The article’s supplementary files as
10.21037/atm-21-49 10.21037/atm-21-49 10.21037/atm-21-49
Acknowledgments
Funding: China International Medical Foundation (No. Z-2014-06-15331).
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02).
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-21-49
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-21-49
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-49). The authors have no conflicts of interest to declare.
(English Language Editor: C. Betlazar-Maseh) | UNK, CYCLIC (2 CYCLES) | DrugDosageText | CC BY-NC-ND | 33708966 | 19,494,768 | 2021-02 |
What was the dosage of drug 'PEMBROLIZUMAB'? | Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma.
The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS).
We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs).
The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4-3.4 months] and the median OS was 12.0 months (95% CI: 10.2-13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028).
In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.
pmcIntroduction
At present, there is still a lack of effective protocols for the treatment of advanced soft tissue sarcoma (STS), and patient prognosis is poor. The first-line treatment for most sarcoma subtypes is anthracycline-based chemotherapy, which can achieve an objective responsive rate (ORR) of 20–40% and disease control in 2.3 to 4.9 months (1-5). After failure of first-line chemotherapy, there is no standard recommended second-line treatment. Some new chemotherapeutic agents, including gemcitabine, trabectedin, and eribulin, have shown some benefit for certain subtypes of STS, but their significance for improving overall survival (OS) is still controversial (6-8). Some tyrosine kinase inhibitors (TKIs), including pazopanib, sunitinib, regorafenib, and anlotinib, amongst others, were reported to offer some benefit for disease control, but there are no large-scale randomized studies which demonstrate their effectiveness in improving OS (9-12). In the PALETTE study, the median progression-free survival (PFS) was 4.6 months for patients receiving pazopanib compared with 1.6 months for the placebo group (P<0.0001), but there was no significant difference in OS between the 2 groups (12.5 vs. 10.7 months, P=0.25) (9).
Recently, immune checkpoint inhibitors (ICIs), including pembrolizumab, have made great breakthroughs in cancer therapy, enabling some patients with advanced melanoma, lung cancer, and bladder cancer to achieve long-term disease control (13-15). However, except for some specific cancers, the response rate of solid tumors to immunotherapy is generally low. Therefore, how to screen for potential patients and how to improve the efficacy of ICIs through combination therapies are 2 promising research directions in the future. The molecular markers reported to be related to the therapeutic effect of ICIs include the expression of programmed death-ligand 1 (PD-L1) on tumor cells, tumor mutation burden, microsatellite instability, tumor infiltrating lymph node cells, and neoplastic antigen, among others (14-18). In addition, some clinical trials have shown that combining chemotherapy, targeted therapy, and radiotherapy can improve the response rate to ICIs (19-22).
Only a few studies have reported on the efficacy and safety of ICIs for STS (23,24). The results of the SARC028 trial showed that the ORR of pembrolizumab for the treatment of STS was 18%. The efficacy of pembrolizumab was reported to be related to the subtype of sarcomas, as it had a relatively high ORR in undifferentiated pleomorphic sarcoma (UPS) (23) and alveolar soft part sarcoma (ASPS) (24,25). Unfortunately, there is no evidence that most molecular markers, including PD-L1, are associated with the therapeutic effect of ICIs. The low incidence of STS and the high variance of responses make research into immunotherapies complex and difficult (26). This study retrospectively analyzed patients with advanced STS treated with pembrolizumab at our hospital, and investigated the potential factors related to its efficacy and safety.
We present the following article in accordance with the STROBE reporting checklist (available at http://dx.doi.org/10.21037/atm-21-49).
Methods
Patient information
We examined 38 patients with pathologically confirmed STS who received pembrolizumab immunotherapy at Peking University Cancer Hospital & Institute from July 2017 to December 2018. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02). All patients had metastatic disease and had measurable lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 standards (18). The Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores were 0–2. Pathological subtypes included leiomyosarcoma (LMS), UPS, ASPS, synovial sarcoma (SS), pleomorphic rhabdomyosarcoma (PRMS), clear cell sarcoma (CCS), dedifferentiated liposarcoma (DDLS), epithelioid sarcoma (ES), malignant peripheral nerve sheath tumor (MPNST), angiosarcoma (AS), carcinosarcoma, exoskeletal chondrosarcoma (ESCS), and desmoplastic small round cell tumor (DSRCT). Based on previous systemic treatments, pembrolizumab was administered in 8 patients as first-line therapy, in 17 patients as second-line therapy, and in 13 patients as third- or further-line therapy. PD-L1 expression was evaluated if the tumor specimen can be obtained, using the proprietary Dako 22C3 IHC assay. PD-L1 expression was determined as positive if it was expressed in more than 1% of tumor cells.
Groups and therapy
Patients were divided into a pembrolizumab monotherapy group (A), combined chemotherapy group (B), and combined targeted therapy group (C), according to their medication strategy. Group A received pembrolizumab injections at 2 mg/kg for 21 days per cycle. In group B, the standard dose of anthracycline-based regimens (AIM, anthracycline, ifosfamide and mesna; or AD, anthracycline and dacarbazine), high dose ifosfamide, or gemcitabine combined with docetaxel or dacarbazine were used simultaneously with pembrolizumab injection. Chemotherapy was repeated for 4 to 6 cycles, or was discontinued if the disease progressed or intolerable adverse events (AEs) occurred. In group C, in addition to pembrolizumab, the patients were treated with either anlotinib (12 mg/day for 14 consecutive days, then discontinued for 7 days, in a 21-day cycle), pazopanib (400–600 mg/day), or lenvatinib (10–18 mg/m2) simultaneously. Target agents were consistently used until disease progression, intolerable toxicity, or complete tumor remission occurred. For all patients, pembrolizumab was continued for up to 2 years or until disease progression or unacceptable AEs occurred.
Treatment outcomes and adverse reactions
Radiographic tumor assessment, including magnetic resonance imaging or computed tomography, was performed at baseline and every 6 to 8 weeks during treatment. Safety assessments, including routine blood and biochemical tests, analysis of thyroid function and myocardial enzymes, and electrocardiograms, were performed at baseline and every 3 weeks before pembrolizumab administration. Special examinations were performed if the patient had suspicious AEs related symptoms. For example, lung CT scans were recommended if dyspnea and cough were present. The adverse reactions of patients were recorded and scored during follow-up. The primary endpoint was ORR, and the secondary endpoints included PFS, OS, and AEs. To further evaluate the effect of pembrolizumab alone, we assessed disease status 6 months after the withdrawal of chemotherapy and targeted therapy in groups B and C. ORR was defined as the ratio of complete response (CR) and partial response (PR) according to RECIST standards (18). PFS was defined as the time from the beginning of treatment to disease progression or death from cancer. OS was defined as the time from the beginning of treatment to patient death. AEs were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (27).
Statistical analysis
SPSS 22.0 software was used for statistical analysis. Count data was expressed as frequency and percentage. The relationships between ORR and different therapeutic methods, treatment lines, and clinical characteristics were tested using Pearson’s chi-square test. Comparisons between PFS and OS were analyzed by Kaplan-Meier survival curves, and the Cox regression model was used to analyze related factors affecting PFS and OS. P<0.05 (two-tailed) was defined as statistically significant.
Results
Basic characteristics of patients
From July 2017 to December 2018, 38 patients with advanced STS received immunotherapy with pembrolizumab in our hospital. Among them, 17 were males and 21 were females, with an average age of 42.6 years (12–79 years). According to the ECOG PS assessments, 5 cases (13.2%) scored 0, 20 cases (52.6%) scored 1, and 13 cases (34.2%) scored 2. The number of cases of each pathological subtype were 9 LMS, 5 ASPS, 4 UPS, 4 PRMS, 4 CCS, 4 DDLS, 2 SS, 1 ES, 1 MPNST, 1 AS, 1 carcinosarcoma, 1 ESCS, and 1 DSRCT. Six cases received pembrolizumab monotherapy, including 2 cases receiving it as first-line treatment, 2 cases receiving it sequentially after chemotherapy, 1 case receiving it after TKI-targeted therapy, and 1 case with a history of both chemotherapy and targeted therapy. Another 16 cases received pembrolizumab combined with chemotherapy, including 7 cases with AD/AIM and 9 cases with other regimens, and 5 cases were treated with pembrolizumab combined with chemotherapy as first-line therapy, 8 cases were treated as second-line therapy, and 3 cases were treated as third- or further-line therapy. Of the 16 patients treated with pembrolizumab combined with targeted therapy, 8 patients received pazopanib, 6 received anlotinib, and 2 received lenvatinib. Only 1 of these patients was treated with pembrolizumab combined with targeted therapy as first-line therapy, while 7 cases were treated as second-line therapy, and 8 cases were treated as third- or further-line therapy.
Therapeutic response
All patients were treated with pembrolizumab for more than 2 cycles. Two patients died within 2 months without evaluation of treatment response. Of the remaining 36 patients, 3 patients survived less than 12 weeks and were evaluated at the 6th week, while the rest of the patients were evaluated every 6–8 weeks. One patient (2.8%) achieved CR, 6 patients (16.7%) achieved PR, 17 patients (47.2%) experienced stable disease (SD), and 12 patients (33.3%) experienced progressive disease (PD). The overall ORR was 19.4% (7/36). The ORRs of patients who received the treatments as first-line, second-line, or third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). However, there was no significant difference between different combination treatment groups (P=0.996), with an ORR of 20.0% (1/5), 18.8% (3/16), and 20.0% (3/15) in groups A, B, and C, respectively. Other clinical features, including sex, age, ECOG PS score, and lactate dehydrogenase (LDH) level, were also not associated with ORR (Table 1). PD-L1 was detected in 15 patients, among which 6 patients (40%) had positive PD-L1 expression. No significant correlation was found between treatment efficacy and PD-L1 expression levels (P=0.235, Table 1).
Table 1 The relationship between treatment response and clinical characteristics
Basic feature Case number ORR P value
Sex 0.418
M 15 4 (26.7%)
F 21 3 (14.3%)
Age 0.209
≤40 14 1 (7.1%)
>40 22 6 (27.3%)
ECOG performance 0.642
0 6 2 (33.3%)
1 18 3 (16.7%)
2 12 2 (16.7%)
LDH 0.652
Elevated 9 1 (11.1%)
Normal 27 6 (22.2%)
PD-L1 0.235
Negative 9 1 (11.1%)
Positive 6 3 (50%)
NA 21 3 (14.3%)
Treatment time 0.052
First-line 7 3 (42.9%)
Second-line 16 4 (25.0%)
Third-line or more 13 0 (0%)
Therapeutic methods 0.996
Monotherapy 5 1 (20.0%)
Chemotherapy combined 16 3 (18.8%)
Target therapy combined 15 3 (20.0%)
ECOG, Eastern Cooperative Oncology Group; ORR, objective responsive rate; LDH, lactate dehydrogenase; PD-L1, programmed cell death-ligand 1; NA, not available.
Four patients (11.1%) maintained CR or PR for at least 6 months with pembrolizumab monotherapy or after withdrawal of chemotherapy or targeted therapy regimens (Table 2), including 1 case each of ASPS, UPS, ESCS, and AS (Figure 1). However, none of the patients with LMS, the subtype with the highest number of cases (9), achieved long-term disease control. No factors were found to be associated with this indicator.
Table 2 Detailed information of the 4 patients who maintained PR or SD for at least 6 months with pembrolizumab
Sex Age Subtype ECOG score LDH Treatment time PD-L1 Treatment group Therapeutic response Time to progression
M 52 ASPS 2 0 Second-line NA Pembrolizumab alone PR Not reached
F 45 UPS 0 0 Second-line NA Combined AD PR Not reached
M 79 ESCS 2 1 Second-line Positive Combined lenvatinib PR 13 months
M 47 AS 1 0 First-line Positive Combined AD CR Not reached
ECOG, Eastern Cooperative Oncology Group; PR, partial response; CR, complete response; SD, stable disease; PD-L1, programmed cell death-ligand 1; LDH, lactate dehydrogenase; ASPS, alveolar soft part sarcoma; UPS, undifferentiated pleomorphic sarcoma; ESCS, exoskeletal chondrosarcoma; AS, angiosarcoma; NA, not available; AD, anthracycline and dacarbazine.
Figure 1 A patient with cardiac angiosarcoma achieved complete response (CR) after treatment with pembrolizumab combined with AD (anthracycline and dacarbazine) chemotherapy. (A) In a patient with cardiac angiosarcoma, pulmonary metastasis and hydrothorax were found after resection of the primary lesion. (B) When the patient started combined pembrolizumab and AD chemotherapy, the lung lesions were significantly reduced and the hydrothorax disappeared 6 cycles later on December 14, 2018. (C) The patient maintained clinical CR after maintenance with pembrolizumab monotherapy for 11.5 months through to November 29, 2019.
Survival conditions
All patients were followed for a median follow-up period of 11.9 months (range, 1.4–31.3 months). The median PFS was 2.9 months [95% confidence interval (CI): 2.4–3.4 months]. There were significant differences in PFS between patients with different lines of treatment, with a median PFS of 5.8 months (95% CI: 2.6–11.0 months), 3.5 months (95% CI: 2.0–5.0 months), and 2.8 months (95% CI: 2.4–3.1 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.005; Figure 2A). The median PFS of patients with normal LDH was 3.2 months (95% CI: 2.3–4.2 months), which was significantly higher than the PFS of 2.1 months (95% CI: 1.3–2.9 months) for patients with elevated LDH (P=0.025; Figure 2B). No significant difference in PFS was detected between treatment groups A, B, and C (P=0.160, 2.8 vs. 4.2 vs. 2.8 months, respectively; Figure 2C). Other clinical characteristics, including age, sex, ECOG PS score, and PD-L1 expression, did not significantly affect PFS.
Figure 2 Kaplan-Meier univariate analysis of progression-free survival (PFS). (A) Influence of treatment time on PFS. (B) Influence of serum lactate dehydrogenase (LDH) level on PFS. (C) Influence of combination strategies on PFS.
The median OS was 12.0 months (95% CI: 10.2–13.8 months). There were significant differences in OS between patients with different lines of treatment, with a median OS of 19.1 months (95% CI: 11.9–26.3 months), 15.4 months (95% CI: 12.8–19.8 months), and 7.0 months (95% CI: 4.1–9.9 months) for patients receiving treatment as first-line, second-line, and third- or further-line therapy, respectively (P=0.002; Figure 3A). ECOG PS also significantly affected OS, with a median OS of 25.2 months (95% CI: 19.9–30.5 months), 12.5 months (95% CI: 7.7–17.3 months), and 7.5 months (95% CI: 4.8–10.2 months) in patients with a score of 0, 1, and 2, respectively (P=0.005; Figure 3B). The median OS of patients with normal serum LDH was significantly longer than those with elevated LDH (14.4 vs. 7.5 months, P=0.007). There were no significant differences in OS between the different treatment groups (P=0.185, Figure 3C). A Cox regression model of PFS was established by incorporating treatment line, therapeutic strategy, and LDH level (Table 3). The results showed that treatment time was the only independent factor affecting PFS. The risk of disease progression after treatment with ICIs as third- or further-line therapy was 3.94 times higher than that for first-line treatment (95% CI: 1.05–11.66, P=0.041). A Cox regression model of OS was established by incorporating treatment time, ECOG PS score, and LDH level (Table 3). The results showed that the ECOG PS score was the only independent factor affecting OS. The risk of death in patients with an ECOG PS score of 2 was 10.6 times greater than for those with a score of 0. The risk of death in patients treated with third- or further-line therapy was 2.75 times the risk for patients treated with first-line therapy, with a marginal statistical difference (95% CI: 0.88–8.59; P=0.057).
Figure 3 Kaplan-Meier univariate analysis of overall survival (OS). (A) Influence of treatment time on OS. (B) Influence of combination strategies on OS. (C) Influence of serum lactate dehydrogenase (LDH) level on OS.
Table 3 Cox regression model and multivariate analysis results
Parameters PFS OS
HR 95% CI P value HR 95% CI P value
Treatment time 0.033 0.057
First-line 1 1
Second-line 1.80 0.65–5.00 0.89 0.27–2.90
Third or more 3.94 1.36–11.51 2.75 0.88–8.59
LDH 0.071 0.434
Normal 1 1
High 2.16 0.94–4.97 1.44 0.58–3.57
ECOG performance status score
0 1 0.028
1 4.24 0.54–33.3
2 10.62 1.28–87.72
Therapeutic methods 0.407
Pembrolizumab 1
Pembro + chemo 0.77 0.27–2.20
Pembro + target 1.27 0.46–3.53
ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio; LDH, lactate dehydrogenase.
Adverse events
The most common adverse reaction was fever, with an incidence of 68.4% (26/38), of which 6 cases (16.3%) had a temperature exceeding 38.5 °C. The other common adverse reactions were leukopenia (34.2%, 13/38), diarrhea (26.3%, 10/38), hypothyroidism (24.3%, 9/37), abnormal liver function (18.4%, 7/38), oral ulceration (18.4%, 7/38), and creatine kinase elevation (13.2%, 5/38). Six patients (15.8%) had severe AEs (SAEs), which led to treatment discontinuation (Table 4). In 1 patient with ASPS, platelets decreased to less than 1×109/L after 2 cycles of pazopanib combined with pembrolizumab. The patient died of gastrointestinal bleeding despite a large dose of glucocorticoids and platelet transfusion. Because it has not been reported that pazopanib can cause severe thrombocytopenia, which occurred in this patient very suddenly and rapidly, it was thought that the thrombocytopenia was related to the combination of pazopanib with pembrolizumab. In another case, a patient with PRMS developed very severe systemic skin bullae after using nonsteroidal anti-inflammatory drugs (NSAIDs) during the 4th cycle of pembrolizumab combined with AIM chemotherapy. We finally decided after discussion with dermatologists that the reaction was epidermolysis bullosa induced by the ICI, and after administration of a glucocorticoid and topical potassium permanganate, the skin bullae completely healed and only mild pigmentation remained. A patient with ASPS developed emergent blindness after 2 cycles of pembrolizumab combined with pazopanib. After discontinuation of both drugs and administration of glucocorticoids, symptoms improved completely within 2 days. Although no fundus examination was performed, the blindness was determined to be related to pembrolizumab. One patient had grade 4 bilirubin elevation, which returned to grade 2 after discontinuation of pembrolizumab and cortisol treatment. Unfortunately, the patient died of heart failure 2 months later due to old age and poor cardiopulmonary function. The other 2 cases of SAEs were pneumonia and liver function injury. After withdrawal of pembrolizumab and treatment with methylprednisolone, symptoms were relieved in both patients. All 6 SAEs occurred in patients receiving combination therapy, including 2 cases (10.5%) receiving pembrolizumab combined with chemotherapy and 4 cases (23.5%) receiving pembrolizumab combined with targeted therapy.
Table 4 Occurrence of severe adverse reactions
Sex Age Subtype Treatment time Treatment group Therapeutic
response Side effects Outcome of treatment
M 54 PRMS First-Line Combined with chemotherapy (AIM) PR Epidermolysis bullosa, G4 Recovered after cortisol treatment
M 79 Carcinosarcoma First-line Combined with anlotinib NA Elevated bilirubin, G4 Recovered and died of heart failure after 1.8 months
M 34 ASPS Second-line Combined with pazopanib NA Bone marrow depression, G4 Death after 1.2 months
F 41 CCS Second-line Combined with pazopanib PD Transaminase elevated, G3; elevated bilirubin, G2 Recovered after cortisol treatment
F 53 LMS Second-line Combined with chemotherapy (AIM) SD Pneumonia Recovered after cortisol treatment
F 38 ASPS Third-line Combined with pazopanib SD Blindness; elevated bilirubin, G2 Recovered after cortisol treatment
PRMS, pleomorphic rhabdomyosarcoma; ASPS, alveolar soft part sarcoma; CCS, clear cell sarcoma; LMS, leiomyosarcoma; NA, not available; AIM, doxorubicin + ifosfamide + mesna; AD, doxorubicin + dacarbazine; G, grade; SD, stable disease; PD, progressive disease; PR, partial response
Discussion
ICI immunotherapy has made breakthroughs in the treatment of advanced solid tumors. However, the response rate of single-drug immunotherapy is still low in individual tumors. The SARC028 study showed that the response rate to pembrolizumab in the treatment of STS was 18%, and the response of osteosarcoma was only 5% (2/40) (23). The overall response rate of the patients in the present study was 19.4%, but this was achieved by combination with chemotherapy or immunotherapy in most patients. The proportion of patients who remained stable or showed PR for more than 6 months after discontinuing combination agents was only 11.1%, which may be a better indicator of the real efficacy of pembrolizumab. This ratio was lower than in the SARC028 trial, and the PFS and OS of patients in our cohort were also relatively shorter. The most likely reason behind this finding may be that many patients had poor general health status and had received multiple lines of systemic therapy before administration of immunotherapy. It has been reported that the ECOG score can affect the effectiveness of pembrolizumab, and both ORR and survival in patients with high ECOG scores were lower than in those with low ECOG scores (28,29). In addition, the time of treatment also had a significant impact on the effectiveness of pembrolizumab. In non-small cell lung cancer (NSCLC) patients with a PD-L1 tumor proportion score ≥50%, the median OS of those who received pembrolizumab as first-line therapy in the KEYNOTE-024 study was 30.0 months, while the OS of patients treated with pembrolizumab as second-line therapy in KEYNOTE-010 was only 10.4 months (28,30). In the real world, most sarcoma patients do not use ICIs early when they develop metastasis because there are no indications. However, due to the lack of effective therapeutic methods, many patients have tried pembrolizumab at a later stage. In the present study, 33.3% of patients had an ECOG PS score of 2, 50.0% had an ECOG PS score of 1, and only 19.4% of patients received pembrolizumab as first-line therapy. Although the sample size was small, the chi-square test showed that time of treatment was a probable related factor affecting ORR, and the survival analysis indicated that it was also an independent factor affecting PFS and OS, while ECOG PS score mainly affected OS.
In this study, no factors were found to be associated with the effectiveness of pembrolizumab, including the expression of PD-L1 and different therapeutic combinations. In fact, no clear molecular marker associated with an immunotherapeutic effect on STS has been identified so far. It was reported that although PD-L1 was positive in 30–50% of STS, it was not found to be associated with the therapeutic effect of pembrolizumab (31,32). In a pooled analysis of a phase II trial with 384 sarcoma patients, the ORR and non-progression rates were similar in patients treated with anti-PD-1/PD-L1 as a single agent and those treated with a combination regimen (33). Different subtypes have different response rates to ICIs. Published studies have confirmed that ASPS and UPS have a high response rate to pembrolizumab (23,25), but only a few cases of other subtypes have been reported. In this study, we found 2 cases of AS and ESCS in which the efficacy lasted more than 6 months. Because the incidence of these 2 subtypes is very low, whether they have a high response rate to pembrolizumab needs to be confirmed in a multi-center clinical study with a large sample size. In addition, among the 9 cases of LMS in this study, there was no case with efficacy lasting more than half a year, suggesting that LMS may have a low response rate to ICIs. Given the inherent heterogeneity of sarcoma, future studies should examine histological subtypes to better understand the mechanisms of resistance and response.
The most common adverse reaction we observed in this study was fever (68.4%). The rates of other adverse reactions were all below 35%. However, 6 patients (15.8%) had SAEs which led to treatment discontinuation, but the organs involved showed no specific pattern, and included liver, lung, bone marrow, skin, and eyes. The incidence of SAEs in this study was higher than that reported in other studies, ranging from 5–8% (23,34,35). In a meta-analysis of immune-related AEs (irAEs), which included 12,808 oncologic patients treated with anti-PD-1/PD-L1 agents, the overall incidence of irAEs was 26.82% in any grade and 6.10% for severe grade irAEs (34). The main reason for the increase in SAEs may be related to the combination strategies. All 6 cases of SAEs in this cohort occurred in the combination treatment groups, including 2 cases with combined chemotherapy and 4 cases with combined targeted agents, accounting for 10.5% and 23.5% of cases in each group, respectively. In patients with NSCLC, discontinuation of treatment due to AEs was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%) (36). Combinations with TKIs can also increase the incidence of SAEs, but the incidence of SAEs with different TKIs combined with pembrolizumab varies greatly. In a clinical trial of renal cell cancer, the percentage of AEs leading to treatment discontinuation reached as high as 80%, and the trial was subsequently terminated (37). However, pembrolizumab combined with axitinib or lenvatinib showed favorable safety, with only 9–21% of patients discontinuing study treatment because of treatment-related AEs (24,38). In the present study, there were 3 cases of SAEs which occurred after combined treatment with pazopanib, confirming the high risk of this combination. Because pazopanib is currently the only FDA-approved broad-spectrum TKI used for non-adipogenic STS, its safety should be strongly considered when combining with ICIs. The efficacy and safety of other TKIs combined with ICIs in the treatment of STS need to be confirmed in further clinical trials.
Our study was limited by its retrospective design and small sample size. In addition, 13 sarcoma subtypes were included in this study, which made it more difficult to analyze the efficacy and factors related to pembrolizumab. Therefore, we were careful when interpreting our findings. For example, in order to exclude the influence of other therapeutic factors on pembrolizumab, we assessed the disease status 6 months after withdrawal of chemotherapy and targeted agents in patients who received combination therapy. However, we did produce some interesting findings. For example, in addition to ASPS and UPS, pembrolizumab was effective in AS and ESCS, but not in LMS, which had the largest number of cases. Furthermore, we found that the major treatment-related SAEs occurred in patients receiving combination therapy, especially those receiving combinations with pazopanib. The low incidence of STS and the high variance of responses are the biggest obstacles to clinical research in this field. Although the results of this study were mostly descriptive, these data may be useful in optimizing future clinical trials of STS and guiding clinical practice.
Conclusions
In the real world, the effectiveness of pembrolizumab in the treatment of STS has been shown to be low. Some subtypes had a better response rate to pembrolizumab, including ASPS, UPS, ESCS, and AS, while the response of LMS was low. The PFS and OS of the patients in this group were poor, which was related to late treatment times and poor ECOG PS scores. Combination therapy with pembrolizumab may increase the risk of SAEs, especially when combined with pazopanib.
Supplementary
The article’s supplementary files as
10.21037/atm-21-49 10.21037/atm-21-49 10.21037/atm-21-49
Acknowledgments
Funding: China International Medical Foundation (No. Z-2014-06-15331).
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). Informed consent was taken from all the patients. This study was approved by the Ethics Committee of Peking University Cancer Hospital. (No. 2019YJZ02).
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at http://dx.doi.org/10.21037/atm-21-49
Data Sharing Statement: Available at http://dx.doi.org/10.21037/atm-21-49
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-49). The authors have no conflicts of interest to declare.
(English Language Editor: C. Betlazar-Maseh) | UNK, CYCLIC (2 CYCLES) | DrugDosageText | CC BY-NC-ND | 33708966 | 19,494,768 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Blood lactic acid increased'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure acute'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiogenic shock'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiomyopathy'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiotoxicity'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mitral valve incompetence'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,077,698 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary oedema'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | CAPECITABINE, OXALIPLATIN | DrugsGivenReaction | CC BY-NC | 33709051 | 19,077,698 | 2021-03 |
What was the administration route of drug 'CAPECITABINE'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Oral | DrugAdministrationRoute | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
What was the outcome of reaction 'Cardiac failure acute'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
What was the outcome of reaction 'Cardiac failure'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
What was the outcome of reaction 'Cardiogenic shock'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
What was the outcome of reaction 'Cardiomyopathy'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
What was the outcome of reaction 'Cardiotoxicity'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,507,644 | 2021-03 |
What was the outcome of reaction 'Mitral valve incompetence'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,061,134 | 2021-03 |
What was the outcome of reaction 'Nausea'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,077,698 | 2021-03 |
What was the outcome of reaction 'Vomiting'? | Capecitabine-mediated heart failure in colorectal cancer: a case series.
Capecitabine is a pyrimidine antimetabolite that inhibits thymidylate synthase and is commonly used in the treatment of colorectal cancer. Adverse cardiac side effects are reported in 1-18% of patients receiving Capecitabine. The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine use is vasospasm of the coronary arteries. However, cardiotoxicity can also present as an acute coronary syndrome, arrhythmia, hypertension, and/or sudden cardiac death. Profound non-vasospastic cardiotoxicity is rare.
We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine. Both patients did not demonstrate the characteristic transient ST elevation seen in patients with coronary artery vasospasms secondary to Capecitabine. Both patients required admission to the Acute Cardiac Care Unit requiring vasopressor and inotropic support. Thorough diagnostic investigations including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography did not identify infarction, myocarditis, or any infiltrative process to explain their symptoms. Both patients had complete resolution of cardiac function, with no long-term sequalae.
In patients receiving Capecitabine, reversible heart failure leading to cardiogenic shock should be considered as a potential cardiotoxic side effect.
Learning points
Cardiotoxicity is a rare side effect of capecitabine chemotherapy, most commonly secondary to coronary artery vasospasm.
Acute heart failure leading to cardiogenic shock is a rare form of cardiotoxicity that should be considered in patients on capecitabine.
Introduction
Capecitabine is the oral pro-drug of 5-Fluorouracil (5-FU) and is a pyrimidine antimetabolite that inhibits thymidylate synthase.1 Fluoropyrimidine-based chemotherapy is a vital aspect of the treatment of colorectal cancer. Side effects of fluoropyrimidine therapy may include myelosuppression, mucositis, nausea, emesis, diarrhoea, palmar-plantar erythrodysesthaesia, and rarely cardiotoxicity.2,3 Cardiotoxicity can present as an acute coronary syndrome, arrhythmia, hypotension, cardiogenic shock, cardiac arrest, and/or sudden cardiac death.2 The most commonly proposed mechanism of cardiotoxicity in the setting of Capecitabine is vasospasm of the coronary arteries. There is pre-clinical4 and clinical5 data that suggests that 5-FU causes vasospasm in a dose–dependent manner. Profound non-vasospastic cardiotoxicity is rare. We describe two cases of acute heart failure leading to cardiogenic shock in patients shortly after exposure to Capecitabine.
Timeline
Time Event
Patient 1
Day 1 Started neoadjuvant chemotherapy with Capecitabine and Oxaliplatin (CAPOX).
Day 7 Presented to Urgent Care with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort. Transthoracic echocardiogram (TTE) demonstrated a reduced left ventricular ejection fraction (LVEF) of <20%.
Day 7–23 Admission to Acute Cardiac Care Unit for inotropic support with milrinone.
Day 21 Repeat TTE demonstrated complete resolution of cardiac function.
Day 29 Discharged from hospital.
Day 36 Started on Raltitrexed and Oxaliplatin for management of rectal cancer.
Two months later Cardiac computed tomography demonstrated no evidence of obstructive coronary artery disease.
Patient 2
Day 1 Started adjuvant chemotherapy with CAPOX
Day 2 Patient experienced two episodes of central chest pain while at rest with associated diaphoresis.
Day 3 Presented to Emergency Department due to increased chest pain and profound fatigue. Patient was tachycardic and hypotensive, unresponsive to fluids. Patient was found to have grossly reduced LVEF on point of care ultrasound.
Day 3–6 Admitted to Acute Cardiac Care Unit with cardiogenic shock requiring vasopressor and inotropic support with norepinephrine and milrinone.
Day 4 TTE revealed LVEF <20% with severely depressed right ventricular systolic function.
Day 5 Coronary angiography revealed no obstructive coronary artery disease.
Day 6 Patient weaned off norepinephrine and milrinone, transferred to Cardiology Ward.
Day 8 Cardiac magnetic resonance imaging (MRI) demonstrated LVEF of 32% with a hypokinetic left ventricle, with no evidence of myocarditis, infarction, or an infiltrative process.
Day 9 Discharged from hospital.
Four months later Repeat cardiac MRI showed significant improvement of LVEF to 59%.
Case presentations
Patient 1
A 32-year-old woman, with no personal or family history of cardiac disease, underwent a diverting ostomy for an obstructing rectal cancer. Staging revealed a clinical T4N2M1 moderately differentiated adenocarcinoma. She was started on neoadjuvant chemotherapy with Capecitabine and Oxaliplatin [CAPOX; Oxaliplatin (130 mg/m2) on Day 1, and oral Capecitabine twice daily (1000 mg/m2) on Days 1–14 of a 3 weeks cycle]. On Day 7 of Cycle 1, she presented with nausea, vomiting, weakness, shortness of breath, and pleuritic chest discomfort.
In Urgent Care, she was afebrile with a blood pressure of 100/71 mmHg and a heart rate of 140–160 b.p.m. Her respiratory rate was 18 with an oxygen saturation of 100% on room air. She appeared unwell and pale but was alert and oriented. Cardiac examination revealed normal heart sounds, with no murmurs or extra heart sounds. Jugular venous pressure (JVP) was elevated and there was no peripheral oedema. On respiratory exam, there was decreased air entry posteriorly with crackles to the mid thorax bilaterally. Laboratory investigations revealed a white blood count (WBC) of 16.9 × 109/L, haemoglobin 99 g/L, sodium of 131 mmol/L, and potassium of 3 mmol/L. The patient had a mildly elevated high-sensitivity troponin T (hsTnT) at 39 (0–14 ng/L). Chest X-ray revealed pulmonary oedema. An electrocardiogram (ECG) demonstrated sinus tachycardia with T-wave inversion laterally and non-specific ST changes (Figure 1A). A venous blood gas revealed a pH 7.44, pO2 32 mmHg, bicarbonate 25 mmol/L, pCO2 38 mmHg, and lactate 2.4 mmol/L. Once the patient was haemodynamically stable, she received diuresis for management of pulmonary oedema. Her tachycardia and dyspnoea did not improve despite diuresis, and her lactate continued to increase to 4.1 mmol/L. A transthoracic echocardiogram (TTE) demonstrated a significantly reduced left ventricular ejection fraction (LVEF) of <20% on the apical four-chamber view following the administration of definity for left ventricular opacification (Figure 2A).
Figure 1 (A) Patient 1: a 12-lead electrocardiogram demonstrating sinus tachycardia with non-specific ST changes. (B) Patient 2: a 12-lead electrocardiogram demonstrating sinus tachycardia.
Figure 2 (A) Patient 1: an apical four-chamber view on transthoracic echocardiography with definity for left ventricular opacification demonstrating severe left ventricular systolic dysfunction with an left ventricular ejection fraction <20%. (B) Patient 1: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular systolic function on inotropic support. (C) Patient 2: an apical four-chamber view on transthoracic echocardiography confirming severe left ventricular systolic dysfunction with a left ventricular ejection fraction <20%.(D) Patient 2: a horizontal long-axis view on balanced steady-state free precession images demonstrating an improvement in left ventricular ejection fraction to 32% ∼5 days after the initial transthoracic echocardiography.
The patient was diagnosed with cardiogenic shock secondary to cardiomyopathy of unknown cause. She was admitted to the Acute Cardiac Care Unit for inotropic support with milrinone and haemodynamic monitoring. Infectious causes of myocarditis, including HIV, hepatitis, and parvovirus, and an autoimmune work-up were negative. Cardiac magnetic resonance (CMR) imaging on admission Day 5 showed an LVEF of 58%, LV end-diastolic volume of 104 mL, LV end-systolic volume of 43 mL, and LV stroke volume of 61 mL. Additionally, the RV volumes and RV systolic function were normal on CMR imaging. There was no evidence of delayed enhancement of the left ventricular myocardium on CMR imaging to suggest a recent infarction, myocarditis, or infiltrative process. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema.
During her admission, she had an elevated lactate for ∼2 weeks and required inotropic support with milrinone for a total of 16 days. A repeat transthoracic echocardiography 14 days post-admission demonstrated normal cardiac function, and she has successfully weaned off milrinone and discharged home on Metoprolol and Ramipril. Two months after discharge, a cardiac computed tomography scan demonstrated no evidence of obstructive coronary artery disease. She was started on Raltitrexed and Oxaliplatin for ongoing management of the rectal cancer and has experienced no further cardiotoxicity.
Patient 2
A 58-year-old functionally well man with a past medical history of hypertension, gout, and alcohol use (3–4 drinks per day), and no personal or family history of cardiac disease, presented post-operatively with a T4aN1aM0 moderately differentiated adenocarcinoma of the upper rectum. Eight weeks after low anterior resection, he received a recommendation of adjuvant CAPOX chemotherapy with chemoradiation. On Day 2 of Cycle 1, he experienced two 30-min episodes of central chest pain while at rest, associated with diaphoresis. On Day 3, his chest pain increased in severity and was associated with profound fatigue, leading him to seek medical attention.
In the emergency department, he was afebrile with a blood pressure of 91/69 mmHg, heart rate of 109 b.p.m., and oxygen saturation of 100% on room air. A cardiovascular exam revealed normal heart sounds, with no murmurs or extra heart sounds. His JVP was elevated to angle of jaw, and he had mild pitting oedema to his ankles. An ECG demonstrated sinus tachycardia and no evidence of ischaemia (Figure 1B). A chest X-ray revealed pulmonary oedema. His serial hsTnT measurements were 233 and 226.
A venous blood gas revealed a pH 7.38, pCO2 38 mmHg, bicarbonate 21 mmol/L, and lactate 3 mmol/L. Point of care ultrasound demonstrated a hypokinetic left ventricle, a grossly reduced LVEF, and a dilated IVC with minimal inspiratory response. He remained hypotensive with systolic blood pressures of 80 mmHg despite resuscitation with 4 L of normal saline. He developed clinical signs of heart failure, including increasing oxygen requirements and shortness of breath. He was admitted to the Acute Cardiac Care Unit for treatment with norepinephrine and milrinone and haemodynamic monitoring.
A formal TTE revealed an LVEF of <20% with an akinetic apex (Figure 2B). The right ventricular (RV) systolic function was also severely depressed with evidence of mild to moderate functional mitral regurgitation. A coronary angiogram revealed minimal coronary artery disease with no flow limiting disease. CMR imaging on admission Day 5 demonstrated an improved LVEF of 32% with a hypokinetic left ventricle, end-diastolic volume of 142 mL, end-systolic volume of 97 mL, and stroke volume of 45 mL. Additionally, T1 myocardial mapping and T2 weight imaging on CMR showed no evidence of myocardial oedema. There was no evidence of myocarditis, infarction, or infiltrative processes on CMR. He was successfully weaned off inotropic support and discharged home on Carvedilol and Ramipril after a 6-day admission.
Four months later, he underwent a repeat CMR. There was a significant improvement in the LVEF to 59%. Due to the severity of his chemotherapy-induced cardiotoxicity, he was not re-started on further fluoropyrimidine chemotherapy and proceeded with adjuvant radiation therapy alone.
Discussion
Capecitabine is a pro-drug that is catalysed by thymidine phosphorylase to fluorouracil. Thymidine phosphorylase has high expression in cancer cells, allowing for more selective accumulation of the antimetabolite in the tumour.1 Although Capecitabine is more selective to tumour cells, the reported incidence of cardiotoxicity with Capecitabine is similar to 5-FU, occurring in 1–18% of patients.6,7
Some of the proposed mechanisms of cardiotoxicity due to fluoropyrimidines include coronary vasospasm,4 myocardial ischaemia,8 and direct toxic effect leading to oxidative stress and destruction of cardiomyocytes.9 Cardiotoxicity can present with a range of symptoms including angina, arrhythmias, cardiogenic shock, and even sudden cardiac death.2 Classically, patients with coronary vasospasm present similar to other causes of acute coronary syndromes, with angina, but transient ST deviation on ECG.2,3 Coronary angiography with provocative testing can support the diagnosis of coronary vasospasm by direct visualization demonstrating no thrombus or narrowing. However, this direct visualization of vasospasm is time sensitive, due to the dose–dependent relationship of vasospasm and fluoropyrimidine cardiotoxicity.4 Both of the cases described herein showed no evidence of regional wall motion abnormalities or obstructive coronary artery disease on cardiac imaging. Although coronary vasospasm can lead to development of cardiogenic shock, other mechanisms, such as toxic myocardial inflammation or stress cardiomyopathy, resulting in myocardial dysfunction may better explain the mechanism of cardiogenic shock in these two cases.
In both cases, non-invasive diagnostic images, including TTE and CMR, were used to confirm the presence of severe left ventricular systolic dysfunction. One limitation of our case series is the lack of myocardial biopsy, which may have provided additional information on the mechanism of cardiotoxicity. However, since there was no evidence of delayed enhancement of the left ventricular myocardium on CMR to suggest myocarditis, or an infiltrative or ischaemic process, we elected not to pursue an invasive myocardial biopsy.
Both of our patients received CAPOX chemotherapy and presented with cardiogenic shock within days of starting chemotherapy. This timeline is similar to what has been reported in a retrospective study, which demonstrated that the first occurrence of cardiotoxicity occurred within 3–6 days of starting chemotherapy.10 In a prospective study of patients receiving 5-FU and oxaliplatin, 8.5% of patients experienced clinical symptoms of cardiotoxicity, which was associated with biochemical changes including an elevated N-terminal pro-brain natriuretic peptide and lactic acid, but not necessarily a change in global LVEF.8 Moreover, the same study found that plasma lactic acid increases significantly during 5-FU treatment, regardless of whether the patient had symptomatic cardiotoxicity.8 This could potentially explain the 2 weeks of elevated serum levels of lactate in Patient 1. It is also possible that the elevated lactate, in this case, was due to the continued stress on the myocardium from severe cardiac dysfunction caused by Capecitabine.
Some of the risk factors for developing cardiotoxicity to fluoropyrimidines include pre-existing cardiovascular disease, continuous infusion schedules, and concomitant cisplatin treatment.2,10,11 Although pre-existing cardiovascular disease has been shown to significantly predispose patients to fluorouracil-associated cardiotoxicity,10 with a relative risk of 6.83,11 a systematic review showed conflicting results.2 Of interest, the patient in Case 2 had predisposing cardiovascular risk factors (hypertension and alcohol use), potentially increasing his risk of cardiotoxicity from Capecitabine, despite exhibiting no exercise-limiting symptoms at baseline. For high-risk patients that require additional chemotherapy treatment, changing the agent to one with a safer cardiac profile should be considered. For example, the patient in case 1 received Raltitrexed, a quinazoline antifolate that selectively inhibits thymidylate synthase and has been shown to have outcomes similar to 5-FU in the treatment of metastatic colorectal cancer.12 Raltitrexed appears to have a safer cardiac profile for high-risk patients who have experienced cardiotoxicity on 5-FU based regimens.13
Dihydropyridine dehydrogenase (DPD) is the enzyme involved in the rate-limiting catabolism of 5-FU. Dihydropyridine dehydrogenase deficiency predisposes individuals to severe 5-FU toxicity, including profound neutropenia, mucositis, diarrhoea, and vomiting.14 In patients with DPD-deficiency, the onset of 5-FU toxicity can be rapid, sometimes even within hours of the first dose.15 In such cases, an antidote, uridine triacetate, can be considered.15 The patients in our case series did not present with these classic symptoms of DPD-deficiency and, therefore, DPD testing was not pursued.
Although both patients described here did not have long-term cardiac dysfunction, some patients may experience irreversible cardiac damage. When patients experience cardiotoxicity related to an anti-cancer agent, referral to a cardio-oncology specialist is recommended, as such an approach may result in improved cardiac optimization, higher rates of cancer treatment continuation, and ultimately improved oncologic outcomes.16–18 Additionally, for patients who have cardiac risk factors, referral to a cardio-oncology specialist pre-chemotherapy can allow for cardiac optimization and ultimately improve completion of cancer therapy.16
Conclusion
In patients receiving Capecitabine, reversible heart failure and cardiogenic shock should be considered as a potential cardiotoxic side effects. Capecitabine should be promptly discontinued and patients should be managed with multidisciplinary collaboration from the disciplines of Cardiology and Oncology.
Lead author biography
Dr Erin McAndrew is an Internal Medicine resident at the University of Manitoba. She completed a Master of Science and Doctor of Medicine at the University of Manitoba. Her research interests include cardio-oncology and long-term cardiac consequence of chemotherapy.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consents for submission and publication of this case report including images and associated text have been obtained from the patients in line with COPE guidance.
Conflict of interest: C.A. Kim reports a research grant from Celgene, outside of this submitted work. No other conflicts of interest are declared.
Funding: None declared.
Supplementary Material
ytab079_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY-NC | 33709051 | 19,077,698 | 2021-03 |
What was the administration route of drug 'LACOSAMIDE'? | Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.
Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.
pmcIntroduction
Novel coronavirus disease (COVID-19) is mostly known to affect the respiratory system, potentially leading to severe acute respiratory failure. Yet, most patients with COVID-19 have also shown nonspecific neurological symptoms, such as confusion or headache, and some of them, particularly those with severe COVID-19-related respiratory failure, developed specific neurological manifestations, such as seizure or cerebrovascular events.
New-onset refractory status epilepticus (NORSE) may occur as a consequence of COVID-19. NORSE is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and without a clear acute or active structural, toxic or metabolic cause. The most frequently identified cause of NORSE is autoimmune encephalitis. Indeed, patients with refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr) encephalitis without lung involvement were recently reported in COVID-19 patients [1, 2], such as probable autoimmune encephalitis and encephalomyelitis [3]. NMDAr encephalitis represents the most frequent cause of autoimmune encephalitis and it may be triggered by viral infection, particularly Herpes Simplex Virus [4]. Early immune therapy (steroids, intravenous immunoglobulins, and plasma exchange) is recommended for autoimmune encephalitis-related NORSE treatment, since a delayed treatment may contribute to worse outcomes.
The aim of this report is to encourage a rapid diagnostic work-up and implementation of intravenous immunoglobulin (IVIG) therapy in possible COVID-19 autoimmune encephalitis-related NORSE. As such, we described two NORSE patients affected by COVID-19 who successfully responded to the IVIG, thus suggesting the basic autoimmune mechanisms in these COVID-19 epileptic statuses.
Materials and methods
This case series described two patients admitted to the hospital affected by bilateral pneumonia due to the novel Coronavirus 2019 (SARS-CoV-2) infection from March to December 2020 diagnosed by a positive nasopharyngeal swab test. Due to positivity for COVID-19, the patients were admitted to the COVID-19 protected areas of the University Hospital of Trieste. COVID-19 diagnosis was confirmed through nasopharyngeal swab testing. COVID-19 management included steroids (dexamethasone 6 mg/die for 10 days) to treat respiratory insufficiency, venous thromboembolism prophylaxis (enoxaparin 4000 IU), initial broad-spectrum antibiotics followed by specific antibiotics according to the antibiogram, artificial ventilation (case 1: orotracheal intubation; case 2: non-invasive ventilation; followed by, both cases: progressive low-flow oxygen therapy). None of the patients was in prone position. The patients presented (one at the admission and one after 11 days of hospitalization) clinical seizures or reduced vigilance and altered mental status, suggestive of a diagnosis of status epilepticus (SE). All the patients received neurological examination at symptoms development, electroencephalography (EEG), routine blood chemistry analyses, and a panel of diagnostic testing, including neuroimaging and biomarkers. Cerebrospinal fluid (CSF) was collected and processed for standard analyses including pressure, cell count, proteins, and glucose. CSF culture and polymerase chain reaction (PCR) for possible organisms, such as bacteria, Mycobacterium tuberculosis, fungi, Herpes viruses, Enteroviruses, Japanese B virus, and Dengue viruses was performed, including analysis for SARS-CoV-2. Serum and CSF were tested for onconeural antibody, as antiamphiphysin, antiCV2, antiMa2/TA, antiRI, antiYo, antiHu, antirecoverin, antiSox1, antitin, antiZic4, antiGAD65/67 (Anti-Glutamate Decarboxylase), antiTr, and antineuronal surface antigens antibodies, as antiNMDAr (N-methyl-d-aspartate receptor), antiVGKC (voltage gated potassium channel) complex LGI1 (leucine-rich glioma inactivated 1) and CASPR2 (Contactin-associated protein-like 2), antiAMPA1r (Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), antiAMPA2r, antiGABABr (Gamma-aminobutyric acid), antiDPPX (dipeptidyl-peptidase-like protein 6). Due to the lack of response to the antiepileptic drugs, all the patients were compatible with a possible autoimmune encephalitis-related NORSE diagnosis and they were treated with IVIG.
EEG acquisition and analysis
Thirteen channel 20-min standard clinical surface EEG was acquired by Be Plus PRO amplifier (EB NEURO, Florence, Italy) and 13 Ag/AgCl electrodes (F7, F3, F4, F8, C3, Cz, C4, T5, P3, P4, T6, O1, O2) placed according the standard 10–20 System. All electrode impedances were kept below 5 kΩ, and sampling rate was set to 256 Hz. EEG signals were filtered by second order band-pass Butterworth filter with 0.1–30 Hz cut-off frequencies. Brain oscillatory activities were assessed by qualitative visual inspection of EEG tracings by two experienced neurologists (P.M. and G.F.) to identify epileptiform patterns and altered EEG rhythms. Furthermore, power spectral density (PSD) was estimated on 120 s segments using Welch’s periodogram and absolute power for each of spectral band (δ: 1–4 Hz; θ: 4–8 Hz; α: 8–13 Hz; β: 13–30 Hz) was calculated and then normalized with a total power across the 1–30 Hz range to obtain relative powers. The physician and the technician wore personal protective equipment (PPE), including appropriate masks, face shields, gowns and gloves according to the American Association of Clinical Neurophysiology guidelines published on its official website (https://www.acns.org/practice/covid-19-resources).
Results
Case 1
A 37-year-old male, with an unremarkable medical history, was admitted to the Intensive Care Unit (ICU), due to convulsive status epilepticus. The nasopharyngeal swab test was found positive for SARS-CoV-2, while serum analysis, head CT scan and toxicological examination were negative. First line treatment and intravenous Levetiracetam infusion (3000 mg/24 h iv) were immediately started but led to no clinical improvement. EEG was performed within the first 24 h, revealing generalized SE (Fig. 1). Additional antiepileptic treatments including Valproic Acid (3000 mg/24 h iv), Phenytoin (18 mg/kg iv) and Lacosamide (400 mg iv in 24 h, increase to 600 mg in 24 h) were progressively administered after following examinations and concomitant to Propofol infusion without significant improvement. Subsequent EEG showed a generalized delta slowing; consequently, continuous infusion of Midazolam was added to Propofol to achieve burst suppression. After 24 h, Propofol was progressively reduced, but the patient suddenly developed generalized myoclonic jerks of axial muscles and face. Continuous EEG monitoring showed persistent generalized epileptic discharges compatible with non-convulsive status epilepticus (NCSE). Early diagnostic work-up was performed as follows: contrast-enhanced Magnetic Resonance Imaging (MRI)—negative results; serum HIV, VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 56.7 mg/dL, glucose 66.1 mg/dL, 1 mononuclear white blood cell, and CSF culture and PCR yielded negative results; serum and CSF onconeural antibody and antineuronal surface antigens antibody were found positive for anti amphiphysin antibody. Contrast-enhanced whole-body CT and testicular ultrasound suggested the absence of any neoplastic process. Given the lack of response to multiple antiepileptic drugs and third-line anesthetics drugs, a diagnosis of possible autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. The EEG showed a dramatic improvement on the fifth day of IVIG infusion, with complete clinical recovery without seizures and a complete normalization of EEG (Fig. 1). The patient was awake and without respiratory support. No side effects were reported for the use of intravenous immunoglobulin therapy. After a negative whole-body PET-CT, the neoplastic origin was excluded and the patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.Fig. 1 EEG raw data before IVIG therapy (pre)—left panel and after IVIG therapy (post)—right panel. EEG spectral analysis showed EEG relative powers indices pre—post modification; Case 1—pre: δ = 0.79, θ = 0.16, α = 0.03, β = 0.02; Case 1—post: δ = 0.17, θ = 0.15, α = 0.48, β = 0.20; Case 2—pre: δ = 0.55, θ = 0.31, α = 0.09, β = 0.05; Case 2—post: δ = 0.16, θ = 0.32, α = 0.41, β = 0.11
Case 2
A 71-year-old male, with a history of arterial hypertension, was admitted to the infectious disease unit, due to severe respiratory failure symptoms compatible with COVID-19 bilateral pneumonia. The nasopharyngeal swab test was found positive for SARS-CoV-2 and the patient was treated with non-invasive ventilation due to respiratory distress. After 11 days, the patient became lethargic and showed negative upper limbs myoclonus and random, involuntary, and rapid vertical eye movements. Kidney and liver function biomarkers, serum electrolytes and ammonia were normal, head CT scan and toxicological examination resulted negative. Clinical evaluation (myoclonic positive and negative jerks, and altered mental status) was compatible with NCSE diagnosis, while EEG revealed generalized epileptic discharges with bilateral frontal high amplitude delta waves (Fig. 1). At first, intravenous Valproic Acid (2000 mg/24 h iv) and secondarily Levetiracetam infusion (3000 mg/24 h iv) were started but led to no clinical nor EEG improvement. Early diagnostic work-up was performed as follows: contrast-enhanced MRI—negative results; serum VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 53.9 mg/dL, glucose 104 mg/dL, 1 mononuclear white blood cell, CSF culture and PCR yielded negative results, as well as serum and CSF onconeural antibody and antineuronal surface antigens antibody. Given the lack of response to multiple antiepileptic drugs, a diagnosis of possible seronegative autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. After the first 5-day cycle, due to the scarce response (remission of myoclonic jerks and vigilance partial improvement), a second 5-day IVIG cycle was started with a progressive improvement of both clinical and EEG features (Fig. 1) without side effects. The patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.
Discussion
This report fosters the implementation of a rapid diagnostic work-up and use of IVIG as a promising therapy to safely and successfully treat possible autoimmune encephalitis-related NORSE triggered by SARS-CoV-2 infection. A rapid diagnosis and appropriate treatment are essential to avoid irreversible sequelae of autoimmune encephalitis-related NORSE. Neurological features may be common in COVID-19 patients, as reported in different studies, and some authors suggest to suspect SARS-CoV-2 infection when seeing patients with neurologic manifestations during the pandemic period [5, 6]. Indeed, evidence suggests a direct neuronal injury, as shown by increased serum neurofilament light chain (sNfL) levels, in critically ill COVID-19 patients compared to critically ill non-COVID-19 patients [7]. Although the exact pathophysiological mechanisms underlying the development of neurological syndromes are not completely appreciated, some explanatory mechanisms are currently debated, such as (1) a systemic inflammatory response, (2) a prothrombotic state, and (3) direct viral invasion [8]. Besides, the reported cases suggest that SARS-CoV-2 infection could trigger autoimmune responses, with a Central Nervous System (CNS) involvement. From a historical perspective, one century ago the “pandemic flu” was followed by an outbreak of encephalitis [9]. The negativity of PCR for other viruses on cerebrospinal fluid and the temporal association between SARS-CoV-2 infection and neurological symptoms suggests a possible causative role of COVID-19 in the development of the autoimmune response, thus resulting in NORSE.
Recently, some patients with autoimmune encephalitis associated with COVID-19 have been reported, in which irritability, confusion, drowsiness, and new-onset epilepsy account for the main symptoms at onset [1–3]. In our study, we reported two cases of encephalitis associated with NORSE rapidly assessed with EEG. The early EEG testing contributes to the rapid recognition of electric abnormalities, which may be common in COVID-19 patients [10, 11] also due to secondary causes, such as cerebrovascular events, electrolytes imbalance, oxidative stress, mitochondrial dysfunction, hypoxia, and prolonged inactivity [12–15]. Despite the fact that continuous EEG monitoring should be preferred, this study could rely only on daily spot EEG measurements due to the complexity of evaluation and testing in a COVID-19 area. Disturbances of background activity have been reported in most COVID-19 patients with seizures, such as generalized and focal slowing and a high level of epileptiform abnormalities and rhythmic or periodic discharges [10–12]. Additionally, the finding of slightly increased CSF protein concentration, without significant cells’ increase, supported the hypothesis of autoimmune mechanisms, although it may also reflect other non-autoimmune neurological diseases.
Our cases highlighted the importance of suspecting an autoimmune cause in NORSE patients positive to SARS-CoV-2 after excluding structural, infectious, metabolic, and toxic etiologies, and that IVIG treatment should be rapidly started to promote symptoms remission, while a complete autoimmune work-up needs to be set up as early as possible to confirm the diagnosis. Although the use of IVIG in NORSE is not supported by conclusive findings [16], the use of such therapy in possible encephalitis-related NORSE in COVID-19 patients suggested favorable results also in large cohorts of patients [3] and in COVID-19 patients affected by other autoimmune peripheral neurological syndromes (e.g., Guillain–Barré and Miller Fisher) [17–20]. The rapid and remarkable improvement of both our patients from resistant status epilepticus not responsive to different antiepileptic drugs is in line with the above-mentioned studies.
Conclusions
Autoimmune encephalitis may be a consequence of COVID-19 and it may result in NORSE. Although a causative relationship cannot be stated due to the retrospective nature of our study, initiating immunotherapy in case of suspected autoimmune etiology is desirable and a rapid diagnostic process should be encouraged (including EEG monitoring). Our findings support the use of IVIG therapy in NORSE COVID-19 patients with suspected autoimmune encephalitis to prevent negative outcomes, due to the time-dependent course of the disease.
Acknowledgements
The authors thank Matteo di Franza for English proof-reading and editorial assistance.
Funding
Open access funding provided by Università degli Studi di Trieste within the CRUI-CARE Agreement.. No funding was received for conducting this study.
Compliance with ethical standards
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in study were approved by the CEUR FVG ethical committee.
Informed consent
Informed consent was obtained from all individual participants included in the study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33709220 | 20,076,567 | 2021-10 |
What was the administration route of drug 'LEVETIRACETAM'? | Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.
Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.
pmcIntroduction
Novel coronavirus disease (COVID-19) is mostly known to affect the respiratory system, potentially leading to severe acute respiratory failure. Yet, most patients with COVID-19 have also shown nonspecific neurological symptoms, such as confusion or headache, and some of them, particularly those with severe COVID-19-related respiratory failure, developed specific neurological manifestations, such as seizure or cerebrovascular events.
New-onset refractory status epilepticus (NORSE) may occur as a consequence of COVID-19. NORSE is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and without a clear acute or active structural, toxic or metabolic cause. The most frequently identified cause of NORSE is autoimmune encephalitis. Indeed, patients with refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr) encephalitis without lung involvement were recently reported in COVID-19 patients [1, 2], such as probable autoimmune encephalitis and encephalomyelitis [3]. NMDAr encephalitis represents the most frequent cause of autoimmune encephalitis and it may be triggered by viral infection, particularly Herpes Simplex Virus [4]. Early immune therapy (steroids, intravenous immunoglobulins, and plasma exchange) is recommended for autoimmune encephalitis-related NORSE treatment, since a delayed treatment may contribute to worse outcomes.
The aim of this report is to encourage a rapid diagnostic work-up and implementation of intravenous immunoglobulin (IVIG) therapy in possible COVID-19 autoimmune encephalitis-related NORSE. As such, we described two NORSE patients affected by COVID-19 who successfully responded to the IVIG, thus suggesting the basic autoimmune mechanisms in these COVID-19 epileptic statuses.
Materials and methods
This case series described two patients admitted to the hospital affected by bilateral pneumonia due to the novel Coronavirus 2019 (SARS-CoV-2) infection from March to December 2020 diagnosed by a positive nasopharyngeal swab test. Due to positivity for COVID-19, the patients were admitted to the COVID-19 protected areas of the University Hospital of Trieste. COVID-19 diagnosis was confirmed through nasopharyngeal swab testing. COVID-19 management included steroids (dexamethasone 6 mg/die for 10 days) to treat respiratory insufficiency, venous thromboembolism prophylaxis (enoxaparin 4000 IU), initial broad-spectrum antibiotics followed by specific antibiotics according to the antibiogram, artificial ventilation (case 1: orotracheal intubation; case 2: non-invasive ventilation; followed by, both cases: progressive low-flow oxygen therapy). None of the patients was in prone position. The patients presented (one at the admission and one after 11 days of hospitalization) clinical seizures or reduced vigilance and altered mental status, suggestive of a diagnosis of status epilepticus (SE). All the patients received neurological examination at symptoms development, electroencephalography (EEG), routine blood chemistry analyses, and a panel of diagnostic testing, including neuroimaging and biomarkers. Cerebrospinal fluid (CSF) was collected and processed for standard analyses including pressure, cell count, proteins, and glucose. CSF culture and polymerase chain reaction (PCR) for possible organisms, such as bacteria, Mycobacterium tuberculosis, fungi, Herpes viruses, Enteroviruses, Japanese B virus, and Dengue viruses was performed, including analysis for SARS-CoV-2. Serum and CSF were tested for onconeural antibody, as antiamphiphysin, antiCV2, antiMa2/TA, antiRI, antiYo, antiHu, antirecoverin, antiSox1, antitin, antiZic4, antiGAD65/67 (Anti-Glutamate Decarboxylase), antiTr, and antineuronal surface antigens antibodies, as antiNMDAr (N-methyl-d-aspartate receptor), antiVGKC (voltage gated potassium channel) complex LGI1 (leucine-rich glioma inactivated 1) and CASPR2 (Contactin-associated protein-like 2), antiAMPA1r (Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), antiAMPA2r, antiGABABr (Gamma-aminobutyric acid), antiDPPX (dipeptidyl-peptidase-like protein 6). Due to the lack of response to the antiepileptic drugs, all the patients were compatible with a possible autoimmune encephalitis-related NORSE diagnosis and they were treated with IVIG.
EEG acquisition and analysis
Thirteen channel 20-min standard clinical surface EEG was acquired by Be Plus PRO amplifier (EB NEURO, Florence, Italy) and 13 Ag/AgCl electrodes (F7, F3, F4, F8, C3, Cz, C4, T5, P3, P4, T6, O1, O2) placed according the standard 10–20 System. All electrode impedances were kept below 5 kΩ, and sampling rate was set to 256 Hz. EEG signals were filtered by second order band-pass Butterworth filter with 0.1–30 Hz cut-off frequencies. Brain oscillatory activities were assessed by qualitative visual inspection of EEG tracings by two experienced neurologists (P.M. and G.F.) to identify epileptiform patterns and altered EEG rhythms. Furthermore, power spectral density (PSD) was estimated on 120 s segments using Welch’s periodogram and absolute power for each of spectral band (δ: 1–4 Hz; θ: 4–8 Hz; α: 8–13 Hz; β: 13–30 Hz) was calculated and then normalized with a total power across the 1–30 Hz range to obtain relative powers. The physician and the technician wore personal protective equipment (PPE), including appropriate masks, face shields, gowns and gloves according to the American Association of Clinical Neurophysiology guidelines published on its official website (https://www.acns.org/practice/covid-19-resources).
Results
Case 1
A 37-year-old male, with an unremarkable medical history, was admitted to the Intensive Care Unit (ICU), due to convulsive status epilepticus. The nasopharyngeal swab test was found positive for SARS-CoV-2, while serum analysis, head CT scan and toxicological examination were negative. First line treatment and intravenous Levetiracetam infusion (3000 mg/24 h iv) were immediately started but led to no clinical improvement. EEG was performed within the first 24 h, revealing generalized SE (Fig. 1). Additional antiepileptic treatments including Valproic Acid (3000 mg/24 h iv), Phenytoin (18 mg/kg iv) and Lacosamide (400 mg iv in 24 h, increase to 600 mg in 24 h) were progressively administered after following examinations and concomitant to Propofol infusion without significant improvement. Subsequent EEG showed a generalized delta slowing; consequently, continuous infusion of Midazolam was added to Propofol to achieve burst suppression. After 24 h, Propofol was progressively reduced, but the patient suddenly developed generalized myoclonic jerks of axial muscles and face. Continuous EEG monitoring showed persistent generalized epileptic discharges compatible with non-convulsive status epilepticus (NCSE). Early diagnostic work-up was performed as follows: contrast-enhanced Magnetic Resonance Imaging (MRI)—negative results; serum HIV, VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 56.7 mg/dL, glucose 66.1 mg/dL, 1 mononuclear white blood cell, and CSF culture and PCR yielded negative results; serum and CSF onconeural antibody and antineuronal surface antigens antibody were found positive for anti amphiphysin antibody. Contrast-enhanced whole-body CT and testicular ultrasound suggested the absence of any neoplastic process. Given the lack of response to multiple antiepileptic drugs and third-line anesthetics drugs, a diagnosis of possible autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. The EEG showed a dramatic improvement on the fifth day of IVIG infusion, with complete clinical recovery without seizures and a complete normalization of EEG (Fig. 1). The patient was awake and without respiratory support. No side effects were reported for the use of intravenous immunoglobulin therapy. After a negative whole-body PET-CT, the neoplastic origin was excluded and the patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.Fig. 1 EEG raw data before IVIG therapy (pre)—left panel and after IVIG therapy (post)—right panel. EEG spectral analysis showed EEG relative powers indices pre—post modification; Case 1—pre: δ = 0.79, θ = 0.16, α = 0.03, β = 0.02; Case 1—post: δ = 0.17, θ = 0.15, α = 0.48, β = 0.20; Case 2—pre: δ = 0.55, θ = 0.31, α = 0.09, β = 0.05; Case 2—post: δ = 0.16, θ = 0.32, α = 0.41, β = 0.11
Case 2
A 71-year-old male, with a history of arterial hypertension, was admitted to the infectious disease unit, due to severe respiratory failure symptoms compatible with COVID-19 bilateral pneumonia. The nasopharyngeal swab test was found positive for SARS-CoV-2 and the patient was treated with non-invasive ventilation due to respiratory distress. After 11 days, the patient became lethargic and showed negative upper limbs myoclonus and random, involuntary, and rapid vertical eye movements. Kidney and liver function biomarkers, serum electrolytes and ammonia were normal, head CT scan and toxicological examination resulted negative. Clinical evaluation (myoclonic positive and negative jerks, and altered mental status) was compatible with NCSE diagnosis, while EEG revealed generalized epileptic discharges with bilateral frontal high amplitude delta waves (Fig. 1). At first, intravenous Valproic Acid (2000 mg/24 h iv) and secondarily Levetiracetam infusion (3000 mg/24 h iv) were started but led to no clinical nor EEG improvement. Early diagnostic work-up was performed as follows: contrast-enhanced MRI—negative results; serum VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 53.9 mg/dL, glucose 104 mg/dL, 1 mononuclear white blood cell, CSF culture and PCR yielded negative results, as well as serum and CSF onconeural antibody and antineuronal surface antigens antibody. Given the lack of response to multiple antiepileptic drugs, a diagnosis of possible seronegative autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. After the first 5-day cycle, due to the scarce response (remission of myoclonic jerks and vigilance partial improvement), a second 5-day IVIG cycle was started with a progressive improvement of both clinical and EEG features (Fig. 1) without side effects. The patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.
Discussion
This report fosters the implementation of a rapid diagnostic work-up and use of IVIG as a promising therapy to safely and successfully treat possible autoimmune encephalitis-related NORSE triggered by SARS-CoV-2 infection. A rapid diagnosis and appropriate treatment are essential to avoid irreversible sequelae of autoimmune encephalitis-related NORSE. Neurological features may be common in COVID-19 patients, as reported in different studies, and some authors suggest to suspect SARS-CoV-2 infection when seeing patients with neurologic manifestations during the pandemic period [5, 6]. Indeed, evidence suggests a direct neuronal injury, as shown by increased serum neurofilament light chain (sNfL) levels, in critically ill COVID-19 patients compared to critically ill non-COVID-19 patients [7]. Although the exact pathophysiological mechanisms underlying the development of neurological syndromes are not completely appreciated, some explanatory mechanisms are currently debated, such as (1) a systemic inflammatory response, (2) a prothrombotic state, and (3) direct viral invasion [8]. Besides, the reported cases suggest that SARS-CoV-2 infection could trigger autoimmune responses, with a Central Nervous System (CNS) involvement. From a historical perspective, one century ago the “pandemic flu” was followed by an outbreak of encephalitis [9]. The negativity of PCR for other viruses on cerebrospinal fluid and the temporal association between SARS-CoV-2 infection and neurological symptoms suggests a possible causative role of COVID-19 in the development of the autoimmune response, thus resulting in NORSE.
Recently, some patients with autoimmune encephalitis associated with COVID-19 have been reported, in which irritability, confusion, drowsiness, and new-onset epilepsy account for the main symptoms at onset [1–3]. In our study, we reported two cases of encephalitis associated with NORSE rapidly assessed with EEG. The early EEG testing contributes to the rapid recognition of electric abnormalities, which may be common in COVID-19 patients [10, 11] also due to secondary causes, such as cerebrovascular events, electrolytes imbalance, oxidative stress, mitochondrial dysfunction, hypoxia, and prolonged inactivity [12–15]. Despite the fact that continuous EEG monitoring should be preferred, this study could rely only on daily spot EEG measurements due to the complexity of evaluation and testing in a COVID-19 area. Disturbances of background activity have been reported in most COVID-19 patients with seizures, such as generalized and focal slowing and a high level of epileptiform abnormalities and rhythmic or periodic discharges [10–12]. Additionally, the finding of slightly increased CSF protein concentration, without significant cells’ increase, supported the hypothesis of autoimmune mechanisms, although it may also reflect other non-autoimmune neurological diseases.
Our cases highlighted the importance of suspecting an autoimmune cause in NORSE patients positive to SARS-CoV-2 after excluding structural, infectious, metabolic, and toxic etiologies, and that IVIG treatment should be rapidly started to promote symptoms remission, while a complete autoimmune work-up needs to be set up as early as possible to confirm the diagnosis. Although the use of IVIG in NORSE is not supported by conclusive findings [16], the use of such therapy in possible encephalitis-related NORSE in COVID-19 patients suggested favorable results also in large cohorts of patients [3] and in COVID-19 patients affected by other autoimmune peripheral neurological syndromes (e.g., Guillain–Barré and Miller Fisher) [17–20]. The rapid and remarkable improvement of both our patients from resistant status epilepticus not responsive to different antiepileptic drugs is in line with the above-mentioned studies.
Conclusions
Autoimmune encephalitis may be a consequence of COVID-19 and it may result in NORSE. Although a causative relationship cannot be stated due to the retrospective nature of our study, initiating immunotherapy in case of suspected autoimmune etiology is desirable and a rapid diagnostic process should be encouraged (including EEG monitoring). Our findings support the use of IVIG therapy in NORSE COVID-19 patients with suspected autoimmune encephalitis to prevent negative outcomes, due to the time-dependent course of the disease.
Acknowledgements
The authors thank Matteo di Franza for English proof-reading and editorial assistance.
Funding
Open access funding provided by Università degli Studi di Trieste within the CRUI-CARE Agreement.. No funding was received for conducting this study.
Compliance with ethical standards
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in study were approved by the CEUR FVG ethical committee.
Informed consent
Informed consent was obtained from all individual participants included in the study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33709220 | 20,076,567 | 2021-10 |
What was the administration route of drug 'PHENYTOIN'? | Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.
Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.
pmcIntroduction
Novel coronavirus disease (COVID-19) is mostly known to affect the respiratory system, potentially leading to severe acute respiratory failure. Yet, most patients with COVID-19 have also shown nonspecific neurological symptoms, such as confusion or headache, and some of them, particularly those with severe COVID-19-related respiratory failure, developed specific neurological manifestations, such as seizure or cerebrovascular events.
New-onset refractory status epilepticus (NORSE) may occur as a consequence of COVID-19. NORSE is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and without a clear acute or active structural, toxic or metabolic cause. The most frequently identified cause of NORSE is autoimmune encephalitis. Indeed, patients with refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr) encephalitis without lung involvement were recently reported in COVID-19 patients [1, 2], such as probable autoimmune encephalitis and encephalomyelitis [3]. NMDAr encephalitis represents the most frequent cause of autoimmune encephalitis and it may be triggered by viral infection, particularly Herpes Simplex Virus [4]. Early immune therapy (steroids, intravenous immunoglobulins, and plasma exchange) is recommended for autoimmune encephalitis-related NORSE treatment, since a delayed treatment may contribute to worse outcomes.
The aim of this report is to encourage a rapid diagnostic work-up and implementation of intravenous immunoglobulin (IVIG) therapy in possible COVID-19 autoimmune encephalitis-related NORSE. As such, we described two NORSE patients affected by COVID-19 who successfully responded to the IVIG, thus suggesting the basic autoimmune mechanisms in these COVID-19 epileptic statuses.
Materials and methods
This case series described two patients admitted to the hospital affected by bilateral pneumonia due to the novel Coronavirus 2019 (SARS-CoV-2) infection from March to December 2020 diagnosed by a positive nasopharyngeal swab test. Due to positivity for COVID-19, the patients were admitted to the COVID-19 protected areas of the University Hospital of Trieste. COVID-19 diagnosis was confirmed through nasopharyngeal swab testing. COVID-19 management included steroids (dexamethasone 6 mg/die for 10 days) to treat respiratory insufficiency, venous thromboembolism prophylaxis (enoxaparin 4000 IU), initial broad-spectrum antibiotics followed by specific antibiotics according to the antibiogram, artificial ventilation (case 1: orotracheal intubation; case 2: non-invasive ventilation; followed by, both cases: progressive low-flow oxygen therapy). None of the patients was in prone position. The patients presented (one at the admission and one after 11 days of hospitalization) clinical seizures or reduced vigilance and altered mental status, suggestive of a diagnosis of status epilepticus (SE). All the patients received neurological examination at symptoms development, electroencephalography (EEG), routine blood chemistry analyses, and a panel of diagnostic testing, including neuroimaging and biomarkers. Cerebrospinal fluid (CSF) was collected and processed for standard analyses including pressure, cell count, proteins, and glucose. CSF culture and polymerase chain reaction (PCR) for possible organisms, such as bacteria, Mycobacterium tuberculosis, fungi, Herpes viruses, Enteroviruses, Japanese B virus, and Dengue viruses was performed, including analysis for SARS-CoV-2. Serum and CSF were tested for onconeural antibody, as antiamphiphysin, antiCV2, antiMa2/TA, antiRI, antiYo, antiHu, antirecoverin, antiSox1, antitin, antiZic4, antiGAD65/67 (Anti-Glutamate Decarboxylase), antiTr, and antineuronal surface antigens antibodies, as antiNMDAr (N-methyl-d-aspartate receptor), antiVGKC (voltage gated potassium channel) complex LGI1 (leucine-rich glioma inactivated 1) and CASPR2 (Contactin-associated protein-like 2), antiAMPA1r (Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), antiAMPA2r, antiGABABr (Gamma-aminobutyric acid), antiDPPX (dipeptidyl-peptidase-like protein 6). Due to the lack of response to the antiepileptic drugs, all the patients were compatible with a possible autoimmune encephalitis-related NORSE diagnosis and they were treated with IVIG.
EEG acquisition and analysis
Thirteen channel 20-min standard clinical surface EEG was acquired by Be Plus PRO amplifier (EB NEURO, Florence, Italy) and 13 Ag/AgCl electrodes (F7, F3, F4, F8, C3, Cz, C4, T5, P3, P4, T6, O1, O2) placed according the standard 10–20 System. All electrode impedances were kept below 5 kΩ, and sampling rate was set to 256 Hz. EEG signals were filtered by second order band-pass Butterworth filter with 0.1–30 Hz cut-off frequencies. Brain oscillatory activities were assessed by qualitative visual inspection of EEG tracings by two experienced neurologists (P.M. and G.F.) to identify epileptiform patterns and altered EEG rhythms. Furthermore, power spectral density (PSD) was estimated on 120 s segments using Welch’s periodogram and absolute power for each of spectral band (δ: 1–4 Hz; θ: 4–8 Hz; α: 8–13 Hz; β: 13–30 Hz) was calculated and then normalized with a total power across the 1–30 Hz range to obtain relative powers. The physician and the technician wore personal protective equipment (PPE), including appropriate masks, face shields, gowns and gloves according to the American Association of Clinical Neurophysiology guidelines published on its official website (https://www.acns.org/practice/covid-19-resources).
Results
Case 1
A 37-year-old male, with an unremarkable medical history, was admitted to the Intensive Care Unit (ICU), due to convulsive status epilepticus. The nasopharyngeal swab test was found positive for SARS-CoV-2, while serum analysis, head CT scan and toxicological examination were negative. First line treatment and intravenous Levetiracetam infusion (3000 mg/24 h iv) were immediately started but led to no clinical improvement. EEG was performed within the first 24 h, revealing generalized SE (Fig. 1). Additional antiepileptic treatments including Valproic Acid (3000 mg/24 h iv), Phenytoin (18 mg/kg iv) and Lacosamide (400 mg iv in 24 h, increase to 600 mg in 24 h) were progressively administered after following examinations and concomitant to Propofol infusion without significant improvement. Subsequent EEG showed a generalized delta slowing; consequently, continuous infusion of Midazolam was added to Propofol to achieve burst suppression. After 24 h, Propofol was progressively reduced, but the patient suddenly developed generalized myoclonic jerks of axial muscles and face. Continuous EEG monitoring showed persistent generalized epileptic discharges compatible with non-convulsive status epilepticus (NCSE). Early diagnostic work-up was performed as follows: contrast-enhanced Magnetic Resonance Imaging (MRI)—negative results; serum HIV, VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 56.7 mg/dL, glucose 66.1 mg/dL, 1 mononuclear white blood cell, and CSF culture and PCR yielded negative results; serum and CSF onconeural antibody and antineuronal surface antigens antibody were found positive for anti amphiphysin antibody. Contrast-enhanced whole-body CT and testicular ultrasound suggested the absence of any neoplastic process. Given the lack of response to multiple antiepileptic drugs and third-line anesthetics drugs, a diagnosis of possible autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. The EEG showed a dramatic improvement on the fifth day of IVIG infusion, with complete clinical recovery without seizures and a complete normalization of EEG (Fig. 1). The patient was awake and without respiratory support. No side effects were reported for the use of intravenous immunoglobulin therapy. After a negative whole-body PET-CT, the neoplastic origin was excluded and the patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.Fig. 1 EEG raw data before IVIG therapy (pre)—left panel and after IVIG therapy (post)—right panel. EEG spectral analysis showed EEG relative powers indices pre—post modification; Case 1—pre: δ = 0.79, θ = 0.16, α = 0.03, β = 0.02; Case 1—post: δ = 0.17, θ = 0.15, α = 0.48, β = 0.20; Case 2—pre: δ = 0.55, θ = 0.31, α = 0.09, β = 0.05; Case 2—post: δ = 0.16, θ = 0.32, α = 0.41, β = 0.11
Case 2
A 71-year-old male, with a history of arterial hypertension, was admitted to the infectious disease unit, due to severe respiratory failure symptoms compatible with COVID-19 bilateral pneumonia. The nasopharyngeal swab test was found positive for SARS-CoV-2 and the patient was treated with non-invasive ventilation due to respiratory distress. After 11 days, the patient became lethargic and showed negative upper limbs myoclonus and random, involuntary, and rapid vertical eye movements. Kidney and liver function biomarkers, serum electrolytes and ammonia were normal, head CT scan and toxicological examination resulted negative. Clinical evaluation (myoclonic positive and negative jerks, and altered mental status) was compatible with NCSE diagnosis, while EEG revealed generalized epileptic discharges with bilateral frontal high amplitude delta waves (Fig. 1). At first, intravenous Valproic Acid (2000 mg/24 h iv) and secondarily Levetiracetam infusion (3000 mg/24 h iv) were started but led to no clinical nor EEG improvement. Early diagnostic work-up was performed as follows: contrast-enhanced MRI—negative results; serum VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 53.9 mg/dL, glucose 104 mg/dL, 1 mononuclear white blood cell, CSF culture and PCR yielded negative results, as well as serum and CSF onconeural antibody and antineuronal surface antigens antibody. Given the lack of response to multiple antiepileptic drugs, a diagnosis of possible seronegative autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. After the first 5-day cycle, due to the scarce response (remission of myoclonic jerks and vigilance partial improvement), a second 5-day IVIG cycle was started with a progressive improvement of both clinical and EEG features (Fig. 1) without side effects. The patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.
Discussion
This report fosters the implementation of a rapid diagnostic work-up and use of IVIG as a promising therapy to safely and successfully treat possible autoimmune encephalitis-related NORSE triggered by SARS-CoV-2 infection. A rapid diagnosis and appropriate treatment are essential to avoid irreversible sequelae of autoimmune encephalitis-related NORSE. Neurological features may be common in COVID-19 patients, as reported in different studies, and some authors suggest to suspect SARS-CoV-2 infection when seeing patients with neurologic manifestations during the pandemic period [5, 6]. Indeed, evidence suggests a direct neuronal injury, as shown by increased serum neurofilament light chain (sNfL) levels, in critically ill COVID-19 patients compared to critically ill non-COVID-19 patients [7]. Although the exact pathophysiological mechanisms underlying the development of neurological syndromes are not completely appreciated, some explanatory mechanisms are currently debated, such as (1) a systemic inflammatory response, (2) a prothrombotic state, and (3) direct viral invasion [8]. Besides, the reported cases suggest that SARS-CoV-2 infection could trigger autoimmune responses, with a Central Nervous System (CNS) involvement. From a historical perspective, one century ago the “pandemic flu” was followed by an outbreak of encephalitis [9]. The negativity of PCR for other viruses on cerebrospinal fluid and the temporal association between SARS-CoV-2 infection and neurological symptoms suggests a possible causative role of COVID-19 in the development of the autoimmune response, thus resulting in NORSE.
Recently, some patients with autoimmune encephalitis associated with COVID-19 have been reported, in which irritability, confusion, drowsiness, and new-onset epilepsy account for the main symptoms at onset [1–3]. In our study, we reported two cases of encephalitis associated with NORSE rapidly assessed with EEG. The early EEG testing contributes to the rapid recognition of electric abnormalities, which may be common in COVID-19 patients [10, 11] also due to secondary causes, such as cerebrovascular events, electrolytes imbalance, oxidative stress, mitochondrial dysfunction, hypoxia, and prolonged inactivity [12–15]. Despite the fact that continuous EEG monitoring should be preferred, this study could rely only on daily spot EEG measurements due to the complexity of evaluation and testing in a COVID-19 area. Disturbances of background activity have been reported in most COVID-19 patients with seizures, such as generalized and focal slowing and a high level of epileptiform abnormalities and rhythmic or periodic discharges [10–12]. Additionally, the finding of slightly increased CSF protein concentration, without significant cells’ increase, supported the hypothesis of autoimmune mechanisms, although it may also reflect other non-autoimmune neurological diseases.
Our cases highlighted the importance of suspecting an autoimmune cause in NORSE patients positive to SARS-CoV-2 after excluding structural, infectious, metabolic, and toxic etiologies, and that IVIG treatment should be rapidly started to promote symptoms remission, while a complete autoimmune work-up needs to be set up as early as possible to confirm the diagnosis. Although the use of IVIG in NORSE is not supported by conclusive findings [16], the use of such therapy in possible encephalitis-related NORSE in COVID-19 patients suggested favorable results also in large cohorts of patients [3] and in COVID-19 patients affected by other autoimmune peripheral neurological syndromes (e.g., Guillain–Barré and Miller Fisher) [17–20]. The rapid and remarkable improvement of both our patients from resistant status epilepticus not responsive to different antiepileptic drugs is in line with the above-mentioned studies.
Conclusions
Autoimmune encephalitis may be a consequence of COVID-19 and it may result in NORSE. Although a causative relationship cannot be stated due to the retrospective nature of our study, initiating immunotherapy in case of suspected autoimmune etiology is desirable and a rapid diagnostic process should be encouraged (including EEG monitoring). Our findings support the use of IVIG therapy in NORSE COVID-19 patients with suspected autoimmune encephalitis to prevent negative outcomes, due to the time-dependent course of the disease.
Acknowledgements
The authors thank Matteo di Franza for English proof-reading and editorial assistance.
Funding
Open access funding provided by Università degli Studi di Trieste within the CRUI-CARE Agreement.. No funding was received for conducting this study.
Compliance with ethical standards
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in study were approved by the CEUR FVG ethical committee.
Informed consent
Informed consent was obtained from all individual participants included in the study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33709220 | 20,076,567 | 2021-10 |
What was the administration route of drug 'VALPROIC ACID'? | Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.
Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.
pmcIntroduction
Novel coronavirus disease (COVID-19) is mostly known to affect the respiratory system, potentially leading to severe acute respiratory failure. Yet, most patients with COVID-19 have also shown nonspecific neurological symptoms, such as confusion or headache, and some of them, particularly those with severe COVID-19-related respiratory failure, developed specific neurological manifestations, such as seizure or cerebrovascular events.
New-onset refractory status epilepticus (NORSE) may occur as a consequence of COVID-19. NORSE is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and without a clear acute or active structural, toxic or metabolic cause. The most frequently identified cause of NORSE is autoimmune encephalitis. Indeed, patients with refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr) encephalitis without lung involvement were recently reported in COVID-19 patients [1, 2], such as probable autoimmune encephalitis and encephalomyelitis [3]. NMDAr encephalitis represents the most frequent cause of autoimmune encephalitis and it may be triggered by viral infection, particularly Herpes Simplex Virus [4]. Early immune therapy (steroids, intravenous immunoglobulins, and plasma exchange) is recommended for autoimmune encephalitis-related NORSE treatment, since a delayed treatment may contribute to worse outcomes.
The aim of this report is to encourage a rapid diagnostic work-up and implementation of intravenous immunoglobulin (IVIG) therapy in possible COVID-19 autoimmune encephalitis-related NORSE. As such, we described two NORSE patients affected by COVID-19 who successfully responded to the IVIG, thus suggesting the basic autoimmune mechanisms in these COVID-19 epileptic statuses.
Materials and methods
This case series described two patients admitted to the hospital affected by bilateral pneumonia due to the novel Coronavirus 2019 (SARS-CoV-2) infection from March to December 2020 diagnosed by a positive nasopharyngeal swab test. Due to positivity for COVID-19, the patients were admitted to the COVID-19 protected areas of the University Hospital of Trieste. COVID-19 diagnosis was confirmed through nasopharyngeal swab testing. COVID-19 management included steroids (dexamethasone 6 mg/die for 10 days) to treat respiratory insufficiency, venous thromboembolism prophylaxis (enoxaparin 4000 IU), initial broad-spectrum antibiotics followed by specific antibiotics according to the antibiogram, artificial ventilation (case 1: orotracheal intubation; case 2: non-invasive ventilation; followed by, both cases: progressive low-flow oxygen therapy). None of the patients was in prone position. The patients presented (one at the admission and one after 11 days of hospitalization) clinical seizures or reduced vigilance and altered mental status, suggestive of a diagnosis of status epilepticus (SE). All the patients received neurological examination at symptoms development, electroencephalography (EEG), routine blood chemistry analyses, and a panel of diagnostic testing, including neuroimaging and biomarkers. Cerebrospinal fluid (CSF) was collected and processed for standard analyses including pressure, cell count, proteins, and glucose. CSF culture and polymerase chain reaction (PCR) for possible organisms, such as bacteria, Mycobacterium tuberculosis, fungi, Herpes viruses, Enteroviruses, Japanese B virus, and Dengue viruses was performed, including analysis for SARS-CoV-2. Serum and CSF were tested for onconeural antibody, as antiamphiphysin, antiCV2, antiMa2/TA, antiRI, antiYo, antiHu, antirecoverin, antiSox1, antitin, antiZic4, antiGAD65/67 (Anti-Glutamate Decarboxylase), antiTr, and antineuronal surface antigens antibodies, as antiNMDAr (N-methyl-d-aspartate receptor), antiVGKC (voltage gated potassium channel) complex LGI1 (leucine-rich glioma inactivated 1) and CASPR2 (Contactin-associated protein-like 2), antiAMPA1r (Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), antiAMPA2r, antiGABABr (Gamma-aminobutyric acid), antiDPPX (dipeptidyl-peptidase-like protein 6). Due to the lack of response to the antiepileptic drugs, all the patients were compatible with a possible autoimmune encephalitis-related NORSE diagnosis and they were treated with IVIG.
EEG acquisition and analysis
Thirteen channel 20-min standard clinical surface EEG was acquired by Be Plus PRO amplifier (EB NEURO, Florence, Italy) and 13 Ag/AgCl electrodes (F7, F3, F4, F8, C3, Cz, C4, T5, P3, P4, T6, O1, O2) placed according the standard 10–20 System. All electrode impedances were kept below 5 kΩ, and sampling rate was set to 256 Hz. EEG signals were filtered by second order band-pass Butterworth filter with 0.1–30 Hz cut-off frequencies. Brain oscillatory activities were assessed by qualitative visual inspection of EEG tracings by two experienced neurologists (P.M. and G.F.) to identify epileptiform patterns and altered EEG rhythms. Furthermore, power spectral density (PSD) was estimated on 120 s segments using Welch’s periodogram and absolute power for each of spectral band (δ: 1–4 Hz; θ: 4–8 Hz; α: 8–13 Hz; β: 13–30 Hz) was calculated and then normalized with a total power across the 1–30 Hz range to obtain relative powers. The physician and the technician wore personal protective equipment (PPE), including appropriate masks, face shields, gowns and gloves according to the American Association of Clinical Neurophysiology guidelines published on its official website (https://www.acns.org/practice/covid-19-resources).
Results
Case 1
A 37-year-old male, with an unremarkable medical history, was admitted to the Intensive Care Unit (ICU), due to convulsive status epilepticus. The nasopharyngeal swab test was found positive for SARS-CoV-2, while serum analysis, head CT scan and toxicological examination were negative. First line treatment and intravenous Levetiracetam infusion (3000 mg/24 h iv) were immediately started but led to no clinical improvement. EEG was performed within the first 24 h, revealing generalized SE (Fig. 1). Additional antiepileptic treatments including Valproic Acid (3000 mg/24 h iv), Phenytoin (18 mg/kg iv) and Lacosamide (400 mg iv in 24 h, increase to 600 mg in 24 h) were progressively administered after following examinations and concomitant to Propofol infusion without significant improvement. Subsequent EEG showed a generalized delta slowing; consequently, continuous infusion of Midazolam was added to Propofol to achieve burst suppression. After 24 h, Propofol was progressively reduced, but the patient suddenly developed generalized myoclonic jerks of axial muscles and face. Continuous EEG monitoring showed persistent generalized epileptic discharges compatible with non-convulsive status epilepticus (NCSE). Early diagnostic work-up was performed as follows: contrast-enhanced Magnetic Resonance Imaging (MRI)—negative results; serum HIV, VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 56.7 mg/dL, glucose 66.1 mg/dL, 1 mononuclear white blood cell, and CSF culture and PCR yielded negative results; serum and CSF onconeural antibody and antineuronal surface antigens antibody were found positive for anti amphiphysin antibody. Contrast-enhanced whole-body CT and testicular ultrasound suggested the absence of any neoplastic process. Given the lack of response to multiple antiepileptic drugs and third-line anesthetics drugs, a diagnosis of possible autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. The EEG showed a dramatic improvement on the fifth day of IVIG infusion, with complete clinical recovery without seizures and a complete normalization of EEG (Fig. 1). The patient was awake and without respiratory support. No side effects were reported for the use of intravenous immunoglobulin therapy. After a negative whole-body PET-CT, the neoplastic origin was excluded and the patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.Fig. 1 EEG raw data before IVIG therapy (pre)—left panel and after IVIG therapy (post)—right panel. EEG spectral analysis showed EEG relative powers indices pre—post modification; Case 1—pre: δ = 0.79, θ = 0.16, α = 0.03, β = 0.02; Case 1—post: δ = 0.17, θ = 0.15, α = 0.48, β = 0.20; Case 2—pre: δ = 0.55, θ = 0.31, α = 0.09, β = 0.05; Case 2—post: δ = 0.16, θ = 0.32, α = 0.41, β = 0.11
Case 2
A 71-year-old male, with a history of arterial hypertension, was admitted to the infectious disease unit, due to severe respiratory failure symptoms compatible with COVID-19 bilateral pneumonia. The nasopharyngeal swab test was found positive for SARS-CoV-2 and the patient was treated with non-invasive ventilation due to respiratory distress. After 11 days, the patient became lethargic and showed negative upper limbs myoclonus and random, involuntary, and rapid vertical eye movements. Kidney and liver function biomarkers, serum electrolytes and ammonia were normal, head CT scan and toxicological examination resulted negative. Clinical evaluation (myoclonic positive and negative jerks, and altered mental status) was compatible with NCSE diagnosis, while EEG revealed generalized epileptic discharges with bilateral frontal high amplitude delta waves (Fig. 1). At first, intravenous Valproic Acid (2000 mg/24 h iv) and secondarily Levetiracetam infusion (3000 mg/24 h iv) were started but led to no clinical nor EEG improvement. Early diagnostic work-up was performed as follows: contrast-enhanced MRI—negative results; serum VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 53.9 mg/dL, glucose 104 mg/dL, 1 mononuclear white blood cell, CSF culture and PCR yielded negative results, as well as serum and CSF onconeural antibody and antineuronal surface antigens antibody. Given the lack of response to multiple antiepileptic drugs, a diagnosis of possible seronegative autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. After the first 5-day cycle, due to the scarce response (remission of myoclonic jerks and vigilance partial improvement), a second 5-day IVIG cycle was started with a progressive improvement of both clinical and EEG features (Fig. 1) without side effects. The patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.
Discussion
This report fosters the implementation of a rapid diagnostic work-up and use of IVIG as a promising therapy to safely and successfully treat possible autoimmune encephalitis-related NORSE triggered by SARS-CoV-2 infection. A rapid diagnosis and appropriate treatment are essential to avoid irreversible sequelae of autoimmune encephalitis-related NORSE. Neurological features may be common in COVID-19 patients, as reported in different studies, and some authors suggest to suspect SARS-CoV-2 infection when seeing patients with neurologic manifestations during the pandemic period [5, 6]. Indeed, evidence suggests a direct neuronal injury, as shown by increased serum neurofilament light chain (sNfL) levels, in critically ill COVID-19 patients compared to critically ill non-COVID-19 patients [7]. Although the exact pathophysiological mechanisms underlying the development of neurological syndromes are not completely appreciated, some explanatory mechanisms are currently debated, such as (1) a systemic inflammatory response, (2) a prothrombotic state, and (3) direct viral invasion [8]. Besides, the reported cases suggest that SARS-CoV-2 infection could trigger autoimmune responses, with a Central Nervous System (CNS) involvement. From a historical perspective, one century ago the “pandemic flu” was followed by an outbreak of encephalitis [9]. The negativity of PCR for other viruses on cerebrospinal fluid and the temporal association between SARS-CoV-2 infection and neurological symptoms suggests a possible causative role of COVID-19 in the development of the autoimmune response, thus resulting in NORSE.
Recently, some patients with autoimmune encephalitis associated with COVID-19 have been reported, in which irritability, confusion, drowsiness, and new-onset epilepsy account for the main symptoms at onset [1–3]. In our study, we reported two cases of encephalitis associated with NORSE rapidly assessed with EEG. The early EEG testing contributes to the rapid recognition of electric abnormalities, which may be common in COVID-19 patients [10, 11] also due to secondary causes, such as cerebrovascular events, electrolytes imbalance, oxidative stress, mitochondrial dysfunction, hypoxia, and prolonged inactivity [12–15]. Despite the fact that continuous EEG monitoring should be preferred, this study could rely only on daily spot EEG measurements due to the complexity of evaluation and testing in a COVID-19 area. Disturbances of background activity have been reported in most COVID-19 patients with seizures, such as generalized and focal slowing and a high level of epileptiform abnormalities and rhythmic or periodic discharges [10–12]. Additionally, the finding of slightly increased CSF protein concentration, without significant cells’ increase, supported the hypothesis of autoimmune mechanisms, although it may also reflect other non-autoimmune neurological diseases.
Our cases highlighted the importance of suspecting an autoimmune cause in NORSE patients positive to SARS-CoV-2 after excluding structural, infectious, metabolic, and toxic etiologies, and that IVIG treatment should be rapidly started to promote symptoms remission, while a complete autoimmune work-up needs to be set up as early as possible to confirm the diagnosis. Although the use of IVIG in NORSE is not supported by conclusive findings [16], the use of such therapy in possible encephalitis-related NORSE in COVID-19 patients suggested favorable results also in large cohorts of patients [3] and in COVID-19 patients affected by other autoimmune peripheral neurological syndromes (e.g., Guillain–Barré and Miller Fisher) [17–20]. The rapid and remarkable improvement of both our patients from resistant status epilepticus not responsive to different antiepileptic drugs is in line with the above-mentioned studies.
Conclusions
Autoimmune encephalitis may be a consequence of COVID-19 and it may result in NORSE. Although a causative relationship cannot be stated due to the retrospective nature of our study, initiating immunotherapy in case of suspected autoimmune etiology is desirable and a rapid diagnostic process should be encouraged (including EEG monitoring). Our findings support the use of IVIG therapy in NORSE COVID-19 patients with suspected autoimmune encephalitis to prevent negative outcomes, due to the time-dependent course of the disease.
Acknowledgements
The authors thank Matteo di Franza for English proof-reading and editorial assistance.
Funding
Open access funding provided by Università degli Studi di Trieste within the CRUI-CARE Agreement.. No funding was received for conducting this study.
Compliance with ethical standards
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in study were approved by the CEUR FVG ethical committee.
Informed consent
Informed consent was obtained from all individual participants included in the study. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33709220 | 20,076,567 | 2021-10 |
What was the dosage of drug 'PHENYTOIN'? | Intravenous immunoglobulin response in new-onset refractory status epilepticus (NORSE) COVID-19 adult patients.
Neurological manifestations may be common in COVID-19 patients. They may include several syndromes, such as a suggested autoimmune abnormal response, which may result in encephalitis and new-onset refractory status epilepticus (NORSE). Quickly recognizing such cases and starting the most appropriate therapy is mandatory due to the related rapid worsening and bad outcomes. This case series describes two adult patients admitted to the university hospital and positive to novel coronavirus 2019 (SARS-CoV-2) infection who developed drug-resistant status epilepticus. Both patients underwent early electroencephalography (EEG) assessment, which showed a pathological EEG pattern characterized by general slowing, rhythmic activity and continuous epileptic paroxysmal activity. A suspected autoimmune etiology, potentially triggered by SARS-CoV-2 infection, encouraged a rapid work-up for a possible autoimmune encephalitis diagnosis. Therapeutic approach included the administration of 0.4 g/kg intravenous immunoglobulin, which resulted in a complete resolution of seizures after 5 and after 10 days, respectively, without adverse effects and followed by a normalization of the EEG patterns.
pmcIntroduction
Novel coronavirus disease (COVID-19) is mostly known to affect the respiratory system, potentially leading to severe acute respiratory failure. Yet, most patients with COVID-19 have also shown nonspecific neurological symptoms, such as confusion or headache, and some of them, particularly those with severe COVID-19-related respiratory failure, developed specific neurological manifestations, such as seizure or cerebrovascular events.
New-onset refractory status epilepticus (NORSE) may occur as a consequence of COVID-19. NORSE is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and without a clear acute or active structural, toxic or metabolic cause. The most frequently identified cause of NORSE is autoimmune encephalitis. Indeed, patients with refractory status epilepticus caused by anti N-methyl-D-aspartate receptor (NMDAr) encephalitis without lung involvement were recently reported in COVID-19 patients [1, 2], such as probable autoimmune encephalitis and encephalomyelitis [3]. NMDAr encephalitis represents the most frequent cause of autoimmune encephalitis and it may be triggered by viral infection, particularly Herpes Simplex Virus [4]. Early immune therapy (steroids, intravenous immunoglobulins, and plasma exchange) is recommended for autoimmune encephalitis-related NORSE treatment, since a delayed treatment may contribute to worse outcomes.
The aim of this report is to encourage a rapid diagnostic work-up and implementation of intravenous immunoglobulin (IVIG) therapy in possible COVID-19 autoimmune encephalitis-related NORSE. As such, we described two NORSE patients affected by COVID-19 who successfully responded to the IVIG, thus suggesting the basic autoimmune mechanisms in these COVID-19 epileptic statuses.
Materials and methods
This case series described two patients admitted to the hospital affected by bilateral pneumonia due to the novel Coronavirus 2019 (SARS-CoV-2) infection from March to December 2020 diagnosed by a positive nasopharyngeal swab test. Due to positivity for COVID-19, the patients were admitted to the COVID-19 protected areas of the University Hospital of Trieste. COVID-19 diagnosis was confirmed through nasopharyngeal swab testing. COVID-19 management included steroids (dexamethasone 6 mg/die for 10 days) to treat respiratory insufficiency, venous thromboembolism prophylaxis (enoxaparin 4000 IU), initial broad-spectrum antibiotics followed by specific antibiotics according to the antibiogram, artificial ventilation (case 1: orotracheal intubation; case 2: non-invasive ventilation; followed by, both cases: progressive low-flow oxygen therapy). None of the patients was in prone position. The patients presented (one at the admission and one after 11 days of hospitalization) clinical seizures or reduced vigilance and altered mental status, suggestive of a diagnosis of status epilepticus (SE). All the patients received neurological examination at symptoms development, electroencephalography (EEG), routine blood chemistry analyses, and a panel of diagnostic testing, including neuroimaging and biomarkers. Cerebrospinal fluid (CSF) was collected and processed for standard analyses including pressure, cell count, proteins, and glucose. CSF culture and polymerase chain reaction (PCR) for possible organisms, such as bacteria, Mycobacterium tuberculosis, fungi, Herpes viruses, Enteroviruses, Japanese B virus, and Dengue viruses was performed, including analysis for SARS-CoV-2. Serum and CSF were tested for onconeural antibody, as antiamphiphysin, antiCV2, antiMa2/TA, antiRI, antiYo, antiHu, antirecoverin, antiSox1, antitin, antiZic4, antiGAD65/67 (Anti-Glutamate Decarboxylase), antiTr, and antineuronal surface antigens antibodies, as antiNMDAr (N-methyl-d-aspartate receptor), antiVGKC (voltage gated potassium channel) complex LGI1 (leucine-rich glioma inactivated 1) and CASPR2 (Contactin-associated protein-like 2), antiAMPA1r (Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), antiAMPA2r, antiGABABr (Gamma-aminobutyric acid), antiDPPX (dipeptidyl-peptidase-like protein 6). Due to the lack of response to the antiepileptic drugs, all the patients were compatible with a possible autoimmune encephalitis-related NORSE diagnosis and they were treated with IVIG.
EEG acquisition and analysis
Thirteen channel 20-min standard clinical surface EEG was acquired by Be Plus PRO amplifier (EB NEURO, Florence, Italy) and 13 Ag/AgCl electrodes (F7, F3, F4, F8, C3, Cz, C4, T5, P3, P4, T6, O1, O2) placed according the standard 10–20 System. All electrode impedances were kept below 5 kΩ, and sampling rate was set to 256 Hz. EEG signals were filtered by second order band-pass Butterworth filter with 0.1–30 Hz cut-off frequencies. Brain oscillatory activities were assessed by qualitative visual inspection of EEG tracings by two experienced neurologists (P.M. and G.F.) to identify epileptiform patterns and altered EEG rhythms. Furthermore, power spectral density (PSD) was estimated on 120 s segments using Welch’s periodogram and absolute power for each of spectral band (δ: 1–4 Hz; θ: 4–8 Hz; α: 8–13 Hz; β: 13–30 Hz) was calculated and then normalized with a total power across the 1–30 Hz range to obtain relative powers. The physician and the technician wore personal protective equipment (PPE), including appropriate masks, face shields, gowns and gloves according to the American Association of Clinical Neurophysiology guidelines published on its official website (https://www.acns.org/practice/covid-19-resources).
Results
Case 1
A 37-year-old male, with an unremarkable medical history, was admitted to the Intensive Care Unit (ICU), due to convulsive status epilepticus. The nasopharyngeal swab test was found positive for SARS-CoV-2, while serum analysis, head CT scan and toxicological examination were negative. First line treatment and intravenous Levetiracetam infusion (3000 mg/24 h iv) were immediately started but led to no clinical improvement. EEG was performed within the first 24 h, revealing generalized SE (Fig. 1). Additional antiepileptic treatments including Valproic Acid (3000 mg/24 h iv), Phenytoin (18 mg/kg iv) and Lacosamide (400 mg iv in 24 h, increase to 600 mg in 24 h) were progressively administered after following examinations and concomitant to Propofol infusion without significant improvement. Subsequent EEG showed a generalized delta slowing; consequently, continuous infusion of Midazolam was added to Propofol to achieve burst suppression. After 24 h, Propofol was progressively reduced, but the patient suddenly developed generalized myoclonic jerks of axial muscles and face. Continuous EEG monitoring showed persistent generalized epileptic discharges compatible with non-convulsive status epilepticus (NCSE). Early diagnostic work-up was performed as follows: contrast-enhanced Magnetic Resonance Imaging (MRI)—negative results; serum HIV, VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 56.7 mg/dL, glucose 66.1 mg/dL, 1 mononuclear white blood cell, and CSF culture and PCR yielded negative results; serum and CSF onconeural antibody and antineuronal surface antigens antibody were found positive for anti amphiphysin antibody. Contrast-enhanced whole-body CT and testicular ultrasound suggested the absence of any neoplastic process. Given the lack of response to multiple antiepileptic drugs and third-line anesthetics drugs, a diagnosis of possible autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. The EEG showed a dramatic improvement on the fifth day of IVIG infusion, with complete clinical recovery without seizures and a complete normalization of EEG (Fig. 1). The patient was awake and without respiratory support. No side effects were reported for the use of intravenous immunoglobulin therapy. After a negative whole-body PET-CT, the neoplastic origin was excluded and the patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.Fig. 1 EEG raw data before IVIG therapy (pre)—left panel and after IVIG therapy (post)—right panel. EEG spectral analysis showed EEG relative powers indices pre—post modification; Case 1—pre: δ = 0.79, θ = 0.16, α = 0.03, β = 0.02; Case 1—post: δ = 0.17, θ = 0.15, α = 0.48, β = 0.20; Case 2—pre: δ = 0.55, θ = 0.31, α = 0.09, β = 0.05; Case 2—post: δ = 0.16, θ = 0.32, α = 0.41, β = 0.11
Case 2
A 71-year-old male, with a history of arterial hypertension, was admitted to the infectious disease unit, due to severe respiratory failure symptoms compatible with COVID-19 bilateral pneumonia. The nasopharyngeal swab test was found positive for SARS-CoV-2 and the patient was treated with non-invasive ventilation due to respiratory distress. After 11 days, the patient became lethargic and showed negative upper limbs myoclonus and random, involuntary, and rapid vertical eye movements. Kidney and liver function biomarkers, serum electrolytes and ammonia were normal, head CT scan and toxicological examination resulted negative. Clinical evaluation (myoclonic positive and negative jerks, and altered mental status) was compatible with NCSE diagnosis, while EEG revealed generalized epileptic discharges with bilateral frontal high amplitude delta waves (Fig. 1). At first, intravenous Valproic Acid (2000 mg/24 h iv) and secondarily Levetiracetam infusion (3000 mg/24 h iv) were started but led to no clinical nor EEG improvement. Early diagnostic work-up was performed as follows: contrast-enhanced MRI—negative results; serum VDRL and hepatitis virus panel—negative; CSF analysis—CSF protein concentration was 53.9 mg/dL, glucose 104 mg/dL, 1 mononuclear white blood cell, CSF culture and PCR yielded negative results, as well as serum and CSF onconeural antibody and antineuronal surface antigens antibody. Given the lack of response to multiple antiepileptic drugs, a diagnosis of possible seronegative autoimmune encephalitis-related NORSE was done. IVIG therapy was initiated at 0.4 g/kg for 5 days. After the first 5-day cycle, due to the scarce response (remission of myoclonic jerks and vigilance partial improvement), a second 5-day IVIG cycle was started with a progressive improvement of both clinical and EEG features (Fig. 1) without side effects. The patient was dismissed from the hospital without severe cognitive defects and with a partial decrease of antiepileptic drugs.
Discussion
This report fosters the implementation of a rapid diagnostic work-up and use of IVIG as a promising therapy to safely and successfully treat possible autoimmune encephalitis-related NORSE triggered by SARS-CoV-2 infection. A rapid diagnosis and appropriate treatment are essential to avoid irreversible sequelae of autoimmune encephalitis-related NORSE. Neurological features may be common in COVID-19 patients, as reported in different studies, and some authors suggest to suspect SARS-CoV-2 infection when seeing patients with neurologic manifestations during the pandemic period [5, 6]. Indeed, evidence suggests a direct neuronal injury, as shown by increased serum neurofilament light chain (sNfL) levels, in critically ill COVID-19 patients compared to critically ill non-COVID-19 patients [7]. Although the exact pathophysiological mechanisms underlying the development of neurological syndromes are not completely appreciated, some explanatory mechanisms are currently debated, such as (1) a systemic inflammatory response, (2) a prothrombotic state, and (3) direct viral invasion [8]. Besides, the reported cases suggest that SARS-CoV-2 infection could trigger autoimmune responses, with a Central Nervous System (CNS) involvement. From a historical perspective, one century ago the “pandemic flu” was followed by an outbreak of encephalitis [9]. The negativity of PCR for other viruses on cerebrospinal fluid and the temporal association between SARS-CoV-2 infection and neurological symptoms suggests a possible causative role of COVID-19 in the development of the autoimmune response, thus resulting in NORSE.
Recently, some patients with autoimmune encephalitis associated with COVID-19 have been reported, in which irritability, confusion, drowsiness, and new-onset epilepsy account for the main symptoms at onset [1–3]. In our study, we reported two cases of encephalitis associated with NORSE rapidly assessed with EEG. The early EEG testing contributes to the rapid recognition of electric abnormalities, which may be common in COVID-19 patients [10, 11] also due to secondary causes, such as cerebrovascular events, electrolytes imbalance, oxidative stress, mitochondrial dysfunction, hypoxia, and prolonged inactivity [12–15]. Despite the fact that continuous EEG monitoring should be preferred, this study could rely only on daily spot EEG measurements due to the complexity of evaluation and testing in a COVID-19 area. Disturbances of background activity have been reported in most COVID-19 patients with seizures, such as generalized and focal slowing and a high level of epileptiform abnormalities and rhythmic or periodic discharges [10–12]. Additionally, the finding of slightly increased CSF protein concentration, without significant cells’ increase, supported the hypothesis of autoimmune mechanisms, although it may also reflect other non-autoimmune neurological diseases.
Our cases highlighted the importance of suspecting an autoimmune cause in NORSE patients positive to SARS-CoV-2 after excluding structural, infectious, metabolic, and toxic etiologies, and that IVIG treatment should be rapidly started to promote symptoms remission, while a complete autoimmune work-up needs to be set up as early as possible to confirm the diagnosis. Although the use of IVIG in NORSE is not supported by conclusive findings [16], the use of such therapy in possible encephalitis-related NORSE in COVID-19 patients suggested favorable results also in large cohorts of patients [3] and in COVID-19 patients affected by other autoimmune peripheral neurological syndromes (e.g., Guillain–Barré and Miller Fisher) [17–20]. The rapid and remarkable improvement of both our patients from resistant status epilepticus not responsive to different antiepileptic drugs is in line with the above-mentioned studies.
Conclusions
Autoimmune encephalitis may be a consequence of COVID-19 and it may result in NORSE. Although a causative relationship cannot be stated due to the retrospective nature of our study, initiating immunotherapy in case of suspected autoimmune etiology is desirable and a rapid diagnostic process should be encouraged (including EEG monitoring). Our findings support the use of IVIG therapy in NORSE COVID-19 patients with suspected autoimmune encephalitis to prevent negative outcomes, due to the time-dependent course of the disease.
Acknowledgements
The authors thank Matteo di Franza for English proof-reading and editorial assistance.
Funding
Open access funding provided by Università degli Studi di Trieste within the CRUI-CARE Agreement.. No funding was received for conducting this study.
Compliance with ethical standards
Conflicts of interest
The authors have no conflicts of interest to declare.
Ethical approval
All procedures performed in study were approved by the CEUR FVG ethical committee.
Informed consent
Informed consent was obtained from all individual participants included in the study. | 18 MG/KG | DrugDosageText | CC BY | 33709220 | 20,076,567 | 2021-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Targeting FGFR in non-small cell lung cancer: implications from the landscape of clinically actionable aberrations of FGFR kinases.
OBJECTIVE
Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in diverse cancer types, including non-small cell lung cancer (NSCLC). The frequency of FGFR aberrations in Chinese NSCLC patients is therefore of great clinical significance.
METHODS
A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing were reviewed. Patients' clinical characteristics and treatment histories were also evaluated.
RESULTS
FGFR aberrations, including mutations, fusions, and gene amplifications, were detected in 1.9% (210/10,966) of the population. FGFR abnormalities were more frequently observed in lung squamous cell carcinomas (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9,596). FGFR oncogenic mutations were identified in 19 patients (~0.17%), of which, 68% were male lung squamous cell carcinoma patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus highlighting a potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in such patients. Furthermore, FGFR fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including 9 FGFR3-TACC3, 1 FGFR2-INA, 1 novel FGFR4-RAPGEFL1, and 1 novel fusion between the FGFR1 and SLC20A2 5'-untranslated regions, which may have caused FGFR1 overexpressions. Concomitant EGFR mutations or amplifications were observed in 6 patients, and 4 patients received anti-EGFR inhibitors, in whom FGFR fusions may have mediated resistance to anti-EGFR therapies. FGFR amplification was detected in 24 patients, with the majority being FGFR1 amplifications. Importantly, FGFR oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events.
CONCLUSIONS
We report the prevalence of FGFR anomalies in a large NSCLC population, including mutations, gene amplifications, and novel FGFR fusions.
Introduction
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays important roles in a variety of biological processes, including development, differentiation, cell proliferation, migration, angiogenesis, and carcinogenesis via several intracellular pathways, including the Ras/Raf/MEK and the phosphatidylinositol 3-kinase (PI3K)-AKT pathways1. The FGF family contains 22 members, which are usually divided into 7 subfamilies according to their sequence similarities, biochemical functions, and evolutionary relationships2. All 4 FGFRs, including FGFR1, FGFR2, FGFR3, and FGFR4 are structurally homologous to vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor (PDGFR), and other tyrosine kinase receptors3, and represent therapeutic targets of great potential.
Previous studies have shown that FGFR2/3 gene alterations, including FGFR3 activating mutations that affect either the extracellular (R248C and S249C) or transmembrane (G370C, S371C, Y373C, and G380R) domains of the protein, and gene fusions such as FGFR3-TACC3, are common in patients with urothelial carcinoma and cause constitutively activated FGF signaling, resulting in carcinogenesis4. Multiple FGFR inhibitors5, including erdafitinib6,7 have shown antitumor activities in preclinical models and in early phase clinical trials involving patients with FGFR alterations. A recent study by Loriot et al.8 reported that the use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic FGFR alteration-positive urothelial carcinomas. Such findings were superior to prior observations of an objective response rate of approximately 10% using second-line, single agent chemotherapy in an advanced urothelial carcinoma population9–11.
Activation of FGF signaling has also been described in lung cancer, including non-small cell lung cancer (NSCLC). As previously described, the incidence of FGFR alterations, particularly FGFR1 amplification, was higher in squamous cell carcinoma (SCC) of the lung than in adenocarcinoma12. Moreover, FGFR2 mutations were also reported in NSCLC patients, including the extracellular domain mutations, W290C and S320C, and the kinase domain mutation, K660E/N13. In this study, we investigated the landscape of FGFR aberrations in a large Chinese NSCLC population by comprehensive genomic profiling using next-generation sequencing (NGS), to identify potential therapeutic options for FGFR-mutated NSCLC patients.
Materials and methods
Patients
A total of 15,150 consecutive clinical lung cancer patients were analyzed using comprehensive genomic profiling targeting 400+ cancer-relevant genes, including all the exons of FGFR genes (FGFR1-4), as well as flanking intronic regions, and other introns selected by a Clinical Laboratory Improvement Amendments-certified, and College of American Pathologists-accredited laboratory (Nanjing Geneseeq Technology, Jiangsu, China), as previously described14. We identified patients with FGFR alterations using a natural language search tool in the laboratory information management system database. Relevant demographic and clinical data were extracted from the database, including age, gender, date of diagnosis, histology, pathological stage, and evaluation of treatment response based on reports by clinical investigators.
For tumor tissue samples, the pathological diagnosis and tumor content of each case was confirmed by pathologists. Peripheral blood (8–10 mL) was collected in EDTA-coated tubes (BD Biosciences, San Jose, CA, USA) and centrifuged at 1,800 × g for 10 min within 2 h of collection to isolate the plasma for circulating tumor DNA (ctDNA) extraction, and white blood cells for genomic DNA extraction as the germline control.
DNA extraction and targeted enrichment
The ctDNA from plasma was purified using a Circulating Nucleic Acid Kit (Qiagen, Hilden, Germany) following the manufacturer’s protocol. Genomic DNA from white blood cells was extracted using the DNeasy Blood and Tissue Kit (Qiagen), while genomic DNA from formalin-fixed paraffin-embedded (FFPE) samples was purified using the QIAamp DNA FFPE Tissue Kit (Qiagen). All DNA was quantified using the dsDNA HS Assay Kit using a Qubit Fluorometer (Life Technologies, Carlsbad, CA, USA). Sequencing libraries were prepared using the KAPA Hyper Prep Kit (Roche, Basel, Switzerland), as described previously14. Indexed DNA libraries were pooled for probe-based hybridization capture of the targeted gene regions covering over 400 cancer-related genes for all solid tumors; all of which contained all exons of FGFR genes and selected introns for the detection of FGFR fusions.
Sequencing data processing
Sequencing was performed using the Illumina HiSeq4000 platform (Illumina, San Diego, CA, USA), followed by data analysis as previously described15. In brief, sequencing data were analyzed by Trimmomatic16 to remove low quality (quality < 15) or n bases, and were then mapped to the human reference genome, hg19, using the Burrows-Wheeler Aligner (https://github.com/lh3/bwa/tree/master/bwakit). PCR duplicates were removed by Picard (https://broadinstitute.github.io/picard/). The Genome Analysis Toolkit (GATK) (https://software.broadinstitute.org/gatk/) was used to perform local realignments around indels and for base quality reassurance. Single nucleotide polymorphisms (SNPs) and indels were analyzed by VarScan217 and HaplotypeCaller/UnifiedGenotyper in GATK, with the mutant allele frequency cutoff at 0.5% for tissue samples, 0.1% for cfDNA samples, and a minimum of three unique mutant reads. Common SNPs were excluded if they were present in > 1% population frequency in the 1,000 Genomes Project or the Exome Aggregation Consortium (ExAC) 65,000 exome database. The resulting mutation list was further filtered using an in-house list of recurrent artifacts based on a normal pool of whole blood samples. Gene fusions were identified by FACTERA18.
Ethical approval
The study was approved by the Ethics Committee of Guangdong General Hospital, China (Approval No. GDREC2016262H). Shanghai Chest Hospital served as one of the hospitals participating in the research project. The study was conducted in accordance with the tenets of the Declaration of Helsinki, and written informed consent was collected from each patient prior to sample collection.
Results
The incidence of FGFR aberrations in NSCLC patients
From December 2016 to February 2019, a total of 15,150 individual clinical lung cancers were successfully evaluated by comprehensive genomic profiling using hybrid capture-based NGS. This work was based on the validated dataset for a total of 10,966 patients in our database system. Lung cancer tumor samples and liquid biopsies, if applicable, were compared to matched normal whole blood controls. A total of 87% of NSCLC samples examined were lung adenocarcinomas [lung adenocarcinoma (LUAC), n = 9,596], 9% were lung squamous cell carcinoma (LUSC, n = 954), and the remainder (4%) were of either mixed adenocarcinomas and squamous cell carcinomas or were missing sub-histological information in the database. Approximately 40% of the entire study population had only liquid biopsy specimens for genetic testing. A total of 210 patients (1.9%, 210/10,966) were identified with somatic aberrations of FGFRs (FGFR1–4), including mutations, gene rearrangements, and gene amplifications (Figure 1A). Fifty-one patients (roughly 24%) had liquid biopsy samples including only plasma and pleural effusion samples. The median age of the cohort was 62 years of age (range: 34–84 years of age). Approximately 72% (152/210) of the patients were male. Approximately 61% of FGFR-positive patients were LUAC (n = 128), 31% were LUSC (n = 65), and the remaining 7 cases were of either mixed or unknown histology. Thus, FGFR alterations were more frequent in LUSC patients (6.8%, 65/954) than in LUAC patients (1.3%, 128/9,596). The majority of the FGFR aberrations were gene mutations (75%) with gene amplification and gene rearrangements being observed in similar frequencies (10% and 15%, respectively) (Figure 1A). FGFR1 alterations were slightly more abundant than alterations in FGFR2-4 (Figure 1B). Notably, we observed more amplification events in FGFR1s than in other FGFRs, and over 90% of FGFR4 alterations were mutations (Figure 1C).
Figure 1 Distribution of FGFR aberrations in a large population of Chinese patients with non-small cell lung cancer. (A) The frequency of FGFR aberrations among all cases and (B) the relative proportion of FGFR aberrations of FGFR genes among all cases, with the breakdown of FGFR alterations (C). (D) Co-mutation plot showing patients who carried FGFR oncogenic mutations, fusions, and gene amplifications, as well as concomitant aberrations of genes, including EGFR, RAS, and components of the PI3K pathway. An additional 9 patients with FGF19 amplifications were also plotted. The asterisk indicates mutations or fusions in FGFRs other than FGFR3. The triangle indicates non-FGFR1 amplifications.
Enrichment of the activated PI3K pathway in the FGFR mutant cohort
We identified a total of 187 patients with somatic point mutations and indels in FGFRs. The most frequent amino acid replacements across all FGFRs were FGFR3 S249C and R248C (Supplementary Figure S1). In particular, 19 patients representing ∼0.17% (19/10,966) of the NSCLC population were identified with FGFR1-4 oncogenic or likely oncogenic mutations according to the OncoKB database19 (Figure 1D, Table 1, and Supplementary Table S1). The majority of these patients (68%, 13/19) had lung squamous cell carcinoma, and two-thirds were male. Intriguingly, more than half of the 19 patients (58%, 11/19) had co-occurring PIK3CA aberrations, including PIK3CA E545K (n = 3), E453K (n = 1), H1049R (n = 1), A1035T (n = 1), PIK3CA amplifications (n = 4), and PIK3R2 G373R (n = 1) mutations. One patient had a concurrent activating EGFR ex19del, 4 patients had KRAS G12D/V or Q61L mutations, and the remaining 6 patients had no other known driver mutations (Table 1). A majority of the 19 patients with FGFR1-4 oncogenic mutations (68%, 13/19) were systemic treatment-naïve, with the exception that 1 patient progressed on multiple lines of EGFR tyrosine kinase inhibitors 9TKIs0, including gefitinib, osimertinib, and afatinib, and 5 patients either received multiple lines of chemotherapy or chemotherapy in combination with radiotherapy or VEGFR antibody therapy (Table 1). Notably, the patient (P2) who received multiple EGFR TKIs likely acquired FGFR3 R248C and/or G380R to overcome the anti-tumor activity of TKIs, including osimertinib and afatinib, although pretreatment samples were unfortunately not available (Table 1).
Table 1 The demographical and clinicopathological characteristics of patients who had FGFR oncogenic mutations
ID Subtype Gender Age Stage Treatment history [TKI (PFS)] Gene AAChange AF Concurrent alteration AF_concurrent alt CNV Sample type
P1 LUSC M 56 NA Chemo, radiotherapy FGFR3 c.746C>G(p.S249C) 2.51% − − − Plasma
P2 LUAC F 52 IV Gefitinib (21 m), chemo plus VEGFR ab (4 m), osimertinib (5 m), afatinib (5 m) FGFR3 c.742C>T(p.R248C), c.1138G>A(p.G380R) 5.52%, 4.94% EGFR c.2240_2257delTAAGAGAAGCAACATCTC (p.L747_P753delinsS), EGFR T790M 4.3%, 1.3% − Plasma (post gefitinib)
P3 LUSC F 66 NA Surgery FGFR3 c.746C>G(p.S249C) 31.64% − − − FFPE
P4 LUSC M 67 NA Chemo FGFR3 c.746C>G(p.S249C) 33.33% PTEN p.K147Rfs*6, PIK3CA amplification 50% 1.7 FFPE
P5 LUSC M 66 IV Treatment-naïve FGFR3 c.746C>G(p.S249C) 36.85% PIK3CA amplification − 2.08 FFPE
P6 LUAC M 74 IV Treatment-naïve FGFR3 c.746C>G(p.S249C) 0.86% PIK3R2 c.1117G>A(p.G373R) 2.35% − Plasma
P7 LUSC F 67 NA Treatment-naïve FGFR3 c.746C>G(p.S249C) 17.34% PIK3CA c.1633G>A(p.E545K), c.2176G>A (p.E726K) 17.84%, 19.76% − FFPE
P8 LUSC F 50 NA Treatment-naïve FGFR3 c.742C>T(p.R248C) 0.67% − − − FFPE
P9 LUSC M 77 NA Treatment-naïve FGFR3 c.742C>T(p.R248C) 44.29% − − − FFPE
P10 LUAC M 78 IV Chemo, VEGFR antibody FGFR3 c.742C>T(p.R248C) 0.62% KRAS c.35G>A(p.G12D), HRAS c.38G>T (p.G13V), PIK3CA amplification 0.7%, 38.11% 1.9 FFPE
P11 LUAC M 57 NA Surgery FGFR3 c.746C>G(p.S249C) 1.42% KRAS c.35G>A(p.G12D), PIK3CA c.3103G>A(p.A1035T) 2.67%, 1.67% − FFPE
P12 LUSC F 59 NA Treatment-naïve FGFR3 c.1138G>A(p.G380R) 8.52% − − − Plasma
P13 LUSC M 55 NA Treatment-naïve FGFR3 c.746C>G(p.S249C) 15.18% PIK3CA c.1633G>A(p.E545K) 18.82% − FFPE
P14 LUSC M 61 NA Treatment-naïve FGFR3 c.1118A>G(p.Y373C) 87.37% PIK3CA c.1633G>A(p.E545K) 46.84% − FFPE
P55 LUSC M 65 NA Chemo FGFR2 c.1975A>G(p.K659E) 78.90% PIK3CA amplification − 3.63 FFPE
P56 LUSC M 71 IV Treatment-naïve FGFR2 c.1977G>C(p.K659N) 2.86% − − − FFPE
P57 LUSC M 74 NA Treatment-naïve FGFR2 c.1977G>C(p.K659N) 34.39% PIK3CA c.3145G>C(p.G1049R) 21.98% − Plasma
P58 LUAC F 64 NA Chemo FGFR2 c.868T>C(p.W290R) 17.12% KRAS c.35G>T(p.G12V) 19.49% − Plasma
P59 LUAC F 78 NA Treatment-naïve FGFR1 c.1638C>A(p.N546K) 3.15% NRAS c.35G>A(p.G12D), NRAS c.182A>T (p.Q61L), PIK3CA c.2702G>T(p.C901F), c.323G>A(p.R108H), c.1357G>A(p.E453K), PTEN p.Y16X 0.385%, 1.22%, 1.7%, 0.54%, 2.06%, 4.05% − FFPE
LUAC, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; NA, not available; AF, allele frequency; CNV, copy number variation.
The identification of novel FGFR fusions in NSCLC patients
FGFR fusions retaining the intact kinase domain were identified in 0.11% (12/10,966) of NSCLC patients examined (Figure 1D and Table 2). A majority of these patients (75%, 9/12) were positive for FGFR3-transforming acidic coiled-coil containing protein 3 gene (TACC3) fusions (FGFR3-TACC3), which were mostly reported in solid tumors20. Four of the 9 (45%) patients with FGFR3-TACC3 fusions had 5′ breakpoints in FGFR3 exon 17 and the remaining 55% were in exon 18, while TACC3 exons 10 and 11 were the most common 3′ breakpoint locations (Figure 2A). We observed 1 case of FGFR3 exon 17 fused to TACC3 exon 14 that may have resulted in a fusion protein with compromised dimerization capacity due to a truncated coiled-coil domain (Figure 2A).
Table 2 The demographical and clinicopathological characteristics of patients who carried FGFR fusions encoding intact kinase domains
ID Subtype Gender Age Stage Treatment history [TKI (PFS)] Gene Fusion AF Concurrent_alteration AF_concurrent alt CNV Pre-treatment concurrent alt Sample type
P15 LUAC M 44 IV Treatment-naïve FGFR1 SLC20A2:5’UTR∼FGFR1:5’UTR 3.44% − − − − Plasma
P16 LUAC F 65 IV Osimertinib (21 mo) FGFR2 FGFR2:exon17∼INA:exon2 16.07% EGFR p.746_750del, EGFR T790M, EGFR C797S 20.6%, 6.35%, 1.53% − EGFR p.746_750del, EGFR T790M Plasma (post osimertinib)
P17 LUSC M 54 IV Chemo, icotinib (7 mo), osimertinib (5 mo) FGFR3 FGFR3:exon18∼TACC3:exon10 1.70% EGFR p.746_750del, EGFR T790M, EGFR amplification 4.8%, 0.2% 1.82 EGFR p.746_750del Plasma (post osimertinib)
P18 LUSC M 57 II/III Treatment-naïve FGFR3 FGFR3:exon18∼TACC3:exon10 26.72% − − − − FFPE
P19 LUAC F 40 IV Treatment-naïve FGFR3 FGFR3:exon17∼TACC3:exon10 2.28% − − − − Plasma
P20 LUSC M 68 IV Treatment-naïve FGFR3 FGFR3:exon17∼TACC3:exon11 23.81% EGFR T790M 0.43% − − FFPE
P21 LUAC F 34 III Gefitinib (7 mo), osimertinib (10 mo) FGFR3 FGFR3:exon17∼TACC3:exon14 1.17% EGFR p.E746_A750del 6.52% − − Plasma (post osimertinib)
P22 LUAC M 44 IV Chemo, erlotinib (10 mo), osimertinib (10 mo), immunotherapy FGFR3 FGFR3:exon17∼TACC3:exon11 30.30% EGFR p.L747_P753delinsS, EGFR T790M, PIK3CA H1047R, EGFR amplification 80.5%, 2.83%, 29.37% 3.3 − Plasma (post erlotinib)
P23 LUAC M 38 IV Treatment-naïve FGFR3 FGFR3:exon18∼TACC3:exon11 2.74% − − − − Plasma&Tissue
P24 LUSC F 58 III Surgery FGFR3 FGFR3:exon18∼TACC3:exon8 7.12% − − − − FFPE
P25 LUSC M 68 NA Treatment-naïve FGFR3 FGFR3:exon18∼TACC3:exon11 1.38% − − − − Plasma
P26 LUAC F 48 IV Treatment-naïve FGFR4 FGFR4:exon17∼RAPGEFL1:exon4 4.04% EGFR p.L747_E749del 21.71% − − FFPE
LUAC, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; NA, not available; AF, allele frequency; CNV, copy number variation.
Figure 2 Visualization of FGFR fusions, including fusion partners, using the Integrative Genomics Viewer Browser. (A) The frequency of FGFR3-TACC3 fusions in the cohort. (B-D) The IGV screenshots display the reads from next generation sequencing and reveal FGFR fusions of (B) FGFR2-INA (F17:I2), (C) FGFR4-RAPGEFL1 (F17:R4), and (D) SLC20A1-FGFR1.
We also observed 1 gene rearrangement event involving FGFR2 and an internexin neuronal intermediate filament protein α gene (INA) fusion (FGFR2 F17: INA I2) in a patient (P16) with stage IV lung adenocarcinoma (Figure 2B). The FGFR2-INA fusion was previously reported in low grade gliomas that drove oncogenesis via MAPK and PI3K/mTOR pathway activation21. Our observations represented the first case of a FGFR2-INA fusion in NSCLC, in particular, lung adenocarcinoma. Furthermore, 1 gene fusion event involving fibroblast growth factor receptor 4 (FGFR4) and the Rap guanine nucleotide exchange factor like 1 gene (RAPGEFL1) (FGFR4 F17: RAPGEFL1 R4) was detected in a lung adenocarcinoma patient (P26) (Figure 2C), which has not been previously documented, and therefore further validation of its function is necessary in future research. Notably, a concurrent activating EGFR ex19del mutation was also detected at an allele frequency of 21.71% in this patient. In addition, we observed 1 patient with a 5′-untranslated region of the Solute Carrier Family 20 Member 2 gene (SLC20A2) fused to FGFR1 exon 17 (Figure 2D).
Of note, concomitant EGFR mutations or EGFR amplifications were observed in 6 of the 12 FGFR fusion patients (Table 2), 4 of which were previously treated with EGFR TKIs, but the disease had progressed prior to NGS tests. Although half the patients (n = 2) did not have pretreatment samples, the remaining 2 patients (P16 and P17) likely acquired FGFR fusions as alternative mechanisms to combat the anti-tumor activity of EGFR TKIs (Table 2). Furthermore, a concurrent PIK3CA H1047R mutation was observed in 1 patient (P22) and may also have acted as a mechanism of acquired resistance to prior therapies including TKIs (Table 2). No other known dominant driver mutations were detected in the remaining 6 patients (Table 2).
Amplification of the FGF19 and FGFR genes in NSCLC patients
As previously mentioned, we observed more amplification events in FGFR1 than other FGFRs (Figure 1B). FGFR amplification was detected in a total of 24 patients, a majority of which (87.5%, 21/24) were FGFR1 amplifications (Figure 1D). Similarly, the majority of FGFR-amplified patients (67%) were LUSC and 92% were male (Table 3). Notably, 25 patients (12%, 25/210) had multiple alterations in FGFR genes, but oncogenic FGFR mutations, fusions, or gene amplifications were almost mutually exclusive events, with the exception that 4 FGFR3-mutant patients had concurrent FGFR1 amplifications (Figure 1D). Two patients had concurrent EGFR activating mutations and received prior EGFR-TKI treatments. However, no pretreatment samples were available for mutation profiling for these patients. The remaining patients (92%, 22/24) had no other dominant driver mutations and were either chemotherapy-refractory or treatment naïve (Table 3).
Table 3 The demographical and clinicopathological characteristics of patients who had FGFR and FGF19 amplifications
ID Subtype Gender Age Stage Treatment history [TKI (PFS)] Gene CNV Concurrent alteration AF_concurr-ent alt Sample type
P27 LUAC F 48 IV Chemo, icotinib (quick PD), osimertinib FGFR4 1.72 − Plasma (post osimertinib)
P1 LUSC M 56 NA Surgery, chemo FGFR1 1.88 − Plasma
P28 LUAC M 73 NA Surgery, gefitinib (17 m), osimertinib (quick PD), afatinib (5 m) FGFR2 2.3 EGFR p.E746_S752delinsA, EGFR p. G724S, PIK3CA p.E545K 16.22%, 17.27%, 18.44% FFPE (post afatinib)
P29 LUAC M 62 IV Treatment-naïve FGFR1 1.78 − FFPE
P30 LUSC M 70 NA Treatment-naïve FGFR1 6.56 − FFPE
P31 LUAC M 62 NA Treatment-naïve FGFR1 1.71 − FFPE
P32 LUAC M 60 IV Treatment-naïve FGFR1 5.14 − FFPE
P33 LUSC M 52 NA Chemo, radiotherapy, anlotinib (PR) FGFR1 2.19 − Plasma
P34 LUSC M 52 NA Chemo, radiotherapy, anlotinib (PR) FGFR1 2.75 − FFPE
P35 LUSC M 60 NA Chemo, nivolumab (quick PD) FGFR3 2.08 − FFPE
P5 LUSC M 66 IV Treatment-naïve FGFR1 3.48 − FFPE
P36 LUSC M 53 NA Surgery, chemo FGFR1 2.45 − FFPE
P37 LUSC M 65 III Treatment-naïve FGFR1 2.55 − Tissue
P38 LUAC M 69 NA NA FGFR1 2.73 − FFPE
P39 LUSC M 73 NA Chemo FGFR1 4.15 − FFPE
P9 LUSC M 77 NA Treatment-naïve FGFR1 7.24 − FFPE
P10 LUAC M 78 IV Chemo, VEGFR mAb FGFR1 1.99 − FFPE
P40 LUAC F 48 IV Chemo, gefitinib (5 m, PD), osimertinib (10 m, PD) FGFR1; FGFR4 2.33; 2.51 EGFR p.E746_A750del, p. T790M, p. C797S 72.43%, 3.91%, 29.68% Pleural effusion (post osimertinib)
P41 LUSC M 70 NA Chemo FGFR1 3.51 − FFPE
P42 LUAC/SC M 72 NA Treatment-naïve FGFR1 1.93 − FFPE
P43 LUSC M 68 NA Treatment-naïve FGFR1 2.33 − FFPE
P44 LUSC M 55 NA Treatment-naïve FGFR1 2.06 PTEN p.L316NfsX4 60.41% Tissue
P45 LUSC M 68 NA Treatment-naïve FGFR1 2.09 PIK3CA p.D843Y, p.F1039L, p.M1043I, EGFR p.G796C 1.29%, 1.33%, 0.82%, 0.88% FFPE
P46 LUSC M 52 NA Treatment-naïve FGFR1 3.17 − FFPE
P47 LUSC M 62 II Chemo FGF19 1.77 − FFPE
P48 LUAC M 62 IV Treatment-naïve FGF19 1.91 − FFPE
P49 LUSC M 61 IV Chemo FGF19 3.02 − Plasma
P50 LUSC M 65 NA Chemo FGF19 8.34 PIK3CA amplification 3.63% FFPE
P51 LUAC F 84 NA Treatment-naïve FGF19 2.91 − Pleural effusion
P52 LUAC M 60 IV Treatment-naïve FGF19 12.88 − FFPE
P6 LUAC M 74 IV Treatment-naïve FGF19 6.99 PIK3R2, c.1117G>A(p.G373R) 2.35% Plasma
P53 LUAC M 73 NA Treatment-naïve FGF19 9.76 − FFPE
P54 LUSC M 68 NA Treatment-naïve FGF19 3.09 − FFPE
LUAC, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; TKI, tyrosine kinase inhibitor; PFS, progression-free survival; NA, not available; AF, allele frequency; CNV, copy number variation.
We also identified 9 patients (0.08%, 9/10,966) who had amplifications of FGF19 (Figure 1D), which encodes a unique, high affinity ligand that specifically binds to FGFR4 in a heparin-dependent manner. Our observations were consistent with previous studies reporting on the role of the FGF19-FGFR4 signaling axis in human cancers, including hepatocellular carcinoma22 and lung squamous cell carcinoma23. Two patients had concomitant aberrations of the PI3K signaling pathway, including PIK3CA amplification and the PIK3R2 G373R missense mutation (Table 3). All patients were either chemotherapy-refractory or treatment naïve.
Discussion
This study represented the first comprehensive survey of FGFR aberrations in a large population of Chinese patients with NSCLC. Approximately 1.9% of the population had FGFR aberrations, including point mutations, gene rearrangements, and amplifications, with the most common abnormality being FGFR point mutations. The prevalence of FGFR alterations in this Chinese NSCLC population was relatively lower than that of a prior study (5.7%), as reported by Helsten et al.24 in which the study population was unlikely to be only Chinese. Currently, there are a number of FGFR inhibitors approved by the Federal Drug Administration (FDA), including ponatinib, regorafenib, pazopanib, lenvatinib, and nintedanib, which were included in a trial specifically targeting NSCLC patients25. All these FGFR inhibitors are multi-kinase inhibitors that also exhibit nonspecific anti-tumor activities against other tyrosine kinases, including VEGFR, PDGFR, ROS1, and/or RET. However, there are also specific FGFR inhibitors in clinical development. Notably, erdafitinib, a functionally selective pan-FGFR inhibitor, has been approved by the FDA to treat advanced metastatic urothelial cancers6,8. Different FGFR abnormalities responded differently to erdafitinib, with the highest response rate seen for patients with FGFR point mutations8. Another selective FGFR inhibitor, pemigatinib, was also recently granted accelerated approval for treatment of late stage FGFR2+ cholangiocarcinoma patients26. It is definitely of great clinical interest to study these FGFR inhibitors in NSCLC patients, so future trials may be warranted.
Unlike lung adenocarcinomas, no targeted molecular therapies have been developed for squamous cell lung cancers because targetable oncogenic aberrations are scarce in this tumor type. Here, we report that FGFR aberrations were present in approximately 6.8% of the LUSC cohort of this study, which was higher than the frequency (1.3%) in LUAC patients. Notably, over 75% of FGFR1 amplification events were observed in LUSC patients, which is consistent with previous findings24,27. More than half of the patients who carried FGFR activating/transforming mutations had concurrent dominant mutations in PI3K pathway genes, including PIK3CA and PIK3R2, consistent with previous reports28–30. Furthermore, we reported the overlapping of activated FGFR genes and genetic alterations of the PI3K pathway in NSCLC, including both LUAC and LUSC. A prior study by Packer et al.31 revealed that PI3K inhibitors enhanced the anti-tumor efficacies of anti-FGFR inhibitors in vitro in endometrial cancers in which the activation of the PI3K pathway was observed in > 90% of FGFR2-mutated cases. The activation of the PI3K pathway was also reported to be enriched in breast cancer patients with activated FGFR/FGF signaling32. Together, our findings highlighted an intriguing molecular feature and potential therapeutic target for combination therapies targeting the FGFR and PI3K pathways in FGFR-positive NSCLC patients exhibiting activated PI3K and MAPK pathways.
Furthermore, we identified a total of 12 FGFR gene rearrangements in the NSCLC population that maintained intact FGFR kinase domains. FGFR fusions did not segregate well by histology or sex, as was previously reported by Wang et al.33 which was likely due to the restricted cohort size. The majority of these patients were FGFR3-TACC3 positive, but we also observed 1 case of a FGFR2-INA fusion that was originally described in gliomas, and 2 novel FGFR fusions, including SLC20A2-FGFR1 and FGFR4-GAPGEFL1. A prior study by Wu et al.34 reported a case of prostate cancer with the SLC45A3 non-coding exon 1 fused to the intact coding region of FGFR2, in which the SLC45A3-FGFR2 fusion was predicted to drive the overexpression of wildtype FGFR2. Thus, the SLC20A2-FGFR1 fusion observed in the current study may also have been able to drive the overexpression of wildtype FGFR1, although additional studies are needed to test this possibility. It is worth noting that half (n = 6) of the FGFR fusion patients carried EGFR aberrations, including EGFR ex19del, T790M, C797S, and EGFR amplifications. Two-thirds of those patients received prior EGFR TKI therapies. Reminiscent of a prior report by Ou et al.35, this observation suggested that FGFR fusions may act as a mechanism of acquired resistance to EGFR inhibitors in patients (P16, P17, P21, and P22) who were previously treated with EGFR TKIs.
Aside from point mutations and gene rearrangements, approximately 15% of all FGFR aberrations were amplifications, with FGFR1 amplifications being the most common anomalies. FGFR amplifications predominated in LUSC patients at a prevalence of 1.6%, in contrast to that of < 0.1% in the LUAC population. These frequencies were relatively lower than those reported by Helsten et al.24 (9% and 4%, respectively), which could be attributed to a number of reasons including the ethnic differences underlying these two study populations, the restricted NSCLC cohort size of Helsten et al., as well as the inclusion of cases who had only liquid biopsy ctDNA samples in this work.
Previous studies have shown that FGFR1 amplification was common in breast cancer patients with early relapses and poor clinical outcomes36. Therefore, antibodies targeting FGFR represent a valid therapeutic strategy to treat breast cancer or other cancer histologies, including NSCLC. In addition, we also observed a low frequency of FGF19 amplifications in our NSCLC population. FGF19 encodes the ligand for FGFR4, and it was previously shown that FGF19 amplifications corresponded with constitutive activation of FGF receptor 4 (FGFR4)-dependent ERK/AKT-p70S6K-S6 signaling activation in head and neck squamous carcinoma cells37; thus, raising the question as to whether the FGF19/FGFR4 axis also acts as an oncogenic driver in these NSCLC patients and represents a therapeutic target.
Conclusions
This study reported the frequency of FGFR aberrations, including activating mutations, gene rearrangements, and gene amplifications in a large population of Chinese NSCLC patients, and revealed the potential clinical utility of targeting FGFR aberrations with FGFR inhibitors in NSCLC patients. We also reported novel FGFR fusion events in NSCLC patients, including SLC20A2-FGFR1, FGFR2-INA, and FGFR4-GAPGEFL1; thus, highlighting potential therapeutic targets for the management of such patients.
Supporting Information
Click here for additional data file.
Acknowledgements
We thank the patients and their family members who provided consent to present their data in this study, as well as the investigators and research staff at all research sites involved. Sincere thanks to Dr. Ryan Lamers for his professional editing and proofreading of the manuscript.
Grant support
This work was supported by the National Key R&D Program of China (Grant No. 2016YFC1303800).
Conflict of interest statement Qiuxiang Ou, Xue Wu, and Yang Shao are employees of Geneseeq Technology Inc. Canada. Xiaonan Wang is an employee of Nanjing Geneseeq Technology Inc. China. The remaining authors have no conflicts of interest to declare. | ERLOTINIB, OSIMERTINIB | DrugsGivenReaction | CC BY | 33710807 | 20,964,792 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Long QT syndrome'. | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | ABIRATERONE ACETATE, LEUPROLIDE, LOSARTAN, METOPROLOL SUCCINATE | DrugsGivenReaction | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ventricular extrasystoles'. | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | ABIRATERONE ACETATE, LEUPROLIDE ACETATE, LOSARTAN, METOPROLOL SUCCINATE | DrugsGivenReaction | CC BY | 33711933 | 19,098,635 | 2021-03-12 |
What was the outcome of reaction 'Cardiomyopathy'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
What was the outcome of reaction 'Hypokalaemia'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
What was the outcome of reaction 'Hypomagnesaemia'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
What was the outcome of reaction 'Long QT syndrome'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
What was the outcome of reaction 'Torsade de pointes'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,896,834 | 2021-03-12 |
What was the outcome of reaction 'Ventricular extrasystoles'? | Syncope due to non-sustained episodes of Torsade de Pointes associated to androgen-deprivation therapy use: a case presentation.
Abiraterone is a medication frequently used for metastatic castrate-resistant prostate cancer. We report a case of non-sustained episodes of TdP associated with severe hypokalemia due to androgen-deprivation therapy. Few case presentations describe this association; the novelty lies in the potentially lethal cardiovascular events among cancer patients receiving hormonal therapy.
A 70-year-old male presented with recurrent syncope without prodrome. ECG revealed frequent ventricular ectopy, non-sustained episodes of TdP, and severe hypomagnesemia and hypokalemia. During potassium and magnesium infusion for repletion, the patient underwent temporary transvenous atrial pacing. As part of the work-up, coronary angiography revealed a mild coronary artery disease, and transthoracic echocardiogram showed a moderately depressed ejection fraction. After electrolyte disturbances were corrected, the QT interval normalized, and transvenous pacing was no longer necessary. Abiraterone was discontinued during the admission, and the patient returned to baseline.
Cancer treatment is complex and requires a multidisciplinary approach. We presented a case of non-sustained TdP associated with androgen-deprivation therapy in an elderly patient with mild coronary artery disease and moderately reduced ejection fraction. Close follow-up and increased awareness are required in patients with hormonal treatment, especially in the setting of other cardiovascular risk factors.
Background
The use of androgen deprivation therapy represents a milestone in treating both castrate sensitive and castrate-resistant metastatic prostate cancer [1–3]. Dual pharmacologic therapy with medications such as leuprolide and abiraterone acetate is directed towards minimizing testosterone levels and blocking the androgen receptors [4]. Abiraterone acetate plus prednisone has demonstrated a reduction in all-cause mortality compared to placebo in randomized controlled clinical trials [5].
As is the case with other cancer treatment types, such as chemotherapy, immunotherapy, and radiotherapy, androgen deprivation treatment is associated with cardiovascular complications [6, 7]. Abiraterone is usually associated with adverse metabolic effects as hyperglycemia, hyperlipidemia, and hypertension. The latter is related to a strong mineralocorticoid effect, which also produces hypokalemia [8]. To prevent this undesired effect prednisone is prescribed along with abiraterone acetate to reduce the incidence of hyperaldosteronism. Despite the use of prednisone, recent studies have reported an increased incidence of cardiovascular events in real-world patients receiving abiraterone acetate and leuprolide [9]. Furthermore, adverse events as ventricular tachycardia and acquired long QT syndrome-related to abiraterone are scarcely reported. In 2019, the Food and Drug Administration (FDA) published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; however, no official statement has been released [10].
We report a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with androgen-deprivation therapy.
Case presentation
A 70-year-old man with a past medical history of hyperlipidemia, hypertension, and castrate-resistant metastatic prostate cancer, presented to the emergency room with recurrent syncope episodes without prodrome, with some episodes occurring in the decubitus position. Medications included abiraterone acetate 1000 mg BID, monthly 7.5 mg injection of leuprolide, losartan 50 mg BID, and metoprolol succinate 12.5 mg QD. Of note, the patient was not receiving prednisone and did not report any chest pain, palpitations, dyspnea, or any other associated symptoms.
Physical exam was notable for a blood pressure of 148/92 mmHg, cardiac auscultation with irregular beats. Presentation ECG showed sinus rhythm with a QTc interval of 580 ms (calculated with Bazett’s formula), frequent premature ventricular beats, and short runs of non-sustained TdP. (Figs. 1, 2). Laboratory results showed severe hypokalemia 2.4 mEq/L (reference range 3.5–5.0 mEq/L), severe hypomagnesemia 0.8 mg/dl (Reference range 1.6–2.6 mg/dl), and preserved renal function (creatinine 0.6 mg/dL and blood urea nitrogen was 10 mg/dL) for an estimated GFR of 102/mL/min/1.73 m2 (calculated by CKD-EPI formula).Fig. 1 Non sustained TdP
Fig. 2 Sinus rhythm, with long QTc: 526 msg (calculated with Bazett’s formula)
The patient was admitted to the coronary care unit for continuous telemetry, electrolyte repletion, and temporary transvenous atrial pacing to suppress ectopy and prevent polymorphic ventricular tachycardia. Transthoracic echocardiogram showed a moderate depressed left ventricular ejection fraction of 38% with global hypokinesis (Fig. 3). Coronary angiography revealed mild lesions in the left anterior descending and the right coronary artery. The ventricular dysfunction was thought to be secondary to arrhythmia induced cardiomyopathy rather than the primary cause of the arrhythmia. After a thorough review of causes of hypokalemia (including medication review, metabolic alkalosis, and gastrointestinal losses), abiraterone acetate was suspected to be the cause and was suspended; this was particularly high on the differential given that the patient was not taking prednisone and the use of abiraterone acetate alone can result in a clinical picture similar to hyperaldosteronism. As potassium and magnesium levels normalized, the QTc interval shortened, the ventricular ectopy and runs of non-sustained episodes of TdP were entirely resolved. The patient was eventually transferred to the general ward and was later discharged after three days of being asymptomatic with no telemetry abnormalities.Fig. 3 a, b Transthoracic echocardiogram parasternal long axis view and apical 4 chamber view. c, d coronary artery angiography showed non-obstructive mild lesions in the left anterior descending artery and the right coronary artery
The patient stopped taking abiraterone acetate and no further electrolyte disturbances were presented, suggesting no underlying genetic abnormalities were the main cause of the arrythmia, such as is the case of Gitelman syndrome, which could have explained the severe hypokalemia and hypomagnesemia (least likely because of the absence of metabolic alkalosis and hypertension medical history).
Discussion and conclusions
Abiraterone inhibits androgen synthesis and is approved by the FDA for castrate-resistant prostate cancer [1, 2]. Cancer therapies are known to be associated with cardiovascular and other side effects [6]. In particular, abiraterone causes hypertension and hypokalemia in 32% and 20% of cases, respectively [5, 8]. However, cardiovascular severe adverse events like long QT and ventricular tachycardia are rarely reported [11, 12]. This cardiovascular event is probably due to the association between androgen deprivation and lower testosterone levels that result in iatrogenic Hypogonadism [13, 14]. A recent study found that testosterone plays an essential role in cardiac repolarization by altering repolarization currents (increasing the repolarizing currents IKr and IKs, and decreasing the depolarizing current ICaL) [15]. This iatrogenic Hypogonadism induced by medications such as abiraterone and leuprolide has been associated with long QTc and TdP [15], even to the point of suggesting androgen deprivation therapy as the second cause of drug-induced long QTc, particularly with abiraterone [16]. It is essential to highlight that leuprolide itself produces and reinforces this hypogonadism state, making an additive effect of these cardiovascular events when it is combined with abiraterone [15].
Androgen deprivation has been associated with cardiotoxicity, including QT prolongation [9, 17, 18]. In 2019, the FDA published a potential signal of serious risks about abiraterone and is currently evaluating the need for regulatory action; nonetheless, no official statement has been released yet [10]. In this setting, we present a case of acquired long QT syndrome complicated with non-sustained Torsades de Pointes ventricular tachycardia associated with severe hypokalemia and hypomagnesemia attributed to the use of abiraterone acetate without prednisone and was enhanced by the concomitant leuprolide use [15]. Furthermore, this acute episode resulted in arrhythmia induced cardiomyopathy that reverted after correction of electrolyte abnormalities and discontinuation of the offending agent. In this particular case, the patient presented with other conditions that are associated with abnormal repolarization and TdP, such as coronary heart disease, hypertension, leuprolide use, male gender and advanced age, suggesting that multiple QTc prolonging phenomena are needed to “hit”, before TdP is ensued [19, 20]. We believe that our case represents a heightened risk of acquired long QTc derived from abiraterone acetate and leuprolide use [15].
Despite having the highest risks due to these medications, the data about the use of abiraterone acetate in men older than 65-years-old is insufficient. Data about adverse events in these specific groups is even more limited because pivotal trials excluded patients with pre-existing cardiovascular disorders [5]. Limited evidence includes a cohort study performed between 1991 and 2013 to evaluate if patients with pre-existing cardiovascular disease, using abiraterone or enzalutamide had increased risk of hospitalization and all-cause mortality. In this study, there was an association between hypertension and the use of abiraterone acetate and higher hospitalization rates [18].
More recently, in 2012, a single-arm open clinical trial of 33 patients taking abiraterone evaluated ECG changes during the first two days of use, finding no significant association with QT prolongation [21]; nevertheless, this is a limited study due to trial design, small sample size, and poor ECG follow-up, limiting the ability to conclude. In 2016 a retrospective analysis of abiraterone use in patients with pre-existing cardiovascular conditions concluded that there was no worsening of cardiovascular diseases, and cardiovascular events more frequently reported were fluid overload and hypertension, without reports of arrhythmias during the follow-up [22]. However, this study also presents limitations mainly related to its retrospective nature. In contrast to the previous two studies, a meta-analysis suggests an increased risk in the pooled occurrence of ischaemic heart disease, myocardial infarction, supraventricular tachyarrhythmias, ventricular tachyarrhythmias, heart failure associated with abiraterone acetate [23]. Finally, there are anecdotal reports of abiraterone acetate resulting in QT prolongation and life-threatening ventricular arrhythmias, similar to our case [11, 12]. Nonetheless, all the studies mentioned above have significant limitations, and further research is required.
Increased follow-up and awareness are required in patients with androgen deprivation therapy to evaluate the presence of QT prolongation and ventricular arrhythmias arising from electrolyte disorders.
Abbreviations
TdP Torsade de Pointes
ECG Electrocardiogram
QTc QT interval corrected for heart rate
FDA Food and Drug Administration
BID bis in die (which means, in Latin, twice a day)
QD quaque die (which means, in Latin, every day/daily
Not applicable.
Authors' contributions
XM collected the data, reviewed the literature, drafted the manuscript contributed to data interpretation, DG reviewed the literature, contributed to data interpretation, and the conception and design of the manuscript, DI extensively revised the manuscript and took care of the patient, NI contributed to data interpretation, FDT extensively revised the manuscript and contributed to data interpretation. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and materials
Data sharing does not apply to this article as no datasets were generated or analyzed during the current study.
Declarations
Competing interests
All authors declare that they have no competing interests.
Consent for publication
The patient gave written consent for clinical and personal details along with any identifying images to be published in this manuscript.
Ethics approval and consent to participate
Not applicable.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ximena Morales and Diego Garnica have contributed equally to this work. | Recovered | ReactionOutcome | CC BY | 33711933 | 19,098,635 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | EPIRUBICIN HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | EPIRUBICIN HYDROCHLORIDE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
What was the administration route of drug 'EPIRUBICIN HYDROCHLORIDE'? | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intra-arterial | DrugAdministrationRoute | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intra-arterial | DrugAdministrationRoute | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 50 ML | DrugDosageText | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
What was the outcome of reaction 'Kounis syndrome'? | Epirubicin-induced Kounis syndrome.
Kounis syndrome is an acute coronary syndrome that appears in the setting of anaphylactic reaction or hypersensitivity. Many drugs and environmental exposures have been identified as potential offenders, and diagnosis and treatment can be challenging.
A 62-year-old man with recurrent bladder cancer underwent an intra-iliac artery epirubicin injection. After the injection, he developed chest pain and a systemic allergic reaction, with electrocardiographic alterations and elevated troponin-I levels. Emergent coronary angiography showed right coronary artery spasm and no stenosis of the other coronary arteries. This reaction was considered compatible with an allergic coronary vasospasm. A diagnosis of Kounis syndrome was made.
Kounis syndrome is common, but a prompt diagnosis is often not possible. This case is the first to suggest that an intraarterial epirubicin injection could potentially be one of its triggers. All physicians should be aware of the pathophysiology of this condition to better recognize it and start appropriate treatment; this will prevent aggravation of the vasospastic cardiac attacks and yield a better outcome.
Background
The simultaneous occurrence of acute coronary syndrome with hypersensitivity reactions is named Kounis syndrome [1]. In 1950, Pfister first reported myocardial infarction and urticaria after penicillin treatment [2]. In 1991, Kounis and Zavras introduced the notion and pathophysiology of vasospastic angina and myocardial infarction related to allergies [3]. This entity was redefined as “acute coronary syndrome related to platelet and mast-cell activation in the course of hypersensitivity and allergic or anaphylactic events” [1]. It is triggered by inflammatory mediators, including histamine, neutral proteases, arachidonic acid products, platelet-activating factor, and a variety of cytokines and chemokines released following hypersensitivity and allergic activation [4]. These mediators can cause coronary vasospasm or atheromatous plaque erosion or rupture or even coronary thrombosis, resulting in myocardial infarction [5]. This syndrome is associated with serious morbidity and mortality, as it could be complicated by cardiac arrest or even death [6]. Although it is rarely reported, it is imperative to understand that Kounis syndrome is usually underdiagnosed [7].
Here, we report the first case of Kounis syndrome induced by an intra-iliac artery epirubicin injection in a bladder cancer patient.
Case presentation
A 62-year-old man with recurrent bladder cancer was scheduled for intra-iliac artery chemotherapy. He was a smoker for more than 30 years and had a 10-year history of hypertension. No allergies were reported. There was no coronary artery disease in his family history. The preoperative echocardiogram showed no abnormalities and normal left ventricular ejection fraction. A percutaneous catheter system was set in the bilateral internal iliac arteries distal to the superior gluteal arteries by applying a modified Seldinger technique. During the operation, epirubicin (50 mg/m2) was dissolved in 50 ml of saline solution and then administered over 10 min. After injection, the patient suddenly developed severe dyspnea, chest pain, a red itchy rash on his face, subcutaneous edema, palpitation, diaphoresis and nausea. He progressively became hypotensive and eventually developed shock, and his blood pressure nadired at 52/48 mmHg. Corticosteroids and norepinephrine were administered for his allergic reaction. In addition, fluid resuscitation with 3L of crystalloids and boluses of dopamine was performed to keep the blood pressure at normal values. The first electrocardiogram (ECG) showed ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, aVL, and V1–V5 (Fig. 1). The patient was taken to the cardiac catheter laboratory for emergent angiography, which revealed 90% stenosis in the proximal segment of the right coronary artery (RCA); the remaining coronary vessels were normal. The RCA stenosis was relieved after administration of 200ug intracoronary nitroglycerin (Fig. 2). The ECG after angiography showed recovery of the ST elevation in the inferior leads (Fig. 3). The patient’s symptoms immediately resolved after coronary angiography, and his vitals stabilized.Fig. 1 Electrocardiogram (ECG) at presentation: ST segment elevation of 3 mm in leads II, III and aVF and ST depression in leads I, and aVL, V1–V5
Fig. 2 Coronary angiography: a Left main coronary artery (LMCA) reveals no significant disease; b left anterior descending branch coronary artery (LAD) and left circumflex coronary artery (LCX) showing no significant disease; c Observation of the right coronary artery (RCA) showing 90% stenosis in the proximal segment; d The stenosis of RCA was relieved after the intracoronary administration of nitrates
Fig. 3 Electrocardiogram (ECG) after angiography: ST segment recovery
The patient was monitored in the cardiac intensive care unit (CCU). His vital signs stabilized (temperature 37.1 °C, blood pressure 107/71 mmHg, heart rate 93 bpm, respiratory rate 22 breaths per minute). His initial ECG in the CCU showed normal sinus rhythm. Serial troponin-I monitoring showed a normal level (normal range 0.01–0.023 ng/mL) at the time of symptom onset, 0.056 ng/mL 5 h after onset, and a peak of 0.113 ng/mL at the 10th hour. The patient was treated with anti-ischemic treatment, including antiplatelet therapy (clopidogrel 75 mg), and nitrates were initiated after the coronary angiogram. During hospitalization, the patient remained free of chest pain, and he did not show any chest pain or systemic reactions again during the follow-up.
Discussion and conclusion
Kounis syndrome, also called allergic angina, is caused by an anaphylactic or anaphylactoid insult. Acute coronary syndrome in Kounis syndrome may manifest as coronary spasm, acute myocardial infarction, or stent thrombosis [8]. A recent large epidemiological study in the USA demonstrated that the prevalence of Kounis syndrome was 1.1%, with a subsequent inpatient all-cause mortality rate of 7.0%. Compared to the non-Kounis acute coronary syndrome group, the Kounis syndrome group was older and had more males, more Caucasian patients, a longer duration of hospitalization and higher hospitalization charges. The rates of arrhythmias, cerebrovascular events and venous thromboembolisms were obviously higher in the Kounis syndrome group than in the non-Kounis syndrome group [9]. Any substance, disease entity or environmental exposure might be the causes of Kounis syndrome. Antibiotic and insect bites represent the most common triggers (27.4% and 23.4% respectively) [6]. Moreover, carboplatin [10], contrast media [11], isotretinoin [12], latex [13], and cobra bites [14] have also been identified as offenders. Therefore, an in-depth patient clinical history is mandatory for diagnosing Kounis syndrome. Laboratory (cardiac biomarkers, serum histamine, eosinophils or immunoglobulin E), electrocardiographic, echocardiographic and angiographic findings are valuable diagnostic tools [6].
Kounis syndrome is divided into three subtypes according to the condition of the coronary arteries: type 1, with normal vessels, where endothelial dysfunction causes allergic vasospastic angina; type 2, with preexisting coronary atheroma, where allergic reaction could lead to myocardial infarction (allergic myocardial infarction); and type 3, with previously treated coronary thrombosis, where recurrent thrombosis may occur. Kounis syndrome type 1 represents the vast majority of cases, with a good response to pharmacological therapy [6]. The clinical manifestations of Kounis syndrome may appear as hypersensitivities or allergic reactions in the early stage, followed by cardiac symptoms such as acute chest pain, palpitations, and dyspnea. Chest pain occurs in 86.8% of patients and represents the most common cardiac manifestation. Anaphylactic symptoms can emerge in approximately 53.0% of patients, however, 40% of patients with perioperative Kounis syndrome may not have an initial anaphylactic reaction [6, 15]. In Kounis type 1, approximately 2.3% of patients may develop shock [6].
There are no large, randomized data to guide the treatment of allergic angina pectoris, as most of the knowledge is based on individual cases reports. Nonetheless, the optimal clinical management of Kounis syndrome not only requires rapid diagnosis and decision-making but also depends on the syndrome subtype [1]. Treating Kounis syndrome patients according to a cardiovascular emergency therapeutic protocol might not be effective [16]. First, it is imperative to remove the potential allergen if feasible, and then the use of fluid resuscitation is particularly important in cases of anaphylactic shock. One should refrain from using medications that could exaggerate anaphylaxis and hypotension. For example, although vasospasm is commonly treated with vasodilators such as nitrates or calcium channel blockers, in Kounis syndrome, they may exacerbate hypotension [1]. Opiates such as morphine are very effective in managing acute coronary syndrome pain, but they have to be used cautiously in patients with Kounis syndrome, as they have been associated with mastocyte activation and worsening allergic symptoms [17]. One should also take into account the cardiac toxicities of the medication used to treat allergic reactions. For example, while intramuscular epinephrine is the key treatment for anaphylaxis, it may aggravate coronary spasm and ischemia or cause arrhythmias and QTc interval prolongation [18, 19].
This case represents a typical Kounis syndrome type 1 patient, characterized by coronary spasm in normal or nearly normal coronary arteries without predisposing factors for coronary artery disease. The vasospastic angina was likely induced by the rapid release of allergic mediators after epirubicin injection. Intra-iliac artery chemotherapy represents an important therapeutic modality for preventing recurrence and the growth of non-muscle invasive bladder carcinoma [20]. Epirubicin, a doxorubicin derivative, is rarely reported to be an allergen or cardiac toxicity [21]. To date, epirubicin had never been reported as a trigger for Kounis syndrome or any allergic reactions of the cardiovascular system. Anaphylaxis to gemcitabine [22] and cisplatin [23] has been reported, including acute myocardial infarction in Kounis syndrome. All anticancer drugs are able to induce allergic reactions and cardiohypersensitivity; consequently, the incidence of cardiovascular complications associated with cancer therapy is increasing and the treatment of malignant and cardiovascular diseases has become closely associated [24]. The need to incorporate several tests, measures, and evaluations before, during and long after chemotherapy to monitor for cardiac adverse events should be emphasized. It is critical to foster collaboration between cardiologists, oncologists, immunologists, pathologists, allergists and other medical professionals associated with cancer to optimize the management of patients with Kounis syndrome and to avoid delaying cancer therapy.
Regardless of the allergenic substances involved or the effective anti-allergic treatment administered, the early diagnosis for this patient was mainly clinical and mostly based on signs and symptoms that indicated allergy and myocardial ischemia after being exposed to the therapeutic modality. Furthermore, the coronary angiogram results showed that severe spasm of the RCA was quite paradigmatic. In addition, it has been reported that vasospasm affects mainly the right coronary artery in Kounis syndrome for no reason. [25].
In summary, Kounis syndrome, or “allergic angina syndrome”, is a rare but likely underdiagnosed entity [1]. Intra-arterial epirubicin injection could be an allergen associated with Kounis syndrome. Hypotension and shock in Kounis syndrome should be managed by treating both the anaphylaxis and the coronary etiology. It is a real challenge for physicians to recognize this syndrome early and to start adequate treatment, which may be needed to avoid fatal complications and improve outcomes.
Abbreviations
ECG Electrocardiogram.
CCU Cardiac intensive care unit
Acknowledgements
Not applicable.
Authors’ contributions
LHZ observed the manifestations of Kounis syndrome in this patient and contributed to writing the manuscript. ZH and CCF used coronary angiography for the patient and analyzed the angiography data. GJ performed intra iliac artery chemotherapy for the patient. WW was the corresponding author. All authors read and approved the final manuscript.
Funding
This work was supported by The National Natural Science Foundation of China (No. 81800316).
Availability of data and materials
All relevant data supporting the conclusions of this article are included within the article.
Declarations
Ethics approval and consent to participate
The study was approved by the ethics committee of Peking University People’s Hospital, the patient had written consent to participate in the study.
Consent for publication
Written informed consent for publication was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33711934 | 19,074,491 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Actinomycosis'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE | DrugsGivenReaction | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute graft versus host disease in skin'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal insufficiency'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE | DrugsGivenReaction | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthritis'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Arthropathy'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE | DrugsGivenReaction | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchiolitis'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 18,668,075 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective for unapproved indication'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE | DrugsGivenReaction | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ill-defined disorder'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Impaired quality of life'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Juvenile idiopathic arthritis'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Lung disorder'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary function test abnormal'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steroid dependence'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, INDOMETHACIN, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Still^s disease'. | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ACYCLOVIR, ADALIMUMAB, ALEMTUZUMAB, ANAKINRA, BUSULFAN, CANAKINUMAB, CYCLOPHOSPHAMIDE, CYCLOSPORINE, FLUDARABINE PHOSPHATE, HYDROCORTISONE, INDOMETHACIN, INDOMETHACIN SODIUM, INFLIXIMAB, METHOTREXATE, METHYLPREDNISOLONE, MYCOPHENOLATE MOFETIL, PREDNISOLONE, PROPICILLIN POTASSIUM, RITUXIMAB, THALIDOMIDE, TOCILIZUMAB | DrugsGivenReaction | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What is the weight of the patient? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 16 kg. | Weight | CC BY | 33712044 | 18,668,075 | 2021-03-12 |
What was the administration route of drug 'INFLIXIMAB'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
What was the dosage of drug 'HYDROCORTISONE'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 12.5 MG/M2, QD | DrugDosageText | CC BY | 33712044 | 19,102,136 | 2021-03-12 |
What was the dosage of drug 'INDOMETHACIN SODIUM'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 25 MG/M2, QD | DrugDosageText | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | PULSE THERAPY | DrugDosageText | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
What was the dosage of drug 'TOCILIZUMAB'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 50 MG, QD | DrugDosageText | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the outcome of reaction 'Actinomycosis'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
What was the outcome of reaction 'Acute graft versus host disease in skin'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
What was the outcome of reaction 'Adrenal insufficiency'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,154,451 | 2021-03-12 |
What was the outcome of reaction 'Aplasia'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the outcome of reaction 'Bronchiolitis'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 18,668,075 | 2021-03-12 |
What was the outcome of reaction 'Clostridium difficile colitis'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,102,136 | 2021-03-12 |
What was the outcome of reaction 'Graft versus host disease in gastrointestinal tract'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 20,229,144 | 2021-03-12 |
What was the outcome of reaction 'Growth retardation'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the outcome of reaction 'Infection reactivation'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33712044 | 19,102,136 | 2021-03-12 |
What was the outcome of reaction 'Infection'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 20,229,144 | 2021-03-12 |
What was the outcome of reaction 'Joint effusion'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the outcome of reaction 'Lung disorder'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,100,589 | 2021-03-12 |
What was the outcome of reaction 'Obliterative bronchiolitis'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,102,136 | 2021-03-12 |
What was the outcome of reaction 'Pulmonary function test abnormal'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
What was the outcome of reaction 'Still^s disease'? | Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis.
BACKGROUND
Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high.
METHODS
A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs.
CONCLUSIONS
Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
Background
Systemic juvenile idiopathic arthritis (SJIA), as well as Adult Onset Still’s disease, are rare diseases of unknown origin characterized by the association of autoinflammatory features, a risk of macrophage activation syndrome and, in most cases, erosive polyarthritis [1]. Over the last 15 years, new treatments, particularly interleukin (IL)-1 and − 6 inhibitors have shown efficacy to control SJIA activity in most patients thereby avoiding long-lasting steroid-dependency [2–5]. However, some patients do not respond well to biologic treatments and may develop life-threatening complications, including severe lung disease [6, 7]. Intensive immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) enabled difficult-to-treat patients to achieve steroid-free remission [8, 9]. However, some patients developed severe complications including infection-induced macrophage activation syndrome, and a disease flare occurred in most cases within the following years [10–12]. More recently, a few patients were successfully treated by intensive immunosuppression followed by allogenic HSCT with an Human Leucocyte Antigen (HLA)-identical or HLA-matched unrelated donor for SJIA [13] or for severe autoimmune disease [14, 15]. Here, we report a three-year-old girl who was successfully treated with haplo-identical allogenic HSCT.
Case description
The patient, a girl, is the second child from third degree consanguineous parents. Her older brother is healthy. Besides a vitiligo in the mother, there was no significant family history. At the age of 15 months she developed typical SJIA features including marked, spiking fever, skin rash, polyarthritis of the hips, knees, ankles, elbows, wrists, metacarpo-phalangeal and proximal interphalangeal joints. Assessment for differential diagnoses, including large infectious screening was negative. A diagnosis of SJIA was made. The association of consanguinity, early-onset and severity of the disease suggested an inherited predisposition, but genetic analyzes including whole exome sequencing in the child and her parents did not reveal any validated genetic variant.
At diagnosis, the child received pulsed methylprednisolone followed by daily prednisolone (2 mg/kg per day) in association with indomethacin. Each time prednisolone was gradually tapered to a daily dose of 1 mg/kg, the disease flared. Combination therapy with methotrexate and tocilizumab, then anakinra, canakinumab and adalimumab did not significantly reduce steroid-dependency. Also, an association of methotrexate, thalidomide and infliximab failed to diminish the daily prednisolone dose below 1 mg/kg. Growth retardation, systemic hypertension, osteopenia, and polyarticular erosions (Fig. 1) developed over the following 2 years. Fig. 1 Conditioning regimen. Shows the patient’s conditioning regimen prior to HSCT. BU: Busulfan. Ri: Rituximab. Al: Alemtuzumab. Flu: Fludarabine. CY: Cyclophosphamide. HSCT: hematopoietic stem cell transplantation
As the patient had severely impaired quality of life as well as treatment related toxicity due to the high dose steroid dependency, there was a clear indication to seek for other treatment options. Allogenic HSCT was considered. In the absence of any possible HLA matched donor, a multidisciplinary team assessed risks and benefits of an alternative graft procedure. Given the high disease burden and treatment related toxicity, the indication for a haploidentical HSCT from her mother was validated. Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
At conditioning regimen onset, the child was 3.7 years old. Her weight was 15.6 kg (+ 0.8 SD) for a size of 92.5 cm (− 1.1 SD). She had a cushingoid appearance, arterial hypertension, persistent active painful arthritis of both knees, ankles, wrists and fingers, persistent biologic inflammation with elevated ESR and CRP. Ongoing treatment by methotrexate (5 mg/week), thalidomide (50 mg/day), indomethacin (25 mg/day), and infliximab (75 mg/4 weeks) was stopped shortly before initiating the conditioning regimen. Prednisolone, administered at 1 mg/kg/day prior to conditioning, was gradually tapered and ultimately stopped during the conditioning regimen.
The conditioning regimen (Fig. 1) consisted of rituximab (375 mg/m2), alemtuzumab (0.5 mg/kg), fludarabine (160 mg/m2), and busulfan with an AUC of 25,638 microM/min. Prophylaxis against graft-versus-host disease (GVHD) contained cyclophosphamide 50 mg/kg at Day 3 and Day 4, as well as cyclosporin and mycophenolate mofetil starting on Day 5. The patient received 3 × 106 CD34+ cells/kg from her donor. Stem cell source was bone marrow. During the aplasia, which lasted 24 days, Actinomyces odonlyticus sepsis required antibiotherapy with a favorable outcome. Hematologic recovery was achieved on Day 25, with 100% donor chimerism.
Several complications occurred in the post-HSCT course. Grade II acute cutaneous GVHD developed at Day 45 and required steroid therapy; grade III gastrointestinal GVHD developed at Day 53 and was treated successfully with steroids and infliximab. GVHD gradually improved and steroid therapy was tapered and finally stopped 6 months after HSCT. Clostridium difficile colitis was diagnosed at Day 59, and the child recovered on antibiotic therapy. Persistent hepatic cytolysis led to an extensive infectious and autoimmune screening that remained negative. Mild nodular hyperplasia was found on a liver biopsy performed at month 11 post HSCT. At the last follow up, liver enzymes were normal (AST 38 UI/l, ALT 13 UI/l).
One year after HSCT, the child developed a clinically asymptomatic autoimmune thrombocytopenia. At this occasion, ongoing intravenous immunoglobulin substitution every 3 weeks was increased temporarily to 1 g/kg. Twenty-three months after HSCT, impaired lung function tests led to a suspicion of obliterating bronchiolitis. However, abnormalities gradually resolved over several months on fluticasone inhalations and oral azithromycin. Two years and 4 months after HSCT, asymptomatic autoimmune thyroiditis was diagnosed upon increased Thyroid stimulating hormone (TSH), positive anti-thyroglobulin, anti-thyroperoxydase and anti-TSH antibodies. L-thyroxin treatment was started. Two years and 9 months after HSCT, the patient presented shingles on the right half of the hemiface with involvement of the ophthalmic (V1) and maxillary branch (V2) of the trigeminal nerve due to varicella-zoster virus reactivation. She had received acyclovir prophylaxis during HSCT until Day 60 according to institutional recommendations. Of note, she had not been vaccinated against VZV. She was treated with IV acyclovir and antibiotics because of a bacterial superinfection (staphylococcal cellulitis). Outcome was favorable.
A transient knee effusion appeared 6 months after HSCT that resolved rapidly without any specific treatment, there was no more evidence of SJIA activity afterwards. At the last follow up, 3.1 years after HSCT, the child was in complete remission of SJIA off steroids and immunosuppressive drugs. She had a regular growth between the 25th and 50th percentile, the weight was at 75th percentile. Clinical examination was normal besides a limited vitiligo at the right upper thorax (situated the previous insertion of the central line), and some white hair strands. Asymptomatic thrombocytopenia had regressed, and the patient was again on weekly subcutaneous immunoglobulin substitution (4 g/week). Platelet count was almost normal (123 G/l, normal values for reticulated platelets). Asymptomatic hypothyroidism required L-Thyroxin treatment. She was also still on 12.5 mg/m2/day hydrocortisone substitution for secondary adrenal insufficiency due to previous glucocorticoid therapy and oracillin prophylaxis. Immunoglobulin substitution was stopped, and she had received all recommended post HSCT vaccinations including live vaccines. Immune reconstitution is described in Table 1 and Fig. 2. Table 1 Immune reconstitution after transplantation
Time after HSCT M + 3 M + 4 M + 5 M + 6 M + 9 M + 12 M + 18 M + 24 M + 36 Normal values in healthy children
Age (years) 3.8 46 47 48 51 54 60 66 78 2 to 6
CD3+ (cells/ μl) 186 346 197 324 394 447 1249 3451 4635 1400–3700
CD4+ (cells/ μl)
- CD31+ CD45RA+ naive (%)
-CD45RO+ memory (%)
158 278 131 211 254 305
24
68
866 2090
62
32
2754 700–2200
43–55
58–70
CD8+ (cells/ μl) 20 56 36 68 79 81 262 1118 1411 490–1300
-CD45RA+CCR7+ naive (%) 55 41 52–68
-CD45RA−CCR7+ central memory (%) 11 1,5 3–4
-CD45RA−CCR7− effector memory (%) 28 4,5 11–20
-CD45RA+CCR7− TEMRA (%) 6,5 13 16–28
CD19+ (cells/ μl) 154 208 55 102 307 417 624 1312 1948 390–1400
CD16+ 56+ (cells/ μl) 57 125 102 125 149 132 121 49 134 130–720
T cell proliferations (cpm/min/10^3)
-PHA, J3 72 > 50
PHA phytohemagglutinin
The patient achieved a CD4+ count > 400/μl at M4. Naïve T cells appeared at M12. The percentage was 24% for CD4 +CD31+CD45RA+ and 54% for CD8 +CD45RA+CCR7+
Fig. 2 Immune reconstitution after transplantation. Shows the patient’s T- and B-cell reconstitution after transplantation
Discussion
To the best of our knowledge, this is the first report of successful haploidentical HSCT in a child with systemic juvenile idiopathic arthritis.
The procedure was very effective in controlling SJIA activity within a few months, similarly as for most patients previously treated by intensive immunosuppressive conditioning regimens followed by autologous HSCT [16] or allogenic HSCT from HLA-matched related or unrelated donors [13] (Table 2). The achievement of long-lasting, complete SJIA remission off-steroids or other immunosuppressive therapy after successful allogenic HSCT offers hope of definitive cure, which is specific to this peculiar therapeutic procedure. However, a longer follow-up is required. In the largest series of allogenic HSCT in SJIA published so far, 16 patients received HSCT either from an HLA identical sibling or a 9/10 or 10/10 HLA matched unrelated donor. Out of these 16 patients fourteen were alive at the latest follow-up with a median follow-up of 29 months. Importantly, eleven of them were in complete remission off immunosuppressive treatments. Table 2 Results and outcome depending on the type of transplantationa
Authors Brinkman et al. Abinum et al. Silva et al.
Year of publication 2007 2009 2017
Number of patients 22 7 16
Location Netherlands UK UK
HLA donor Autologous stem cell transplantation (with T cell depletion) Autologous stem cell transplantation (with T cell depletion) MUDb 9/16
MSD: 4/16
mMUD: 3/16
Age at HSCT (median) 9.1 years (range 4.2 to 18.2 years) 10.8 years (range 6 to 18 years) 21.5 months (range, 5 months to 12 years)
Follow up (median) 70 months (range 13–135 months) 80 months (range 60–96 months) 29 months (range, 2.8–8 years)
Deaths 2d 1e 2f
Complete clinical remission 8/20 4/6 11/14
Partial responders 7/20 0/6 1/14
Relapse of the disease 5/20 2/6 1/14
Infections: 19/22 4/7 10/16
Viralc (CMV, HSV, EBV, VZV, BK virus) 25 6 10
Bacterial 8 NC 3
Fungal 2 NC 1
Allo/auto-immune complications – 1/6 4/14
GVHD (grade II-IV) – – 3/16
a Two other cases report of autologous hematopoietic stem cell transplantation
- Mistric et al. (Vntir Lek, 1999) which was a success
- Quartier.P et al. (Lancet, 1999), the child died from toxoplasma infection
bMUD Matched Unrelated Donor, MSD Matched Sibling Donor, mMUD Mismatched Unrelated Donor
c HSV herpes simplex virus, CMV cytomegalovirus, EBV Epstein-Barr virus, VZV Varicella zoster virus
d Two children died from Macrophage Activation Syndrome (P1 at D + 18, P2 at D + 120)
e One patient died 4 months post-transplant from disseminated adenovirus reactivation
f One child died from invasive fungal infection and one from sepsis twenty months after HSCT
An obvious caveat of allogenic HSCT is the risk of severe complications. Autoimmunity developed in our patient as in others following HSCT. It is unclear whether this was linked to the patient’s genetic background, to the fact that her donor had an autoimmune disease (vitiligo), or to post HSCT dysimmunity in the setting of T replete haploidentical graft procedure. As expected, patients with a long-lasting history of systemic inflammation and corticosteroid therapy cumulate a high risk of infections, drug-induced toxicity and, peculiar to allogenic BMT, GVHD. In the series published by Juliana M. F. Silva et al [13], there were 2 procedure-related deaths among 16 patients, many severe infections, including viral infections favored by intensive immunosuppressive therapy, and 3 cases of grade II to IV graft-versus-host-disease [13]. As there are more and more innovative therapeutic options in SJIA, as witnessed by several currently ongoing trials with new biologics and Janus Kinase inhibitors, only a tiny minority of SJIA patients should be proposed allogenic HSCT. However, the feasibility and safety of this therapeutic approach is also regularly improving, thanks to the increasing experience of haploidentical HSCT in other non-malignant diseases, particularly in patients with primary immunodeficiencies [16].
Conclusion
SJIA may in some patients have a severe disease course and an inappropriate response to steroids and currently available medications, including biologics. Allogenic HSCT with an HLA-identical sibling or an unrelated HLA-matched donor has been successfully performed in a few patients. We show here that allogenic HSCT with a haplo-identical donor is also feasible in patients with severe, refractory SJIA, and seems to offer long-lasting, if not definitive cure. However, this procedure should remain exceptional in this indication as it is associated with a high risk of complications.
Abbreviations
CRP C-reactive protein
ESR Erythrocyte sedimentation rate
GVHD Graft-versus-host disease
HLA Human leucocyte antigen
HSCT Hematopoietic stem cell transplantation
IL Interleukin
SD Standard deviation
SJIA Systemic juvenile idiopathic arthritis
TSH Thyroid stimulating hormone
Acknowledgements
to Ms. Solimda Sotou-Bere, Mame Diagne and Betty Bosc from the Clinical Research Centre and Clinical Research Unit Paris Necker-Cochin.
Authors’ contributions
GM participated in clinical care and wrote the manuscript. MC, GP, SB, MB, CB, RM, BBM, MS, AF, MC, BN, SB participated in clinical care. PQ and DM participated in clinical care, designed and wrote the manuscript. All authors read and approved the final manuscript.
Funding
not applicable.
Availability of data and materials
Please contact authors for data requests.
Declarations
Ethics approval and consent to participate
Both parents gave their written informed consent for the procedure, which was approved by the ethics committee of our institution.
Consent for publication
not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33712044 | 19,050,516 | 2021-03-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Latex anaphylaxis in a recipient child during kidney transplant performed in a latex-free environment: case report.
Latex responds for most allergic reactions in children, and repeated exposure to the agent is the main cause of sensitization. We report the case of a child allergic to latex who developed anaphylaxis during kidney transplantation performed in a latex-free environment. After immediate treatment with epinephrine the patient gradually improved. Subsequent investigation revealed that kidney harvesting was performed without latex allergy precautions, suggesting graft contamination by the antigen. We conclude that, for preventing this type of anaphylaxis, it is essential to implement latex-free procedures during donor organ harvesting.
pmcIntroduction and objectives
Latex represents the leading cause of anaphylaxis in the pediatric population, and repeated exposure to latex products is the main cause of sensitization to this antigen.1 Therefore a past medical history with multiple procedures, such as of patients with urological malformations, is more prone to present this condition. Latex sensitization refers to the presence of circulating IgE antibodies against latex, while allergy refers to any immune-mediated reaction to latex.2 In sensitized patients, a latex-free environment is mandatory at all steps of perioperative management. Even though it seems obvious that for patients being submitted to transplant surgery, this tenet should also be extended to the donor, there is little information highlighting the importance of this routine, which now and then is overlooked. The present report aims to discuss the management of a kidney transplant recipient with a past medical history of latex allergy and the implications for donor management considering this aspect.
Case report
The patient was a male, eight-year old, 28 kg, with chronic renal failure secondary to obstructive nephropathy due to posterior urethral valve with bilateral vesicoureteral reflux. Past medical history revealed continuing moderate bronchial asthma, several urinary tract surgical procedures, and during a previous surgery, an episode of severe allergic latex-related reaction as revealed by a positive test performed at the time. The child was admitted to our hospital to be submitted to a deceased-donor kidney transplant. The operating room was prepared abiding latex allergy precautions. The patient was monitored with electrocardiography, capnography and gas analyzer, pulse oximetry, invasive arterial pressure, and central venous pressure. Then, 1 g of cefazolin was administered, and anesthetic induction was performed with 75 μg of fentanyl, 4.2 mg of cisatracurium and sevoflurane. Anesthesia was maintained with sevoflurane inhalation and no other anesthetic or adjuvant drug was administered. Anesthesia progressed with patient showing no respiratory changes and with hemodynamic stability, with mean blood pressure kept around 75 mmHg, and heart rate around 90 beats per minute just to the beginning of the kidney graft implant. During vascular anastomosis, a low dose of norepinephrine (0.05 μg-1. kg-1. min-1) was initiated to ensure higher blood pressure levels during graft reperfusion. Roughly five minutes after transplanted kidney reperfusion, the patient developed severe bronchospasm, low peripheral oxygen saturation, rhonchi and wheezing on pulmonary auscultation, tachycardia and hypotension. The dose of norepinephrine was increased, with no response. Then, administration of 200 μg bolus of epinephrine started, with partial respiratory improvement and increase in blood pressure, therefore a continuous infusion of epinephrine (0.2 to 0.6 μg-1 kg-1. min-1) was maintained. The patient persisted with moderate bronchospasm and 30 mg of ketamine was associated. Then he underwent gradual clinical improvement, and, at the end of the surgery, was referred to the intensive care center intubated, sedated, receiving continuous infusion of epinephrine (0.4 μg-1 kg-1 min-1), with no diuresis. The patient remained hemodynamically dependent of epinephrine support, and infusion discontinuation was possible only after 48 hours. He presented progressive clinical improvement and hemodynamic stability. A new laboratory test for latex specific IgE was performed on the first postoperative day and showed high levels (8.2 kUA.L-1). The patient began to present diuresis from the third postoperative day, with gradual improvement in renal function. He was extubated on the seventh postoperative day and was discharged three days later. Serum creatinine reached levels of 0.78 mg.dL-1 in the third month after surgery. After more than one-year regular follow-up at our hospital, the patient remains with adequate renal function. The child`s guardian signed a consent form agreeing with the anonymous case report.
Discussion
Although rare, latex reaction can lead to death even when properly managed. It is crucial to implement preventive measures for such events. Nonetheless, adopting a latex-free environment, the key recommendation for managing sensitized patients, was not enough to avert the severe anaphylaxis reported here.
The diagnosis of anaphylaxis is mostly clinical and based on the classic triad of cardiovascular collapse, wheezing and skin rash, but symptoms can vary from simple skin manifestations to cardiorespiratory arrest. If the causal agent has been administered intravenously, clinical signs start within 5 to 10 minutes, or within seconds in the most severe cases. On the other hand, when resulting from latex exposure, anaphylaxis usually starts later, as it follows a cutaneous-mucous contact.3 In the case reported, the patient presented hemodynamic and respiratory signs consistent with the diagnosis of anaphylaxis, and the reaction started immediately after reperfusion, suggesting more direct contact of the antigen with circulation than with a cutaneous-mucous surface. This information, associated with the fact that patient care was being performed in a latex-free environment, could pose a disadvantage to the hypothesis of latex as the causal agent. But examination into donor organ harvesting found lack of latex allergy precautions. Thus, the organ was contaminated by the antigen, which reached the circulation at the time of reperfusion. A similar event was described by Jacqmarcq et al.4 They reported an adult patient who developed anaphylactic shock during a kidney transplant performed in a latex-free environment and discussed contamination of the graft, which was removed without latex allergy precautions. Given the recipient population comprises a group of patients undergoing various medical procedures and frequent hospitalizations, we could infer that a considerable number of them is at higher risk of latex allergy. Conversely, there seems to be no special concern with this aspect in Brazil, as no investigation into latex allergy is routinely carried out for receptors. Likewise, there is no special regulation in the donor-recipient processes of management when a recipient has latex allergy. Therefore, based on the experience presented here and the discussion above, we suggest the implementation of a latex-free environment during the harvesting and handling of organs intended for transplantation. In addition, latex sensitization, using skin and serological tests, should be recommended for recipients. In the case of sensitized recipients, the professionals involved in the process need to be alerted to ensure that latex-free care is extended to the donor.
In the diagnostic investigation of anaphylactic reactions to latex, some laboratory tests are useful. The chief immune mechanism of anaphylaxis is mediated by specific IgE class antibodies, which results in mast cell and basophil activation, and in the rapid release of pre-formed mediators, such as tryptase and histamine. Thus, measuring IgE and the mediators can help confirm the diagnosis. Tryptase peaks in approximately 30 minutes, then gradually decreases. It has a half-life of two hours, which is the ideal time for its measurement, although it can persist for several hours, or even days, depending on the intensity of reaction. Histamine is not routinely measured because of its short half-life, and ideally should be collected from blood in the first minutes of the reaction, and from urine within 24 hours after reaction.2 In the case in question, the patient had a previous diagnosis of latex allergy and, due to the unavailability of other tests, only IgE specific for latex was measured. This test has high specificity, but low sensitivity,2 which certainly represented a limiting factor for diagnosis confirmation and, therefore, in the implications of the case.
Thus, it is important to highlight the differential diagnoses that were considered. The first, allergy to other drugs. This suspicion was considered unlikely, given that no drugs, including antibiotics and muscle relaxants, were administered in the moments preceding the reaction. Asthma attack would be another hypothesis; however, bronchospasm was not seen during anesthesia until that moment, and the symptoms of the patient were not only respiratory. Finally, the most relevant differential diagnosis would be post-reperfusion syndrome. This is classically characterized by bradycardia, hypotension and increased cardiac filling pressures. Criteria for its diagnosis include reduction in blood pressure to values less than 30% from baseline, with a minimum duration of one minute, occurring within the first five minutes after reperfusion.5 Although such hemodynamic instability was observed, other cardiovascular changes were also observed, such as tachycardia and bronchospasm, which favor the diagnosis of latex allergy more. Moreover, post-reperfusion syndrome during kidney transplant is rare, estimated at 4%.5
In the treatment of anaphylaxis, fast intervention is essential for a favorable outcome. Epinephrine is the recommended drug because it has inotropic and chronotropic effects. It also prevents or reduces mucosal edema, promotes bronchodilation, and suppresses the release of mast cell and basophil mediators. Intravenous doses of 5 to 10 μg.kg-1 are recommended in cases of mild to moderate hypotension, titrated according to results. Larger doses or continuous infusion (0.1 to 1.0 μg-1 kg-1 min-1) may be required in the face of cardiovascular collapse.1, 2 In the case reported, high doses were necessary and the infusion had to be maintained for 48 hours, period of time for likely elimination of the causal antigen.
Conclusion
Special care is requested when managing donor/recipient regarding latex-related risks. The correct approach seeks to avert allergic reactions during surgery, including anaphylaxis, to improve outcomes. As to the recipient, it is essential to identify individuals sensitized to implement latex-free care. As for the donor, we recommend routine harvesting and handling of organs intended for transplant in a latex-free environment.
Conflicts of interest
The authors declare no conflicts of interest.
☆ Institution: Santa Casa de Belo Horizonte. | NOREPINEPHRINE | DrugsGivenReaction | CC BY-NC-ND | 33712257 | 20,672,373 | 2021 |
What is the weight of the patient? | Latex anaphylaxis in a recipient child during kidney transplant performed in a latex-free environment: case report.
Latex responds for most allergic reactions in children, and repeated exposure to the agent is the main cause of sensitization. We report the case of a child allergic to latex who developed anaphylaxis during kidney transplantation performed in a latex-free environment. After immediate treatment with epinephrine the patient gradually improved. Subsequent investigation revealed that kidney harvesting was performed without latex allergy precautions, suggesting graft contamination by the antigen. We conclude that, for preventing this type of anaphylaxis, it is essential to implement latex-free procedures during donor organ harvesting.
pmcIntroduction and objectives
Latex represents the leading cause of anaphylaxis in the pediatric population, and repeated exposure to latex products is the main cause of sensitization to this antigen.1 Therefore a past medical history with multiple procedures, such as of patients with urological malformations, is more prone to present this condition. Latex sensitization refers to the presence of circulating IgE antibodies against latex, while allergy refers to any immune-mediated reaction to latex.2 In sensitized patients, a latex-free environment is mandatory at all steps of perioperative management. Even though it seems obvious that for patients being submitted to transplant surgery, this tenet should also be extended to the donor, there is little information highlighting the importance of this routine, which now and then is overlooked. The present report aims to discuss the management of a kidney transplant recipient with a past medical history of latex allergy and the implications for donor management considering this aspect.
Case report
The patient was a male, eight-year old, 28 kg, with chronic renal failure secondary to obstructive nephropathy due to posterior urethral valve with bilateral vesicoureteral reflux. Past medical history revealed continuing moderate bronchial asthma, several urinary tract surgical procedures, and during a previous surgery, an episode of severe allergic latex-related reaction as revealed by a positive test performed at the time. The child was admitted to our hospital to be submitted to a deceased-donor kidney transplant. The operating room was prepared abiding latex allergy precautions. The patient was monitored with electrocardiography, capnography and gas analyzer, pulse oximetry, invasive arterial pressure, and central venous pressure. Then, 1 g of cefazolin was administered, and anesthetic induction was performed with 75 μg of fentanyl, 4.2 mg of cisatracurium and sevoflurane. Anesthesia was maintained with sevoflurane inhalation and no other anesthetic or adjuvant drug was administered. Anesthesia progressed with patient showing no respiratory changes and with hemodynamic stability, with mean blood pressure kept around 75 mmHg, and heart rate around 90 beats per minute just to the beginning of the kidney graft implant. During vascular anastomosis, a low dose of norepinephrine (0.05 μg-1. kg-1. min-1) was initiated to ensure higher blood pressure levels during graft reperfusion. Roughly five minutes after transplanted kidney reperfusion, the patient developed severe bronchospasm, low peripheral oxygen saturation, rhonchi and wheezing on pulmonary auscultation, tachycardia and hypotension. The dose of norepinephrine was increased, with no response. Then, administration of 200 μg bolus of epinephrine started, with partial respiratory improvement and increase in blood pressure, therefore a continuous infusion of epinephrine (0.2 to 0.6 μg-1 kg-1. min-1) was maintained. The patient persisted with moderate bronchospasm and 30 mg of ketamine was associated. Then he underwent gradual clinical improvement, and, at the end of the surgery, was referred to the intensive care center intubated, sedated, receiving continuous infusion of epinephrine (0.4 μg-1 kg-1 min-1), with no diuresis. The patient remained hemodynamically dependent of epinephrine support, and infusion discontinuation was possible only after 48 hours. He presented progressive clinical improvement and hemodynamic stability. A new laboratory test for latex specific IgE was performed on the first postoperative day and showed high levels (8.2 kUA.L-1). The patient began to present diuresis from the third postoperative day, with gradual improvement in renal function. He was extubated on the seventh postoperative day and was discharged three days later. Serum creatinine reached levels of 0.78 mg.dL-1 in the third month after surgery. After more than one-year regular follow-up at our hospital, the patient remains with adequate renal function. The child`s guardian signed a consent form agreeing with the anonymous case report.
Discussion
Although rare, latex reaction can lead to death even when properly managed. It is crucial to implement preventive measures for such events. Nonetheless, adopting a latex-free environment, the key recommendation for managing sensitized patients, was not enough to avert the severe anaphylaxis reported here.
The diagnosis of anaphylaxis is mostly clinical and based on the classic triad of cardiovascular collapse, wheezing and skin rash, but symptoms can vary from simple skin manifestations to cardiorespiratory arrest. If the causal agent has been administered intravenously, clinical signs start within 5 to 10 minutes, or within seconds in the most severe cases. On the other hand, when resulting from latex exposure, anaphylaxis usually starts later, as it follows a cutaneous-mucous contact.3 In the case reported, the patient presented hemodynamic and respiratory signs consistent with the diagnosis of anaphylaxis, and the reaction started immediately after reperfusion, suggesting more direct contact of the antigen with circulation than with a cutaneous-mucous surface. This information, associated with the fact that patient care was being performed in a latex-free environment, could pose a disadvantage to the hypothesis of latex as the causal agent. But examination into donor organ harvesting found lack of latex allergy precautions. Thus, the organ was contaminated by the antigen, which reached the circulation at the time of reperfusion. A similar event was described by Jacqmarcq et al.4 They reported an adult patient who developed anaphylactic shock during a kidney transplant performed in a latex-free environment and discussed contamination of the graft, which was removed without latex allergy precautions. Given the recipient population comprises a group of patients undergoing various medical procedures and frequent hospitalizations, we could infer that a considerable number of them is at higher risk of latex allergy. Conversely, there seems to be no special concern with this aspect in Brazil, as no investigation into latex allergy is routinely carried out for receptors. Likewise, there is no special regulation in the donor-recipient processes of management when a recipient has latex allergy. Therefore, based on the experience presented here and the discussion above, we suggest the implementation of a latex-free environment during the harvesting and handling of organs intended for transplantation. In addition, latex sensitization, using skin and serological tests, should be recommended for recipients. In the case of sensitized recipients, the professionals involved in the process need to be alerted to ensure that latex-free care is extended to the donor.
In the diagnostic investigation of anaphylactic reactions to latex, some laboratory tests are useful. The chief immune mechanism of anaphylaxis is mediated by specific IgE class antibodies, which results in mast cell and basophil activation, and in the rapid release of pre-formed mediators, such as tryptase and histamine. Thus, measuring IgE and the mediators can help confirm the diagnosis. Tryptase peaks in approximately 30 minutes, then gradually decreases. It has a half-life of two hours, which is the ideal time for its measurement, although it can persist for several hours, or even days, depending on the intensity of reaction. Histamine is not routinely measured because of its short half-life, and ideally should be collected from blood in the first minutes of the reaction, and from urine within 24 hours after reaction.2 In the case in question, the patient had a previous diagnosis of latex allergy and, due to the unavailability of other tests, only IgE specific for latex was measured. This test has high specificity, but low sensitivity,2 which certainly represented a limiting factor for diagnosis confirmation and, therefore, in the implications of the case.
Thus, it is important to highlight the differential diagnoses that were considered. The first, allergy to other drugs. This suspicion was considered unlikely, given that no drugs, including antibiotics and muscle relaxants, were administered in the moments preceding the reaction. Asthma attack would be another hypothesis; however, bronchospasm was not seen during anesthesia until that moment, and the symptoms of the patient were not only respiratory. Finally, the most relevant differential diagnosis would be post-reperfusion syndrome. This is classically characterized by bradycardia, hypotension and increased cardiac filling pressures. Criteria for its diagnosis include reduction in blood pressure to values less than 30% from baseline, with a minimum duration of one minute, occurring within the first five minutes after reperfusion.5 Although such hemodynamic instability was observed, other cardiovascular changes were also observed, such as tachycardia and bronchospasm, which favor the diagnosis of latex allergy more. Moreover, post-reperfusion syndrome during kidney transplant is rare, estimated at 4%.5
In the treatment of anaphylaxis, fast intervention is essential for a favorable outcome. Epinephrine is the recommended drug because it has inotropic and chronotropic effects. It also prevents or reduces mucosal edema, promotes bronchodilation, and suppresses the release of mast cell and basophil mediators. Intravenous doses of 5 to 10 μg.kg-1 are recommended in cases of mild to moderate hypotension, titrated according to results. Larger doses or continuous infusion (0.1 to 1.0 μg-1 kg-1 min-1) may be required in the face of cardiovascular collapse.1, 2 In the case reported, high doses were necessary and the infusion had to be maintained for 48 hours, period of time for likely elimination of the causal antigen.
Conclusion
Special care is requested when managing donor/recipient regarding latex-related risks. The correct approach seeks to avert allergic reactions during surgery, including anaphylaxis, to improve outcomes. As to the recipient, it is essential to identify individuals sensitized to implement latex-free care. As for the donor, we recommend routine harvesting and handling of organs intended for transplant in a latex-free environment.
Conflicts of interest
The authors declare no conflicts of interest.
☆ Institution: Santa Casa de Belo Horizonte. | 28 kg. | Weight | CC BY-NC-ND | 33712257 | 20,672,373 | 2021 |
What was the dosage of drug 'NOREPINEPHRINE'? | Latex anaphylaxis in a recipient child during kidney transplant performed in a latex-free environment: case report.
Latex responds for most allergic reactions in children, and repeated exposure to the agent is the main cause of sensitization. We report the case of a child allergic to latex who developed anaphylaxis during kidney transplantation performed in a latex-free environment. After immediate treatment with epinephrine the patient gradually improved. Subsequent investigation revealed that kidney harvesting was performed without latex allergy precautions, suggesting graft contamination by the antigen. We conclude that, for preventing this type of anaphylaxis, it is essential to implement latex-free procedures during donor organ harvesting.
pmcIntroduction and objectives
Latex represents the leading cause of anaphylaxis in the pediatric population, and repeated exposure to latex products is the main cause of sensitization to this antigen.1 Therefore a past medical history with multiple procedures, such as of patients with urological malformations, is more prone to present this condition. Latex sensitization refers to the presence of circulating IgE antibodies against latex, while allergy refers to any immune-mediated reaction to latex.2 In sensitized patients, a latex-free environment is mandatory at all steps of perioperative management. Even though it seems obvious that for patients being submitted to transplant surgery, this tenet should also be extended to the donor, there is little information highlighting the importance of this routine, which now and then is overlooked. The present report aims to discuss the management of a kidney transplant recipient with a past medical history of latex allergy and the implications for donor management considering this aspect.
Case report
The patient was a male, eight-year old, 28 kg, with chronic renal failure secondary to obstructive nephropathy due to posterior urethral valve with bilateral vesicoureteral reflux. Past medical history revealed continuing moderate bronchial asthma, several urinary tract surgical procedures, and during a previous surgery, an episode of severe allergic latex-related reaction as revealed by a positive test performed at the time. The child was admitted to our hospital to be submitted to a deceased-donor kidney transplant. The operating room was prepared abiding latex allergy precautions. The patient was monitored with electrocardiography, capnography and gas analyzer, pulse oximetry, invasive arterial pressure, and central venous pressure. Then, 1 g of cefazolin was administered, and anesthetic induction was performed with 75 μg of fentanyl, 4.2 mg of cisatracurium and sevoflurane. Anesthesia was maintained with sevoflurane inhalation and no other anesthetic or adjuvant drug was administered. Anesthesia progressed with patient showing no respiratory changes and with hemodynamic stability, with mean blood pressure kept around 75 mmHg, and heart rate around 90 beats per minute just to the beginning of the kidney graft implant. During vascular anastomosis, a low dose of norepinephrine (0.05 μg-1. kg-1. min-1) was initiated to ensure higher blood pressure levels during graft reperfusion. Roughly five minutes after transplanted kidney reperfusion, the patient developed severe bronchospasm, low peripheral oxygen saturation, rhonchi and wheezing on pulmonary auscultation, tachycardia and hypotension. The dose of norepinephrine was increased, with no response. Then, administration of 200 μg bolus of epinephrine started, with partial respiratory improvement and increase in blood pressure, therefore a continuous infusion of epinephrine (0.2 to 0.6 μg-1 kg-1. min-1) was maintained. The patient persisted with moderate bronchospasm and 30 mg of ketamine was associated. Then he underwent gradual clinical improvement, and, at the end of the surgery, was referred to the intensive care center intubated, sedated, receiving continuous infusion of epinephrine (0.4 μg-1 kg-1 min-1), with no diuresis. The patient remained hemodynamically dependent of epinephrine support, and infusion discontinuation was possible only after 48 hours. He presented progressive clinical improvement and hemodynamic stability. A new laboratory test for latex specific IgE was performed on the first postoperative day and showed high levels (8.2 kUA.L-1). The patient began to present diuresis from the third postoperative day, with gradual improvement in renal function. He was extubated on the seventh postoperative day and was discharged three days later. Serum creatinine reached levels of 0.78 mg.dL-1 in the third month after surgery. After more than one-year regular follow-up at our hospital, the patient remains with adequate renal function. The child`s guardian signed a consent form agreeing with the anonymous case report.
Discussion
Although rare, latex reaction can lead to death even when properly managed. It is crucial to implement preventive measures for such events. Nonetheless, adopting a latex-free environment, the key recommendation for managing sensitized patients, was not enough to avert the severe anaphylaxis reported here.
The diagnosis of anaphylaxis is mostly clinical and based on the classic triad of cardiovascular collapse, wheezing and skin rash, but symptoms can vary from simple skin manifestations to cardiorespiratory arrest. If the causal agent has been administered intravenously, clinical signs start within 5 to 10 minutes, or within seconds in the most severe cases. On the other hand, when resulting from latex exposure, anaphylaxis usually starts later, as it follows a cutaneous-mucous contact.3 In the case reported, the patient presented hemodynamic and respiratory signs consistent with the diagnosis of anaphylaxis, and the reaction started immediately after reperfusion, suggesting more direct contact of the antigen with circulation than with a cutaneous-mucous surface. This information, associated with the fact that patient care was being performed in a latex-free environment, could pose a disadvantage to the hypothesis of latex as the causal agent. But examination into donor organ harvesting found lack of latex allergy precautions. Thus, the organ was contaminated by the antigen, which reached the circulation at the time of reperfusion. A similar event was described by Jacqmarcq et al.4 They reported an adult patient who developed anaphylactic shock during a kidney transplant performed in a latex-free environment and discussed contamination of the graft, which was removed without latex allergy precautions. Given the recipient population comprises a group of patients undergoing various medical procedures and frequent hospitalizations, we could infer that a considerable number of them is at higher risk of latex allergy. Conversely, there seems to be no special concern with this aspect in Brazil, as no investigation into latex allergy is routinely carried out for receptors. Likewise, there is no special regulation in the donor-recipient processes of management when a recipient has latex allergy. Therefore, based on the experience presented here and the discussion above, we suggest the implementation of a latex-free environment during the harvesting and handling of organs intended for transplantation. In addition, latex sensitization, using skin and serological tests, should be recommended for recipients. In the case of sensitized recipients, the professionals involved in the process need to be alerted to ensure that latex-free care is extended to the donor.
In the diagnostic investigation of anaphylactic reactions to latex, some laboratory tests are useful. The chief immune mechanism of anaphylaxis is mediated by specific IgE class antibodies, which results in mast cell and basophil activation, and in the rapid release of pre-formed mediators, such as tryptase and histamine. Thus, measuring IgE and the mediators can help confirm the diagnosis. Tryptase peaks in approximately 30 minutes, then gradually decreases. It has a half-life of two hours, which is the ideal time for its measurement, although it can persist for several hours, or even days, depending on the intensity of reaction. Histamine is not routinely measured because of its short half-life, and ideally should be collected from blood in the first minutes of the reaction, and from urine within 24 hours after reaction.2 In the case in question, the patient had a previous diagnosis of latex allergy and, due to the unavailability of other tests, only IgE specific for latex was measured. This test has high specificity, but low sensitivity,2 which certainly represented a limiting factor for diagnosis confirmation and, therefore, in the implications of the case.
Thus, it is important to highlight the differential diagnoses that were considered. The first, allergy to other drugs. This suspicion was considered unlikely, given that no drugs, including antibiotics and muscle relaxants, were administered in the moments preceding the reaction. Asthma attack would be another hypothesis; however, bronchospasm was not seen during anesthesia until that moment, and the symptoms of the patient were not only respiratory. Finally, the most relevant differential diagnosis would be post-reperfusion syndrome. This is classically characterized by bradycardia, hypotension and increased cardiac filling pressures. Criteria for its diagnosis include reduction in blood pressure to values less than 30% from baseline, with a minimum duration of one minute, occurring within the first five minutes after reperfusion.5 Although such hemodynamic instability was observed, other cardiovascular changes were also observed, such as tachycardia and bronchospasm, which favor the diagnosis of latex allergy more. Moreover, post-reperfusion syndrome during kidney transplant is rare, estimated at 4%.5
In the treatment of anaphylaxis, fast intervention is essential for a favorable outcome. Epinephrine is the recommended drug because it has inotropic and chronotropic effects. It also prevents or reduces mucosal edema, promotes bronchodilation, and suppresses the release of mast cell and basophil mediators. Intravenous doses of 5 to 10 μg.kg-1 are recommended in cases of mild to moderate hypotension, titrated according to results. Larger doses or continuous infusion (0.1 to 1.0 μg-1 kg-1 min-1) may be required in the face of cardiovascular collapse.1, 2 In the case reported, high doses were necessary and the infusion had to be maintained for 48 hours, period of time for likely elimination of the causal antigen.
Conclusion
Special care is requested when managing donor/recipient regarding latex-related risks. The correct approach seeks to avert allergic reactions during surgery, including anaphylaxis, to improve outcomes. As to the recipient, it is essential to identify individuals sensitized to implement latex-free care. As for the donor, we recommend routine harvesting and handling of organs intended for transplant in a latex-free environment.
Conflicts of interest
The authors declare no conflicts of interest.
☆ Institution: Santa Casa de Belo Horizonte. | 0.5 MCG/KG/MIN | DrugDosageText | CC BY-NC-ND | 33712257 | 20,672,373 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Cerebral metastasis of Merkel cell carcinoma following resection with negative margins and adjuvant external beam radiation: a case report.
BACKGROUND
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. It is associated with advanced age, ultraviolet (UV) radiation, and Merkel cell polyomavirus. It has a predilection for the lymphatic system, but rarely spreads to the central nervous system.
METHODS
A 71-year-old Caucasian man with a history of rheumatoid arthritis and MCC of the right lower eyelid and cheek presented with left-sided hemineglect and word-finding difficulty. Twenty months earlier he had undergone local excision of a 3 cm lesion with negative margins, negative sentinel lymph node biopsy, and external beam radiation. On presentation he was found to have a 6.3 cm mass in the right frontotemporal region. He underwent prompt resection, with pathological analysis consistent with metastatic MCC. He subsequently underwent stereotactic radiosurgery (SRS) and adjunctive immunotherapy with pembrolizumab. He has since tolerated the therapy well and is currently without neurological symptoms or evidence of recurrence.
CONCLUSIONS
Cerebral metastasis of MCC is a rare event and should be considered when a patient with a history of MCC presents with neurological symptoms. Optimal treatment regimens of these rare cases are unclear; however, prompt resection, stereotactic radiosurgery, and adjunctive immunotherapy have shown an initial positive response in this patient.
Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin. This cancer is named because of the dense neurosecretory granules found in the core of the cell which are reminiscent of Merkel cells, the mechanoreceptors found in the basal layer of the epidermis [1, 2]. While these are assumed to be the cells of origin of this malignancy, there are multiple hypotheses that suggest a possible different cell of origin such as immature totipotent stem cells, dermal fibroblasts, or epidermal keratinocytes [3–5]. Pathogenesis is believed to be related to Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation [6–9]. The incidence of MCC is estimated at 0.7 cases per 100,000 persons and predominantly affects older, lighter-skinned adults [10, 11]. Roughly 70% occur on the head and neck and the upper limbs [9, 12]. Treatment is centered on surgical excision for local disease; however, there is frequent local recurrence [12, 13]. Metastases are common, particularly to the lymph nodes, and sentinel node biopsy is an important aspect of staging [12]. Cerebral metastases are uncommon, with fewer than 20 cases reported in the literature [14–26]. We report here a case of MCC metastasis to the brain nearly 2 years following excision of the primary skin mass with negative margins, negative sentinel nodes, and local radiation.
Case presentation
A 71-year-old Caucasian man presented to the emergency department with 3 weeks of forgetfulness, word-finding difficulty, gait disturbance, and left-sided hemineglect. He had a history of a 3 cm × 2 cm T2N0M0 stage IIa MCC of the right lower eyelid and cheek which had been treated with local excision with negative margins, negative sentinel lymph node biopsy, and external beam radiation (45 Gray total) to the parotid and ipsilateral neck roughly 20 months earlier. No imaging of his brain was performed at that time. His past medical history was significant for hypertension and rheumatoid arthritis (RA), for which he was prescribed hydroxychloroquine. Upon presentation to the emergency department he had normal vital signs. His physical exam was notable for left-sided hemineglect as well as left-sided tactile extinction. His laboratory results were notable only for a small increase in his serum creatinine from 1.1 to 1.4. Due to a history of anaphylaxis to intravenous contrast, a computed tomography (CT) scan of the brain without contrast was performed, which showed a mass-like area of hypodensity with mass effect on the right lateral ventricle and 6 mm of right-to-left midline shift. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain (Fig. 1) showed a 6.3 cm heterogeneous cystic and solid mass with surrounding increased T2 signal in the right frontotemporal regions, with an additional 5 mm lesion (Fig. 2) in the middle of the right superior frontal gyrus 9 mm from the longitudinal fissure. A 3.9 mm right-to-left midline shift with trapping of the temporal horn of the right lateral ventricle was described.Fig. 1 a, b Fluid-attenuated inversion recovery (FLAIR) and c, d T2-weighted imaging show increased T2 signal involving the right temporal lobe and right frontal lobe and no evidence of hemorrhage. A 9 mm right-to-left midline shift is shown with early right uncal herniation, effacement of the right lateral ventricle, and dilatation of the temporal horn of the right lateral ventricle. The hyperintense areas surrounding the lateral ventricles (a, b) are likely representative of leukoaraiosis rather than tumor lesions. e, f T1 imaging shows a 6.3 cm × 5.5 cm × 4.8 cm ring-enhancing heterogeneous cystic mass in the right frontotemporal region with a 3.5 cm × 3.0 cm avidly enhancing mural nodule with diffusion restriction (diffusion imaging not shown) on the lateral aspect of the mass
Fig. 2 Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) images demonstrating a 5 mm enhancing lesion (yellow arrow) in the right superior frontal gyrus
Neurosurgery was consulted and the patient was started on dexamethasone and levetiracetam. He was taken to the operating room the following morning for awake craniotomy and resection of the tumor. The neurosurgical team performed a BrainLAB-guided right temporal craniotomy with physiologic monitoring. They removed the entire frontotemporal mass, but did not attempt excision of the 5 mm superior front gyrus lesion. Histological analysis of the tumor showed signs of neuroendocrine features consistent with MCC. Serologic analysis showed he was MCPyV-negative. The patient was discharged home and followed up with radiation oncology and medical oncology. His positron emission tomography (PET)-CT scan showed no evidence of metastatic disease within the chest, abdomen, or pelvis. In order to treat the residual 5 mm right frontal lesion and the resection cavity, he received stereotactic radiation surgery (SRS) to both areas 1 month after diagnosis. SRS was selected over whole brain radiation therapy (WBRT) to avoid the neurotoxic effects from WBRT. He was started on pembrolizumab 1 week after radiation. He experienced improvement in his gait, strength, mental status, and vision in the weeks following treatment. His hemineglect gradually improved over the course of the next 6 months without evidence of new disease (Fig. 3). At 6 months from initiation, he had tolerated pembrolizumab without significant complication or worsening of his RA.Fig. 3 Magnetic resonance imaging of the brain 4.5 months postoperatively. Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) show mild irregular rim of enhancement around resection. Resolution of previously seen mass effect and midline shift. Decreased surrounding T2/FLAIR hyperintense signal change. FLAIR (d), T2 (e), and T1 (f) images showing interval resolution of previously noted 5 mm enhancing lesion in the right superior frontal gyrus
Discussion
MCC is a rare cancer of the skin which shows a predilection for sun-exposed areas and frequently affects older, lighter-skinned individuals. Regional lymph node metastasis is common at the time of presentation, with roughly 25% of individuals presenting with regional lymph node disease and ~ 10% of individuals with distant lymph node metastases. The 5-year survival rates range from 13 to 55% depending on the size and depth of the initial lesion, presence of occult or clinical regional lymph node metastases, and presence of distant metastases, with the worst prognosis in the last group [12]. Head and neck lesions provide a particularly challenging staging evaluation due to the variable lymphatic drainage in the region [27]. In our patient’s case, it is likely that the sentinel lymph node biopsy was a false negative given his subsequent metastasis.
Central nervous system (CNS) metastases are particularly rare, but have been reported previously in the literature. Fewer than 20 cases have been reported, with variable presentations, survival, and treatment modalities [14–26]. The mechanism for metastasis to the CNS is unclear; however, MCC’s predilection for the lymphatic system and recently discovered lymphatic system of the meninges in humans offers a potential explanation [28]. Due to the rarity of CNS metastases of Merkel cell, the optimal treatment is unknown, but there is some evidence that more aggressive regimens with resection, radiation, and chemotherapy improve survival [14, 20].
Immunotherapy therapy has become the treatment of choice in advanced MCC, with multiple phase I/II trials involving avelumab, nivolumab, and pembrolizumab showing encouraging responses [29–32]. Pertinent to our patient, a phase 2 non-controlled study of pembrolizumab for initial treatment showed a response rate of 56%, with 6-month progression-free survival of 67% [29]. Importantly, this trial showed durable responses, with 85% of responders in remission at 1 year and 79% at 2 years [33]. This was notably superior to traditional chemotherapy regimens, which have shown median progression-free survival of approximately 3 months and disease progression in 90% of patients by 10 months [34]. Avelumab is currently the only US Food and Drug Administration (FDA)-approved immunotherapy for metastatic MCC based on the JAVELIN Merkel 200 study; however, this study notably excluded patients with CNS metastasis and only included patients with previous systemic therapies, thus limiting the applicability to our patient [31].
While adjuvant pembrolizumab is not currently FDA-approved for MCC, the anti-programmed death protein 1 (PD1) agent was chosen based on the size of this MCC lesion (despite radiation therapy), the overall immunogenicity seen in MCC, the efficacy of this therapy in systemic treatment-naïve patients, the efficacy of the therapy in stage III melanoma, and efficacy demonstrated in treating CNS metastases of melanoma [35–37]. There is ongoing research into adjuvant immunotherapy for MCC, with two randomized phase II trials using avelumab or nivolumab. Lastly, given our patient’s history of RA, there is concern for exacerbation in the setting of pembrolizumab use [38]. Fortunately, he has not had exacerbation of his rheumatologic disease to date.
The patient also underwent SRS to his surgical cavity and additional 5 mm lesion. While WBRT is the standard of care for brain metastasis after surgical resection to prevent recurrence, SRS is increasingly used as an alternative [39]. This is because SRS after surgical resection of 1–3 metastases improves survival compared to observation alone and is associated with less neurocognitive decline than WBRT [40, 41]. Still, this is an area of ongoing investigation, and decisions regarding WBRT versus SRS should be made on an individualized basis, with shared decision-making between providers and patient.
This case highlights the aggressive nature of MCC and the difficulty in predicting the clinical course and optimal treatment of these lesions in the head and neck. Despite an initial lesion with negative resection margins and adjuvant radiation, our patient still had subsequent cerebral metastases. Interestingly, our patient had RA and had been treated for years with hydroxychloroquine. MCC incidence is increased among immunosuppressed patients such as those with organ transplantation, B cell malignancies, and human immunodeficiency virus (HIV) [42–44]. While hydroxychloroquine does not “suppress” the immune system in the classical sense, it has many immunomodulatory properties. It is unclear what role, if any, this may have on MCC incidence and progression. This case also highlights a potential blueprint for treatment of these rare metastases with the combination of prompt resection, SRS, and immunotherapy.
Conclusion
While it is certainly a rare event, consideration should be given for metastatic spread of MCC to the CNS when the patient has a known MCC primary and presents with neurological symptoms. Tissue diagnosis in these cases is of paramount importance, as it will influence treatment regimens moving forward. Aggressive treatment with prompt resection, SRS, and adjunctive immunotherapy has shown favorable results in this patient and should be considered in the rare event of CNS metastasis of MCC.
Abbreviations
MCC Merkel cell carcinoma
SRS Stereotactic radiosurgery
MCPyV Merkel cell polyomavirus
RA Rheumatoid arthritis
CNS Central nervous system
PD1 Programmed cell death protein 1
Acknowledgements
Not applicable.
Authors' contributions
Both Dr. Grubb and Dr. Hankollari participated in the care of this patient as well as the writing and editing of this manuscript. Both authors read and approved the final manuscript.
Funding
There were no funding sources for this article.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
All parts of this case report were conducted in line with the principles outlined in the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests, either financial or nonfinancial.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33714267 | 20,230,857 | 2021-03-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to central nervous system'. | Cerebral metastasis of Merkel cell carcinoma following resection with negative margins and adjuvant external beam radiation: a case report.
BACKGROUND
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. It is associated with advanced age, ultraviolet (UV) radiation, and Merkel cell polyomavirus. It has a predilection for the lymphatic system, but rarely spreads to the central nervous system.
METHODS
A 71-year-old Caucasian man with a history of rheumatoid arthritis and MCC of the right lower eyelid and cheek presented with left-sided hemineglect and word-finding difficulty. Twenty months earlier he had undergone local excision of a 3 cm lesion with negative margins, negative sentinel lymph node biopsy, and external beam radiation. On presentation he was found to have a 6.3 cm mass in the right frontotemporal region. He underwent prompt resection, with pathological analysis consistent with metastatic MCC. He subsequently underwent stereotactic radiosurgery (SRS) and adjunctive immunotherapy with pembrolizumab. He has since tolerated the therapy well and is currently without neurological symptoms or evidence of recurrence.
CONCLUSIONS
Cerebral metastasis of MCC is a rare event and should be considered when a patient with a history of MCC presents with neurological symptoms. Optimal treatment regimens of these rare cases are unclear; however, prompt resection, stereotactic radiosurgery, and adjunctive immunotherapy have shown an initial positive response in this patient.
Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin. This cancer is named because of the dense neurosecretory granules found in the core of the cell which are reminiscent of Merkel cells, the mechanoreceptors found in the basal layer of the epidermis [1, 2]. While these are assumed to be the cells of origin of this malignancy, there are multiple hypotheses that suggest a possible different cell of origin such as immature totipotent stem cells, dermal fibroblasts, or epidermal keratinocytes [3–5]. Pathogenesis is believed to be related to Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation [6–9]. The incidence of MCC is estimated at 0.7 cases per 100,000 persons and predominantly affects older, lighter-skinned adults [10, 11]. Roughly 70% occur on the head and neck and the upper limbs [9, 12]. Treatment is centered on surgical excision for local disease; however, there is frequent local recurrence [12, 13]. Metastases are common, particularly to the lymph nodes, and sentinel node biopsy is an important aspect of staging [12]. Cerebral metastases are uncommon, with fewer than 20 cases reported in the literature [14–26]. We report here a case of MCC metastasis to the brain nearly 2 years following excision of the primary skin mass with negative margins, negative sentinel nodes, and local radiation.
Case presentation
A 71-year-old Caucasian man presented to the emergency department with 3 weeks of forgetfulness, word-finding difficulty, gait disturbance, and left-sided hemineglect. He had a history of a 3 cm × 2 cm T2N0M0 stage IIa MCC of the right lower eyelid and cheek which had been treated with local excision with negative margins, negative sentinel lymph node biopsy, and external beam radiation (45 Gray total) to the parotid and ipsilateral neck roughly 20 months earlier. No imaging of his brain was performed at that time. His past medical history was significant for hypertension and rheumatoid arthritis (RA), for which he was prescribed hydroxychloroquine. Upon presentation to the emergency department he had normal vital signs. His physical exam was notable for left-sided hemineglect as well as left-sided tactile extinction. His laboratory results were notable only for a small increase in his serum creatinine from 1.1 to 1.4. Due to a history of anaphylaxis to intravenous contrast, a computed tomography (CT) scan of the brain without contrast was performed, which showed a mass-like area of hypodensity with mass effect on the right lateral ventricle and 6 mm of right-to-left midline shift. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain (Fig. 1) showed a 6.3 cm heterogeneous cystic and solid mass with surrounding increased T2 signal in the right frontotemporal regions, with an additional 5 mm lesion (Fig. 2) in the middle of the right superior frontal gyrus 9 mm from the longitudinal fissure. A 3.9 mm right-to-left midline shift with trapping of the temporal horn of the right lateral ventricle was described.Fig. 1 a, b Fluid-attenuated inversion recovery (FLAIR) and c, d T2-weighted imaging show increased T2 signal involving the right temporal lobe and right frontal lobe and no evidence of hemorrhage. A 9 mm right-to-left midline shift is shown with early right uncal herniation, effacement of the right lateral ventricle, and dilatation of the temporal horn of the right lateral ventricle. The hyperintense areas surrounding the lateral ventricles (a, b) are likely representative of leukoaraiosis rather than tumor lesions. e, f T1 imaging shows a 6.3 cm × 5.5 cm × 4.8 cm ring-enhancing heterogeneous cystic mass in the right frontotemporal region with a 3.5 cm × 3.0 cm avidly enhancing mural nodule with diffusion restriction (diffusion imaging not shown) on the lateral aspect of the mass
Fig. 2 Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) images demonstrating a 5 mm enhancing lesion (yellow arrow) in the right superior frontal gyrus
Neurosurgery was consulted and the patient was started on dexamethasone and levetiracetam. He was taken to the operating room the following morning for awake craniotomy and resection of the tumor. The neurosurgical team performed a BrainLAB-guided right temporal craniotomy with physiologic monitoring. They removed the entire frontotemporal mass, but did not attempt excision of the 5 mm superior front gyrus lesion. Histological analysis of the tumor showed signs of neuroendocrine features consistent with MCC. Serologic analysis showed he was MCPyV-negative. The patient was discharged home and followed up with radiation oncology and medical oncology. His positron emission tomography (PET)-CT scan showed no evidence of metastatic disease within the chest, abdomen, or pelvis. In order to treat the residual 5 mm right frontal lesion and the resection cavity, he received stereotactic radiation surgery (SRS) to both areas 1 month after diagnosis. SRS was selected over whole brain radiation therapy (WBRT) to avoid the neurotoxic effects from WBRT. He was started on pembrolizumab 1 week after radiation. He experienced improvement in his gait, strength, mental status, and vision in the weeks following treatment. His hemineglect gradually improved over the course of the next 6 months without evidence of new disease (Fig. 3). At 6 months from initiation, he had tolerated pembrolizumab without significant complication or worsening of his RA.Fig. 3 Magnetic resonance imaging of the brain 4.5 months postoperatively. Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) show mild irregular rim of enhancement around resection. Resolution of previously seen mass effect and midline shift. Decreased surrounding T2/FLAIR hyperintense signal change. FLAIR (d), T2 (e), and T1 (f) images showing interval resolution of previously noted 5 mm enhancing lesion in the right superior frontal gyrus
Discussion
MCC is a rare cancer of the skin which shows a predilection for sun-exposed areas and frequently affects older, lighter-skinned individuals. Regional lymph node metastasis is common at the time of presentation, with roughly 25% of individuals presenting with regional lymph node disease and ~ 10% of individuals with distant lymph node metastases. The 5-year survival rates range from 13 to 55% depending on the size and depth of the initial lesion, presence of occult or clinical regional lymph node metastases, and presence of distant metastases, with the worst prognosis in the last group [12]. Head and neck lesions provide a particularly challenging staging evaluation due to the variable lymphatic drainage in the region [27]. In our patient’s case, it is likely that the sentinel lymph node biopsy was a false negative given his subsequent metastasis.
Central nervous system (CNS) metastases are particularly rare, but have been reported previously in the literature. Fewer than 20 cases have been reported, with variable presentations, survival, and treatment modalities [14–26]. The mechanism for metastasis to the CNS is unclear; however, MCC’s predilection for the lymphatic system and recently discovered lymphatic system of the meninges in humans offers a potential explanation [28]. Due to the rarity of CNS metastases of Merkel cell, the optimal treatment is unknown, but there is some evidence that more aggressive regimens with resection, radiation, and chemotherapy improve survival [14, 20].
Immunotherapy therapy has become the treatment of choice in advanced MCC, with multiple phase I/II trials involving avelumab, nivolumab, and pembrolizumab showing encouraging responses [29–32]. Pertinent to our patient, a phase 2 non-controlled study of pembrolizumab for initial treatment showed a response rate of 56%, with 6-month progression-free survival of 67% [29]. Importantly, this trial showed durable responses, with 85% of responders in remission at 1 year and 79% at 2 years [33]. This was notably superior to traditional chemotherapy regimens, which have shown median progression-free survival of approximately 3 months and disease progression in 90% of patients by 10 months [34]. Avelumab is currently the only US Food and Drug Administration (FDA)-approved immunotherapy for metastatic MCC based on the JAVELIN Merkel 200 study; however, this study notably excluded patients with CNS metastasis and only included patients with previous systemic therapies, thus limiting the applicability to our patient [31].
While adjuvant pembrolizumab is not currently FDA-approved for MCC, the anti-programmed death protein 1 (PD1) agent was chosen based on the size of this MCC lesion (despite radiation therapy), the overall immunogenicity seen in MCC, the efficacy of this therapy in systemic treatment-naïve patients, the efficacy of the therapy in stage III melanoma, and efficacy demonstrated in treating CNS metastases of melanoma [35–37]. There is ongoing research into adjuvant immunotherapy for MCC, with two randomized phase II trials using avelumab or nivolumab. Lastly, given our patient’s history of RA, there is concern for exacerbation in the setting of pembrolizumab use [38]. Fortunately, he has not had exacerbation of his rheumatologic disease to date.
The patient also underwent SRS to his surgical cavity and additional 5 mm lesion. While WBRT is the standard of care for brain metastasis after surgical resection to prevent recurrence, SRS is increasingly used as an alternative [39]. This is because SRS after surgical resection of 1–3 metastases improves survival compared to observation alone and is associated with less neurocognitive decline than WBRT [40, 41]. Still, this is an area of ongoing investigation, and decisions regarding WBRT versus SRS should be made on an individualized basis, with shared decision-making between providers and patient.
This case highlights the aggressive nature of MCC and the difficulty in predicting the clinical course and optimal treatment of these lesions in the head and neck. Despite an initial lesion with negative resection margins and adjuvant radiation, our patient still had subsequent cerebral metastases. Interestingly, our patient had RA and had been treated for years with hydroxychloroquine. MCC incidence is increased among immunosuppressed patients such as those with organ transplantation, B cell malignancies, and human immunodeficiency virus (HIV) [42–44]. While hydroxychloroquine does not “suppress” the immune system in the classical sense, it has many immunomodulatory properties. It is unclear what role, if any, this may have on MCC incidence and progression. This case also highlights a potential blueprint for treatment of these rare metastases with the combination of prompt resection, SRS, and immunotherapy.
Conclusion
While it is certainly a rare event, consideration should be given for metastatic spread of MCC to the CNS when the patient has a known MCC primary and presents with neurological symptoms. Tissue diagnosis in these cases is of paramount importance, as it will influence treatment regimens moving forward. Aggressive treatment with prompt resection, SRS, and adjunctive immunotherapy has shown favorable results in this patient and should be considered in the rare event of CNS metastasis of MCC.
Abbreviations
MCC Merkel cell carcinoma
SRS Stereotactic radiosurgery
MCPyV Merkel cell polyomavirus
RA Rheumatoid arthritis
CNS Central nervous system
PD1 Programmed cell death protein 1
Acknowledgements
Not applicable.
Authors' contributions
Both Dr. Grubb and Dr. Hankollari participated in the care of this patient as well as the writing and editing of this manuscript. Both authors read and approved the final manuscript.
Funding
There were no funding sources for this article.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
All parts of this case report were conducted in line with the principles outlined in the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests, either financial or nonfinancial.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33714267 | 20,211,717 | 2021-03-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuroendocrine carcinoma of the skin'. | Cerebral metastasis of Merkel cell carcinoma following resection with negative margins and adjuvant external beam radiation: a case report.
BACKGROUND
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. It is associated with advanced age, ultraviolet (UV) radiation, and Merkel cell polyomavirus. It has a predilection for the lymphatic system, but rarely spreads to the central nervous system.
METHODS
A 71-year-old Caucasian man with a history of rheumatoid arthritis and MCC of the right lower eyelid and cheek presented with left-sided hemineglect and word-finding difficulty. Twenty months earlier he had undergone local excision of a 3 cm lesion with negative margins, negative sentinel lymph node biopsy, and external beam radiation. On presentation he was found to have a 6.3 cm mass in the right frontotemporal region. He underwent prompt resection, with pathological analysis consistent with metastatic MCC. He subsequently underwent stereotactic radiosurgery (SRS) and adjunctive immunotherapy with pembrolizumab. He has since tolerated the therapy well and is currently without neurological symptoms or evidence of recurrence.
CONCLUSIONS
Cerebral metastasis of MCC is a rare event and should be considered when a patient with a history of MCC presents with neurological symptoms. Optimal treatment regimens of these rare cases are unclear; however, prompt resection, stereotactic radiosurgery, and adjunctive immunotherapy have shown an initial positive response in this patient.
Background
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cancer of the skin. This cancer is named because of the dense neurosecretory granules found in the core of the cell which are reminiscent of Merkel cells, the mechanoreceptors found in the basal layer of the epidermis [1, 2]. While these are assumed to be the cells of origin of this malignancy, there are multiple hypotheses that suggest a possible different cell of origin such as immature totipotent stem cells, dermal fibroblasts, or epidermal keratinocytes [3–5]. Pathogenesis is believed to be related to Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation [6–9]. The incidence of MCC is estimated at 0.7 cases per 100,000 persons and predominantly affects older, lighter-skinned adults [10, 11]. Roughly 70% occur on the head and neck and the upper limbs [9, 12]. Treatment is centered on surgical excision for local disease; however, there is frequent local recurrence [12, 13]. Metastases are common, particularly to the lymph nodes, and sentinel node biopsy is an important aspect of staging [12]. Cerebral metastases are uncommon, with fewer than 20 cases reported in the literature [14–26]. We report here a case of MCC metastasis to the brain nearly 2 years following excision of the primary skin mass with negative margins, negative sentinel nodes, and local radiation.
Case presentation
A 71-year-old Caucasian man presented to the emergency department with 3 weeks of forgetfulness, word-finding difficulty, gait disturbance, and left-sided hemineglect. He had a history of a 3 cm × 2 cm T2N0M0 stage IIa MCC of the right lower eyelid and cheek which had been treated with local excision with negative margins, negative sentinel lymph node biopsy, and external beam radiation (45 Gray total) to the parotid and ipsilateral neck roughly 20 months earlier. No imaging of his brain was performed at that time. His past medical history was significant for hypertension and rheumatoid arthritis (RA), for which he was prescribed hydroxychloroquine. Upon presentation to the emergency department he had normal vital signs. His physical exam was notable for left-sided hemineglect as well as left-sided tactile extinction. His laboratory results were notable only for a small increase in his serum creatinine from 1.1 to 1.4. Due to a history of anaphylaxis to intravenous contrast, a computed tomography (CT) scan of the brain without contrast was performed, which showed a mass-like area of hypodensity with mass effect on the right lateral ventricle and 6 mm of right-to-left midline shift. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain (Fig. 1) showed a 6.3 cm heterogeneous cystic and solid mass with surrounding increased T2 signal in the right frontotemporal regions, with an additional 5 mm lesion (Fig. 2) in the middle of the right superior frontal gyrus 9 mm from the longitudinal fissure. A 3.9 mm right-to-left midline shift with trapping of the temporal horn of the right lateral ventricle was described.Fig. 1 a, b Fluid-attenuated inversion recovery (FLAIR) and c, d T2-weighted imaging show increased T2 signal involving the right temporal lobe and right frontal lobe and no evidence of hemorrhage. A 9 mm right-to-left midline shift is shown with early right uncal herniation, effacement of the right lateral ventricle, and dilatation of the temporal horn of the right lateral ventricle. The hyperintense areas surrounding the lateral ventricles (a, b) are likely representative of leukoaraiosis rather than tumor lesions. e, f T1 imaging shows a 6.3 cm × 5.5 cm × 4.8 cm ring-enhancing heterogeneous cystic mass in the right frontotemporal region with a 3.5 cm × 3.0 cm avidly enhancing mural nodule with diffusion restriction (diffusion imaging not shown) on the lateral aspect of the mass
Fig. 2 Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) images demonstrating a 5 mm enhancing lesion (yellow arrow) in the right superior frontal gyrus
Neurosurgery was consulted and the patient was started on dexamethasone and levetiracetam. He was taken to the operating room the following morning for awake craniotomy and resection of the tumor. The neurosurgical team performed a BrainLAB-guided right temporal craniotomy with physiologic monitoring. They removed the entire frontotemporal mass, but did not attempt excision of the 5 mm superior front gyrus lesion. Histological analysis of the tumor showed signs of neuroendocrine features consistent with MCC. Serologic analysis showed he was MCPyV-negative. The patient was discharged home and followed up with radiation oncology and medical oncology. His positron emission tomography (PET)-CT scan showed no evidence of metastatic disease within the chest, abdomen, or pelvis. In order to treat the residual 5 mm right frontal lesion and the resection cavity, he received stereotactic radiation surgery (SRS) to both areas 1 month after diagnosis. SRS was selected over whole brain radiation therapy (WBRT) to avoid the neurotoxic effects from WBRT. He was started on pembrolizumab 1 week after radiation. He experienced improvement in his gait, strength, mental status, and vision in the weeks following treatment. His hemineglect gradually improved over the course of the next 6 months without evidence of new disease (Fig. 3). At 6 months from initiation, he had tolerated pembrolizumab without significant complication or worsening of his RA.Fig. 3 Magnetic resonance imaging of the brain 4.5 months postoperatively. Fluid-attenuated inversion recovery (FLAIR) (a), T2 (b), and T1 (c) show mild irregular rim of enhancement around resection. Resolution of previously seen mass effect and midline shift. Decreased surrounding T2/FLAIR hyperintense signal change. FLAIR (d), T2 (e), and T1 (f) images showing interval resolution of previously noted 5 mm enhancing lesion in the right superior frontal gyrus
Discussion
MCC is a rare cancer of the skin which shows a predilection for sun-exposed areas and frequently affects older, lighter-skinned individuals. Regional lymph node metastasis is common at the time of presentation, with roughly 25% of individuals presenting with regional lymph node disease and ~ 10% of individuals with distant lymph node metastases. The 5-year survival rates range from 13 to 55% depending on the size and depth of the initial lesion, presence of occult or clinical regional lymph node metastases, and presence of distant metastases, with the worst prognosis in the last group [12]. Head and neck lesions provide a particularly challenging staging evaluation due to the variable lymphatic drainage in the region [27]. In our patient’s case, it is likely that the sentinel lymph node biopsy was a false negative given his subsequent metastasis.
Central nervous system (CNS) metastases are particularly rare, but have been reported previously in the literature. Fewer than 20 cases have been reported, with variable presentations, survival, and treatment modalities [14–26]. The mechanism for metastasis to the CNS is unclear; however, MCC’s predilection for the lymphatic system and recently discovered lymphatic system of the meninges in humans offers a potential explanation [28]. Due to the rarity of CNS metastases of Merkel cell, the optimal treatment is unknown, but there is some evidence that more aggressive regimens with resection, radiation, and chemotherapy improve survival [14, 20].
Immunotherapy therapy has become the treatment of choice in advanced MCC, with multiple phase I/II trials involving avelumab, nivolumab, and pembrolizumab showing encouraging responses [29–32]. Pertinent to our patient, a phase 2 non-controlled study of pembrolizumab for initial treatment showed a response rate of 56%, with 6-month progression-free survival of 67% [29]. Importantly, this trial showed durable responses, with 85% of responders in remission at 1 year and 79% at 2 years [33]. This was notably superior to traditional chemotherapy regimens, which have shown median progression-free survival of approximately 3 months and disease progression in 90% of patients by 10 months [34]. Avelumab is currently the only US Food and Drug Administration (FDA)-approved immunotherapy for metastatic MCC based on the JAVELIN Merkel 200 study; however, this study notably excluded patients with CNS metastasis and only included patients with previous systemic therapies, thus limiting the applicability to our patient [31].
While adjuvant pembrolizumab is not currently FDA-approved for MCC, the anti-programmed death protein 1 (PD1) agent was chosen based on the size of this MCC lesion (despite radiation therapy), the overall immunogenicity seen in MCC, the efficacy of this therapy in systemic treatment-naïve patients, the efficacy of the therapy in stage III melanoma, and efficacy demonstrated in treating CNS metastases of melanoma [35–37]. There is ongoing research into adjuvant immunotherapy for MCC, with two randomized phase II trials using avelumab or nivolumab. Lastly, given our patient’s history of RA, there is concern for exacerbation in the setting of pembrolizumab use [38]. Fortunately, he has not had exacerbation of his rheumatologic disease to date.
The patient also underwent SRS to his surgical cavity and additional 5 mm lesion. While WBRT is the standard of care for brain metastasis after surgical resection to prevent recurrence, SRS is increasingly used as an alternative [39]. This is because SRS after surgical resection of 1–3 metastases improves survival compared to observation alone and is associated with less neurocognitive decline than WBRT [40, 41]. Still, this is an area of ongoing investigation, and decisions regarding WBRT versus SRS should be made on an individualized basis, with shared decision-making between providers and patient.
This case highlights the aggressive nature of MCC and the difficulty in predicting the clinical course and optimal treatment of these lesions in the head and neck. Despite an initial lesion with negative resection margins and adjuvant radiation, our patient still had subsequent cerebral metastases. Interestingly, our patient had RA and had been treated for years with hydroxychloroquine. MCC incidence is increased among immunosuppressed patients such as those with organ transplantation, B cell malignancies, and human immunodeficiency virus (HIV) [42–44]. While hydroxychloroquine does not “suppress” the immune system in the classical sense, it has many immunomodulatory properties. It is unclear what role, if any, this may have on MCC incidence and progression. This case also highlights a potential blueprint for treatment of these rare metastases with the combination of prompt resection, SRS, and immunotherapy.
Conclusion
While it is certainly a rare event, consideration should be given for metastatic spread of MCC to the CNS when the patient has a known MCC primary and presents with neurological symptoms. Tissue diagnosis in these cases is of paramount importance, as it will influence treatment regimens moving forward. Aggressive treatment with prompt resection, SRS, and adjunctive immunotherapy has shown favorable results in this patient and should be considered in the rare event of CNS metastasis of MCC.
Abbreviations
MCC Merkel cell carcinoma
SRS Stereotactic radiosurgery
MCPyV Merkel cell polyomavirus
RA Rheumatoid arthritis
CNS Central nervous system
PD1 Programmed cell death protein 1
Acknowledgements
Not applicable.
Authors' contributions
Both Dr. Grubb and Dr. Hankollari participated in the care of this patient as well as the writing and editing of this manuscript. Both authors read and approved the final manuscript.
Funding
There were no funding sources for this article.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
All parts of this case report were conducted in line with the principles outlined in the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests, either financial or nonfinancial.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33714267 | 20,230,857 | 2021-03-14 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemorrhage in pregnancy'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | ASPIRIN, AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,766,637 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normal newborn'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | ASPIRIN, AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,454,032 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Placenta accreta'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | ASPIRIN, AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,766,637 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Placenta praevia haemorrhage'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,817,356 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rebound effect'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | ASPIRIN, AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,454,032 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Systemic lupus erythematosus'. | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | ASPIRIN, AZATHIOPRINE, ETANERCEPT, HYDROXYCHLOROQUINE, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY | 33715506 | 19,454,032 | 2021-06 |
What was the outcome of reaction 'Haemorrhage in pregnancy'? | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | Recovered | ReactionOutcome | CC BY | 33715506 | 19,766,637 | 2021-06 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | Recovered | ReactionOutcome | CC BY | 33715506 | 19,766,637 | 2021-06 |
What was the outcome of reaction 'Placenta accreta'? | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | Recovered | ReactionOutcome | CC BY | 33715506 | 19,766,637 | 2021-06 |
What was the outcome of reaction 'Placenta praevia haemorrhage'? | Systemic lupus erythematosus and COVID-19 during pregnancy.
Background: The ongoing corona virus disease 2019 (COVID-19) pandemic is having a worldwide impact. Valuable information on the clinical characteristics of COVID-19 in pregnant patients with an autoimmune disease, such as systemic lupus erythematosus (SLE), is currently lacking. Methods: Herein, we describe the clinical presentation of 2 pregnant patients with SLE and mild symptomatic COVID-19 infection. Results: In both pregnant SLE patients, a watchful-waiting approach without initiation of treatment for COVID-19 was taken. No adverse outcomes were reported and both pregnancies resulted in healthy neonates born at term. In one patient we observed a flare in SLE disease activity, most likely attributed to discontinuing SLE treatment. Conclusion: Our report highlights the importance of multidisciplinary collaboration between health care professionals as well as individualized treatment decisions during unprecedented periods such as the current COVID-19 pandemic. Discontinuation of immunosuppressive drugs during the acute phase of a COVID-19 infection should be considered on a case-by-case basis. Maternal treatment decisions should be in line with current recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection and in line with treatment of COVID- 19 during pregnancy.
The corona virus disease 2019 (COVID-19) pandemic has spread across the world. Infection with the novel corona virus can result in hypoxemic respiratory failure in a small percentage of patients.1 Compared to the SARS-CoV-1 (SARS) pandemic in 2008, which is associated with spontaneous miscarriage, preterm delivery, and intrauterine growth restriction, COVID-19 seems to have less impact on pregnancy.2 To date, evidence suggest that there is no increased risk of severe disease in pregnant women, with low risks of vertical transmission or fetal distress.3–5
Systemic lupus erythematosus (SLE) is characterized by an abnormal activation of the immune system and subsequent generation of autoantibodies resulting in a wide spectrum of systemic clinical manifestations.6 The clinical and therapeutic management of SLE during pregnancy is considered a clinical challenge due to the teratogenicity of effective drugs and because SLE flares are associated with a higher risk of pregnancy complications and serious adverse pregnancy outcomes.6,7
Currently, practical clinical information is lacking on the characteristics of COVID-19 in pregnant patients with an autoimmune disease. During the beginning of the current pandemic, we encountered 2 pregnant patients with SLE and symptomatic COVID-19. To the best of our knowledge, no reports on the presentation and outcome of pregnant SLE patients suffering from COVID-19 have been published. An overview of the cases is described in Table 1.
Table 1. Clinical and demographic features of the described SLE patients with COVID-19 during pregnancy and their offspring.
Case 1 Case 2
Maternal age (years) 31 39
Disease duration (years) 16 20
Disease characteristics (SLICC/ACR score)Damage Index, organ involvement 1 (arthritis) 2 (arthritis, renal)
SLEDAI score, (description) 2 (low complement) 4 (arthritis)
Medication use Azathioprine Azathioprine
Hydroxychloroquine Etanercept
Prednisone
Gravidity, parity (n) G1P0 G2P1
Mode of delivery Induced labor Caesarean section
Sex of the newborn Female Male
Gestational age (weeks, days) 38, 1 38, 5
Birthweight (grams) 2880 4205
APGAR score (after 5 minutes) 9 9
Congenital malformations – –
SLICC/ACR damage index indicates Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index, SLEDAI indicates Systemic Lupus Erythematosus Disease Activity Index score.
Case 1: 31 year old, gravida 1, para 0, gestational age of 38 weeks, diagnosed with SLE at age 15 and preexisting hypertension. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI)8 was 1. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive. At the time she was being treated with azathioprine (25 mg/day), hydroxychloroquine (200 mg/day), prednisone (5 mg/day). Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed, this was agreed after multidisciplinary consultation. During pregnancy, SLE disease activity was mild. Based on her risk profile, she was admitted at 38 + 1 weeks of gestation to induce labor. At admission, she reported mild respiratory symptoms and tested positive for COVID-19 the next day. Her SLE treatment (azathioprine, hydroxychloroquine and prednisone) was not stopped nor reduced in dosage. She was induced on the same day as the positive test and protective measures were taken to prevent viral spreading during labor. A healthy girl with an Apgar score of 9/10, birthweight of 2880 grams, without congenital malformations was born. Vertical transmission of SARS-CoV-2 was ruled out by a negative PCR. Pathological examination of the placenta was not performed. Mother and daughter spent the night in isolation in the hospital and were discharged the next morning. The patient did not breastfeed and made a full recovery without residual symptoms.
Case 2: 39 year old patient diagnosed with SLE at age 19, SDI score 2 (lupus nephritis class 4, anti-phospholipid antibodies negative), gravida 2 para 1, 19 weeks of gestation and an obstetric history of preeclampsia. She presented herself at our Reproductive-Rheumatology outpatient clinic with a wish to conceive while being treated with hydroxychloroquine, azathioprine and etanercept. She was treated with etanercept because of disabling and therapy resistant arthritis. Prophylactic acetyl sialic acid was initiated after pregnancy was confirmed. At 19 + 0 weeks of gestation she presented herself at the emergency room with complaints of dyspnea and coughing. The diagnosis of COVID-19 was confirmed by a positive PCR test. No signs of severe disease were detected (O2 = 99%). Treatment with azathioprine and etanercept was discontinued. She was sent home to recover in quarantine. 9 days after the positive test, the patient reported arthralgia after which azathioprine was restarted. At day 15 after testing, she did not report any further symptoms related to COVID-19 and treatment with etanercept was restarted. Following current treatment recommendations etanercept was stopped at 30 weeks of gestation.9 Henceforth, oligoarthritis was confirmed by her rheumatologist (CMC1, MCP2, right knee and ankle). For this reason, she received local injections with glucocorticoids (triamcinolone acetonide). The patient was admitted to the hospital for a repeat caesarean section. A healthy son was born, Apgar score of 9/10 and a birthweight of 4205 gram. The delivery was complicated by a placenta accrete resulting in a massive hemorrhage which was treated with intravenous sulpostron, tranexamic acid, calcium en fibrinogen as well as two packed cells. Postpartum hemoglobin was 7.57 g/dl. Pathological examination of the placenta (weight: 460 gram, P33) showed no abnormalities related to a COVID-19 infection4: no local inflammation or fibrin depositions. Three days after delivery, the patient and her newborn were discharged from the hospital in good health.
Herein, we present two cases of pregnant patients with SLE with confirmed COVID-19 disease and mild symptoms during pregnancy. In both cases a watchful-waiting approach, in line with (inter)national guidelines, was taken without initiation of treatment for COVID-19. In both cases healthy newborns were born. One patient showed a flare in SLE disease activity, most likely induced by discontinuation of treatment and unrelated to the COVID-19 infection. Our cases highlight the importance of individualizing treatment decisions that present during unprecedented times like the current COVID-19 pandemic. Currently there is no information on how to manage COVID-19 during pregnancy in patients diagnosed with rheumatic diseases. Therefore, close collaboration between rheumatologists and gynaecologists is encouraged. The decisions whether to continue or discontinue immunosuppressive drugs should be taken using a multidisciplinary approach and should be dynamic in line with possible rapidly changing, new insights. Patients should also be informed and involved in this shared decision making process. If needed, consultation with expertise centers is advised. In mild cases, like the ones presented here, discontinuation of immunosuppressive drugs in the acute phase of COVID-19 infection should be considered on a case-by-case basis. Our approach was in line with the current European League Against Rheumatism (EULAR) recommendations for treatment of rheumatic and musculoskeletal diseases during COVID-19 infection outside pregnancy [9]. Current information on the safety of breastfeeding of COVID-19 patients is reassuring and seems to be safe.10 Case reports on neonatal COVID-19 are scarce and show mild disease in newborns.10 In the coming months, the discussion on this topic should expand and cover the safety and need of the future COVID-19 vaccine in pregnant patients with auto-immune diseases.
Key message
An individualized and multidisciplinary therapeutic approach in pregnant SLE patients diagnosed with COVID-19 is recommended.
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Dutch Arthritis Foundation (ReumaNederland) (project number: LLP-26), a non-profit organization.
Ethical approval: Informed consent was obtained.
Contributorship: All authors met the authorship criteria. They had a substantial contribution to the conception and design of the work and the acquisition and interpretation of the data used for the work. They were involved in revising a draft of this work, gave final approval of this version to be published, and are accountable for all aspects of the work in ensuring accuracy and integrity.
ORCID iD: Hieronymus TW Smeele https://orcid.org/0000-0001-7724-7712 | Recovering | ReactionOutcome | CC BY | 33715506 | 19,817,356 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Contraindicated product administered'. | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | ASPIRIN, AZELNIDIPINE, CARVEDILOL, CILOSTAZOL, CLOPIDOGREL BISULFATE, EDOXABAN TOSYLATE, FEBUXOSTAT, HYDROCORTISONE, PRAVASTATIN, PROPAFENONE, REPAGLINIDE, TENELIGLIPTIN, VERAPAMIL HYDROCHLORIDE, VONOPRAZAN | DrugsGivenReaction | CC BY-NC-ND | 33716254 | 19,180,403 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coronary artery dissection'. | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | ASPIRIN, AZELNIDIPINE, CARVEDILOL, CILOSTAZOL, CLOPIDOGREL BISULFATE, EDOXABAN TOSYLATE, FEBUXOSTAT, HYDROCORTISONE, PRAVASTATIN SODIUM, PROPAFENONE, REPAGLINIDE, TENELIGLIPTIN, UNSPECIFIED INGREDIENT, VERAPAMIL HYDROCHLORIDE, VONOPRAZAN | DrugsGivenReaction | CC BY-NC-ND | 33716254 | 19,137,817 | 2021 |
What was the administration route of drug 'REPAGLINIDE'? | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33716254 | 19,140,109 | 2021 |
What was the administration route of drug 'TENELIGLIPTIN'? | Hypoglycemia during the Concomitant Use of Repaglinide and Clopidogrel in an Elderly Patient with Type 2 Diabetes and Severe Renal Insufficiency.
Hypoglycemia should be avoided when treating patients with diabetes. Repaglinide is an insulin secretagogue with a low hypoglycemic risk because of its rapid- and short-acting effects. However, its blood concentration has been reported to increase in combination with clopidogrel, an antiplatelet drug, and in patients with severe renal insufficiency. We herein report an elderly patient with type 2 diabetes mellitus and severe renal insufficiency who received repaglinide and hypoglycemia three days after starting clopidogrel. The concomitant use of repaglinide and clopidogrel can lead to hypoglycemia, especially in patients with severe renal insufficiency.
Introduction
The main goal of diabetes treatment is to ensure these patients have the same quality of life and longevity as healthy people by reducing the risk of micro- and macrovascular complications, such as diabetic nephropathy and cardiovascular disease (CVD). To achieve this goal, the comprehensive control of blood glucose without hypoglycemia as well as that of blood pressure, lipid, and body weight are crucial (1).
In Japan, as of June 2020, seven types of oral hypoglycemic agents (OHA) have been approved for the treatment of type 2 diabetes mellitus (T2DM). Repaglinide, as well as nateglinide and mitiglinide, belongs to the class of medications known as meglitinides, which act on sulfonylurea receptors on pancreatic β-cells to promote postprandial insulin secretion, thus mainly reducing postprandial glucose levels (2). Patients taking repaglinide are at risk of hypoglycemia, similar to that conferred by insulin and sulfonylureas. However, based on its rapid- and short-acting effects, repaglinide has a lower hypoglycemic risk than insulin or sulfonylureas (3). In addition, repaglinide is almost completely metabolized in the liver, and its metabolites are excreted primarily through the bile. Only a very small fraction (less than 8%) of the administered dose is excreted through the urine (4). Therefore, patients taking repaglinide are considered to have a low risk of hypoglycemia even when they have mild or moderate renal insufficiency (5).
Clopidogrel is a second-generation thienopyridine antiplatelet drug that is the mainstay of the treatment and secondary prevention of CVD in patients with T2DM. Recently, the concomitant use of repaglinide and clopidogrel has been shown to result in the elevation of blood concentration of repaglinide (6). In addition, few reports have shown that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). However, there are no reports on the clinical course of hypoglycemia due to the interaction of these drugs in patients with T2DM and severe renal insufficiency.
We herein report a patient with T2DM with severe renal insufficiency and describe the patient's clinical course, which included hypoglycemia owing to concomitant use of repaglinide and clopidogrel.
Case Report
Informed consent was obtained from the patient, and all procedures were approved by the appropriate institutional review board (the Ethics Committee of Osaka Police Hospital) and comply with the Declaration of Helsinki and its amendments.
We encountered an 81-year-old Japanese woman with T2DM and severe renal insufficiency who was receiving repaglinide and who developed hypoglycemia 3 days after starting clopidogrel. At 50 years old, she was diagnosed with T2DM and treated with OHAs. She subsequently had hypertension, dyslipidemia, atrial fibrillation, CVD, peripheral artery disease (PAD), and adrenal insufficiency owing to approximately five years of glucocorticoid treatment for autoimmune hepatitis, and her renal function gradually deteriorated. At 81 years old, she was admitted to our hospital for the treatment of acute coronary artery dissection. On admission, she was prescribed the following medications for T2DM, dyslipidemia, hyperuricemia, hypertension, CVD, PAD, atrial fibrillation, gastroesophageal reflux disease, and secondary adrenal insufficiency: teneligliptin 40 mg, repaglinide 1.5 mg, pravastatin 10 mg, febuxostat 20 mg, carvedilol 1.25 mg, azelnidipine 16 mg, verapamil 80 mg, cilostazol 200 mg, aspirin 100 mg, adoxaban 10 mg, propafenone 300 mg, vonoprazan 20 mg and hydrocortisone 10 mg per day, respectively.
She underwent emergent percutaneous coronary intervention for the dissection site of the left main coronary artery, and aspirin was changed to clopidogrel, while cilostazol was continued. At that time, her diabetes was treated with a 1,440-kcal diabetic diet and two OHAs (teneligliptin 20 mg×2/day, and repaglinide 0.5 mg×3/day). She did not develop hypoglycemia with these agents. However, her fasting plasma glucose level before breakfast gradually decreased, and hypoglycemia (63 mg/dL) developed 3 days after starting clopidogrel. Her cardiologist then reduced the 40 mg dose of teneligliptin to 20 mg, but her hypoglycemia (50-64 mg/dL) did not disappear. Nine days after starting clopidogrel, she was referred to our department for a detailed examination and treatment of her recurrent hypoglycemia (Figure).
Figure. Clinical course of the daily profile of blood glucose and medications. Blood glucose was measured with a glucometer. [ ] indicates the plasma glucose levels measured in the laboratory. PCI: percutaneous coronary intervention
On referral, the patient had no obvious hypoglycemic symptoms despite her pre-breakfast plasma glucose level of 50 mg/dL. Her body weight was 44.1 kg (body mass index: 16.0 kg/m2), blood pressure 101/60 mmHg, pulse rate 103 bpm, and body temperature 36.8°C. She had no abnormal physical signs. We suspected that her hypoglycemia was caused by the concomitant use of repaglinide and clopidogrel based on her clinical course and therefore discontinued repaglinide from before lunch on the referral day.
Her laboratory examination results the day after referral to our department are shown in Table 1. Her fasting plasma glucose level was 85 mg/dL, indicating no hypoglycemia, probably because repaglinide had been discontinued; her fasting C-peptide was 2.71 ng/mL, and her immunoreactive insulin level was 3.7 μU/mL. In addition, an insulin autoantibody test was negative. Her renal function was impaired, with a plasma urea nitrogen of 25.5 mg/dL, creatinine of 1.3 mg/dL, and estimated glomerular filtration ratio of 30.5 mL/min/1.73 m2. Endocrinological examinations revealed that the baseline levels of adrenocorticotropic hormone and cortisol were within the normal ranges, and the patient had a postmenopausal status.
Table 1. Laboratory Findings on Referral to Our Department.
Hematology ALP 128 U/L
WBC 8,400 /μL γ-GTP 20 U/L
RBC 284×10,000 /μL CRP 3.62 mg/dL
Hb 8.7 g/dL Glucose 85 mg/dL
Ht 25.3 % HbA1c 6.4 %
Plt 24.9×10,000 /μL IRI 3.7 μU/mL
C-peptide 2.71 ng/mL
Biochemistry Insulin antibody <0.4 %
TP 6.1 g/dL
Alb 2.8 g/dL Endocrine examination
BUN 25.5 mg/dL ACTH 15.7 pg/mL
Cr 1.3 mg/dL Cortisol 10.3 μg/dL
eGFR 30.5 mL/min/1.73 m2 TSH 2.43 μU/mL
Na 133 mEq/L Free T4 1.09 ng/mL
K 3.9 mEq/L GH 0.76 ng/mL
Cl 101 mEq/L IGF-1 76 ng/mL
Ca 9.1 mg/dL LH 16.61 mIU/mL
P 2.7 mg/dL FSH 48.7 mIU/mL
TB 0.5 mg/dL Estoradiol 22 pg/mL
AST 16 U/L Prolactin 16.52 ng/mL
ALT 10 U/L
WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, HT: hematocrit, Plt: platelet, TP: total protein, Alb: albumin, BUN: urea nitrogen, Cr: creatinine, eGFR: estimated glomerular filtration ratio, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, TB: total bilirubin, AST: aspartate aminotransaminase, ALT: alanine aminotransaminase, ALP: alkaline phosphatase, γ-GTP: gamma glutamyl transpeptidase, CRP: C-reactive protein, HbA1c: glycated hemoglobin A1c, IRI: immunoreactive insulin, ACTH: adrenocorticotropic hormone, TSH: thyroid stimulating hormone, Free T4: free thyroxine, GH: growth hormone, IGF-1: insulin-like growth factor-1, LH: luteinizing hormone, FSH: follicle stimulating hormone
After discontinuing repaglinide, her fasting plasma glucose level increased. We evaluated fasting C-peptide levels using her preserved serum 2 days before stopping repaglinide, when hypoglycemia occurred repeatedly. We found that her fasting serum C-peptide level was high (4.73 ng/mL), glucose level was low (64 mg/dL), and C-peptide index (CPI; fasting plasma C-peptide ×100/fasting plasma glucose) was high at 7.4. However, her CPI decreased to 2.3 at 5 days after stopping repaglinide (15 days after admission) (Table 2). Based on these results and her clinical course, we diagnosed her with hypoglycemia due to the concomitant use of repaglinide and clopidogrel. Although we prescribed mitiglinide 10 mg×3/day 8 days after discontinuing repaglinide while continuing clopidogrel, her fasting plasma glucose levels were around 150 mg/dL without hypoglycemia at discharge. Thereafter, her diabetes was treated with teneligliptin 20 mg×2/day and mitiglinide 10 mg×3/day while continuing clopidogrel, and hypoglycemia was not detected 4 months after discharge.
Table 2. Changes in CPI with and without Repaglinide and Clopidogrel.
repaglinide clopidogrel FPG (mg/dL) CPR (ng/mL) CPI eGFR (mL/min/1.73 m2)
Day 8 + + 64 4.73 7.4 34.2
Day 10 - + 85 2.71 3.2 30.5
Day 15 - + 135 3.04 2.3 35.9
Day: Days after admission, FPG: fasting plasma glucose, CPI: C-peptide index (fasting plasma C-peptide×100/fasting plasma glucose), eGFR: estimated glomerular filtration ratio
Discussion
We encountered a patient with T2DM and severe renal insufficiency who received repaglinide and developed hypoglycemia three days after starting clopidogrel. To our knowledge, this is the first report to describe the clinical course leading to hypoglycemia due to the concomitant use of repaglinide and clopidogrel in a patient with T2DM and severe renal insufficiency.
Severe hypoglycemia has been shown to be associated with macro- and microvascular events, dementia, fracture, and mortality in patients with diabetes (9, 10). In addition, observational studies have suggested that hypoglycemia is associated with an increased risk of death in patients with diabetes hospitalized for acute coronary syndrome (11, 12). Furthermore, elderly patients with diabetes are more susceptible to hypoglycemic adverse events than younger ones owing to their unspecific and uncharacteristic hypoglycemic symptoms, probably caused by less effective counterregulatory mechanisms, reduced drug elimination caused by renal insufficiency, and motor and cognitive impairment (13). Fortunately, our patient did not experience any hypoglycemic adverse events. However, if she had not been under hospital observation, she might have experienced hypoglycemic adverse events because she did not present with typical hypoglycemic symptoms, and this may have delayed the detection of hypoglycemia. Therefore, various treatment guidelines for diabetes generally recommend not only avoiding hypoglycemia but also enacting less stringent glycemic control in elderly patients (14, 15). The Japan Diabetes Society recommends setting a lower limit for the target HbA1c value in elderly patients receiving insulin, sulfonylureas, or meglitinide, who are at risk of hypoglycemia (1). According to this recommendation, the target HbA1c value in our patient was 7.0-8.0%. Considering that the patient had mild anemia, probably because of severe renal insufficiency, and her actual HbA1c value was assumed to be slightly higher than the measured value (6.4%), we believe that our patient's condition was adequately controlled.
It has recently been reported that the concomitant use of repaglinide and clopidogrel causes hypoglycemia in patients with T2DM (7, 8). Wei et al. reported that the concomitant use of repaglinide and clopidogrel was associated with an increased risk of hypoglycemia compared with repaglinide alone in a population-based study using real-world data in Taiwan (adjusted odds ratio: 2.42; 95% confidence interval: 1.75, 3.35). In addition, no significant associations of hypoglycemia were found with the concomitant use of repaglinide with aspirin or with that of nateglinide and clopidogrel (7). Akagi et al. also reported a risk of hypoglycemia associated with the combined use of repaglinide and clopidogrel in a retrospective cohort study using hospitalized patients who started repaglinide and whose preprandial plasma glucose level was measured. In that study, hypoglycemia was observed in 6 of 15 patients in the repaglinide and clopidogrel group, while it was observed only in 1 of 15 patients in the mitiglinide and clopidogrel group; no patients in the repaglinide alone group developed hypoglycemia. All patients who developed hypoglycemia had a plasma glucose level of ＜150 mg/dL measured 5 days before starting glinide (8). Based on this finding, our patient likely had hypoglycemia, since the preprandial plasma glucose level before starting clopidogrel was 112 mg/dL.
The mechanism underlying hypoglycemia development caused by the concomitant use of repaglinide and clopidogrel is assumed to be as follows: repaglinide is primarily metabolized by cytochrome P450 (CYP) 2C8 (16). However, clopidogrel is metabolized by multiple CYP enzymes, mainly CYP2C19, and its metabolite, clopidogrel acyl-β-D-glucuronide, has been shown to inhibit CYP2C8 potently in a time-dependent manner in vitro (6). A physiologically based pharmacokinetic model has also indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment (6). These results suggest that clopidogrel causes drug interactions with other medications metabolized by CYP2C8, such as repaglinide. In actuality, a placebo-controlled crossover study in 9 healthy volunteers who received clopidogrel for 3 days (300 mg on day 1 followed by 75 mg daily) and repaglinide (0.25 mg at 9 AM, 1 hour after clopidogrel intake on day 1 and 3) showed that the geometric mean area under the concentration-time curve (AUC0-∞) of repaglinide was increased by 5.1- and 3.9-fold on days 1 and 3 of clopidogrel treatment, respectively. In addition, that study showed that the maximum plasma concentration (Cmax) was increased 2.0- and 2.5-fold, the elimination half-life (t1/2) was prolonged by 42% and 22%, and the CYP2C8-dependent metabolite (M)4 to repaglinide AUC0-9h ratio was reduced to 19% and 27%, respectively. Furthermore, the lowest mean blood glucose for the study participants was 59.5 mg/dL despite an adequate food intake (6). These results strengthen the possibility that clopidogrel substantially increases the hypoglycemic risk in patients with T2DM who receive repaglinide. In fact, a retrospective survey in our hospital revealed that two of four patients who underwent concomitant use of repaglinide and clopidogrel, except for the patient in the present case, developed hypoglycemia (unpublished data). Based on these results and the fact that the concomitant use of repaglinide and clopidogrel has been contraindicated since 2015 in Canada (17) and cautioned against on the drug package insert since 2016 in Japan (18), the concomitant use of repaglinide and clopidogrel is now (as of 2020) contraindicated under the approval of our pharmaceutical affairs committee in our hospital. However, meglitinides other than repaglinide, such as nateglinide and mitiglinide, are presumed to not cause hypoglycemia when used concomitantly with clopidogrel, although this presumption needs to be confirmed. This is because nateglinide is metabolized by CYP2C9 (70%) and CYP3A4 (30%), on which clopidogrel has little inhibitory effect, and because mitiglinide is eliminated through gluconidation by uridine 5'-diphospho-glucuronosyltransferases 1A3 and 2B7 (19, 20). Therefore, if patients receiving clopidogrel need meglitinides, nateglinide or mitiglinide may be suitable for avoiding hypoglycemia.
Our patient had severe renal insufficiency due to diabetic kidney disease. Repaglinide is theoretically considered to confer a low risk of hypoglycemia even in patients with renal insufficiency, because repaglinide is metabolized mainly in the liver, and most of its metabolites are excreted through the bile. However, the AUC0-∞, Cmax and t1/2 of repaglinide in patients with severe renal insufficiency (creatinine clearance: 20-39 mL/min) as in our case, have been reported to be increased 1.7- and 1.3-fold and prolonged 130%, respectively, although these parameters in patients with mild-to-moderate renal insufficiency are comparable to those with a normal renal function (5). In addition, renal insufficiency impairs not only renal glucogenesis but also insulin clearance, leading to an increased risk of hypoglycemia (21). Therefore, based on these findings, severe renal insufficiency as in our case is assumed to enhance the risk of hypoglycemia owing to the concomitant use of repaglinide and clopidogrel.
Several limitations associated with the present study warrant mention. First, it is possible that hypoglycemia was caused by the direct effect of repaglinide, via the induction of glucose toxicity, rather than to the concomitant use of repaglinide and clopidogrel. Unfortunately, we were unable to evaluate the clinical course and CPI levels with repaglinide and without clopidogrel after hypoglycemia. However, considering the patient's HbA1c values with anemia 3 months before and after admission (6.7% and 6.4%, respectively) and the daily profile of blood glucose after hospitalization, we believe that the patient's diabetes was controlled without remarkable glucose toxicity. In addition, considering that the patient had no detected hypoglycemia during the treatment with repaglinide and without clopidogrel, before and after admission, and that hypoglycemia occurred after initiating clopidogrel, we considered the hypoglycemia to be due to the concomitant use of repaglinide and clopidogrel. Second, it is possible that adrenal insufficiency influenced the hypoglycemia. However, we speculate that adrenal insufficiency had little effect on the hypoglycemia in this patient, as the hypoglycemia did not occur before starting clopidogrel, and the discontinuation of repaglinide improved the hypoglycemia without changing the dose of hydrocortisone. In addition, insulin secretion was not suppressed during hypoglycemia. Third, the patient's blood concentration of repaglinide was not investigated. Fourth, CYP2C8 gene polymorphisms may have affected the blood concentration of repaglinide and were also not investigated (22). However, we believe that our report provides information on safe diabetes treatment that aims to prevent incidental hypoglycemia in patients with macrovascular complications requiring repaglinide and/or clopidogrel.
In conclusion, we encountered an elderly patient with T2DM and severe renal insufficiency who developed hypoglycemia due to the concomitant use of repaglinide and clopidogrel. The risk of developing hypoglycemia is considered to vary from patient to patient, but we should recognize that a patient's concomitant use of repaglinide and clopidogrel puts them at high risk of developing hypoglycemia, especially those with T2DM and severe renal insufficiency.
Author's disclosure of potential Conflicts of Interest (COI).
Tetsuyuki Yasuda: Honoraria, Takeda Pharmaceutical, Novartis Pharmaceuticals and Nippon Boehringer Ingelheim. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33716254 | 19,140,109 | 2021 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.