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6,701 | logistically impractical, disruptive to the family, expensive, andor a potential source of future feeding disorders. IgE mediated food allergic reactions are generally very food spe cific, so the use of broad exclusionary diets, such as avoidance of all legumes, cereal grains, or animal products, is not warranted (Table 192.5). When the earlier diagnostic modalities are not definitive, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1446 Part XIII u Allergic Disorders Fig. 192.1 Algorithm for diagnosis of food allergy. (From Sicherer SH. Food allergy. Lancet. 2002;360:701710.) History, physical NegativePositive NoYes Consistent with intolerance, or other nonimmune disorders Confirm alternative diagnosis May require additional tests (e.g., breath hydrogen, stool culture, dietary elimination and rechallenge) IgE antibody screening to suspected foods to establish potential triggers for elimination, otherwise devise elimination based upon epidemiological variables Consider: confirmatory diagnostic tests (endoscopy, serology for coeliac, etc.). Consider IgE testing to verify pathophysiology. Reconsider diagnosis, foods involved Oral food challenges Avoid food(s) Add food back Periodic reassessment based on natural history of allergy in the particular disorder, the food(s) involved, and age of patient. NegativePositive NegativePositive Avoid food(s) Add food back NegativePositive Convincing history of anaphylaxis to isolated ingestion andor diagnostic test value Food tested is likely to be tolerated, but if history suspicious, consider retesting and supervised oral food challenge NoYes Reconsider diagnosis, foods involved Oral food challenges (deferred for foods with diagnostic values) Avoid food(s) Add food back NoYes Consider oral food challenges if unclear cause Trial elimination diet Resolution? Trial elimination diet Resolution? Moderatesevere atopic dermatitis, eosinophilic gastroenteropathies (biopsyproven) Consistent with cellmediated food allergy Consistent with IgEdependent disorders Test for IgE antibody reactive to suspect foods Table 192.5 Clinical Implications of Cross Reactive Proteins in IgE Mediated Allergy FOOD FAMILY RISK OF ALLERGY TO 1 MEMBER (; APPROXIMATE) FEATURE(S) Legumes 550 If allergic to peanut, 520 likelihood of allergy to other legumes (lupine, green bean, green pea, soy) If allergic to chickpea (garbanzo bean), 50 likelihood of allergy to lentil andor pea. Tree nuts (e.g., almond, cashew, hazelnut, walnut, Brazil) 1533 Reactions are often severe Fish 50 Reactions can be severe Shellfish (crustaceans) 75 (other crustaceans) 50 (mollusks) Reactions can be severe Grains 20 Wheat shows crossreactivity with barley and rye Mammalian milks 90 Cows milk is highly cross reactive to goats or sheeps milk (92) but not with mares milk (4) Rosaceae (pitted fruits) 55 Risk of reactions to 3 related foods is very low (10); symptoms are usually mild (pollen food allergy syndrome) Modified from Sicherer SH. Food allergy. Lancet. 2002;360:701710. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 192 u Food Allergy and Adverse Reactions to Foods 1447 which is a common scenario, oral food challenges (OFCs), |
6,702 | observed incremental feedings of a food performed under physician supervi sion, are useful in ruling out or confirming the presence or reso lution of a food allergy. Allergists experienced in dealing with food allergic reactions and able to treat anaphylaxis should perform food challenges. There are no laboratory studies to help identify foods that are already in the diet but may be responsible for nonIgE and cell mediated food reactions. Consequently, elimination diets followed by OFCs are the only way to establish the diagnosis. This approach may be recommended for atopic dermatitis, eosinophilic GI dis eases, and some forms of contact dermatitis. Before a food chal lenge is initiated, the suspected food should be eliminated from the diet for 10 14 days for IgE mediated food allergy and up to 8 weeks for some cell mediated disorders, such as EoE (see Chapter 192.1). Some children with cell mediated reactions to cows milk do not tolerate hydrolysate formulas and must receive amino acidderived formulas. If symptoms remain unchanged despite appropriate elim ination diets, it is unlikely that food allergy is responsible for the childs disorder. TREATMENT Appropriate identification and elimination of foods responsible for food hypersensitivity reactions are the most established and vali dated management strategies for food allergies. Complete elimina tion of common foods (milk, egg, soy, wheat, rice, chicken, fish, peanut, nuts) is very difficult because of their widespread use in a variety of processed foods. The lay organizations Food Allergy Research and Education (FARE; www.foodallergy.org) and the Asthma Allergy Foundation of America (Kids with Food Aller gies Division; www.kidswithfoodallergies.orgrecipes diet.aspx) provide excellent information to help parents deal with both the practical and emotional issues surrounding these diets. Egg allergy is not a contraindication for vaccination with measles, mumps, rubella, or influenza vaccines, but remains a concern for the yellow fever vaccine where referral to an allergist is recommended. Children at risk of food induced anaphylaxis should be given self injectable epinephrine and a written emergency plan in case of accidental ingestion (see Chapter 190). Because many food allergies resolve, children should be reevaluated periodically by an allergist to determine whether they have lost their clinical reactivity. A num ber of clinical trials are evaluating the efficacy of oral, sublingual, and epicutaneous (patch) immunotherapy for the treatment of IgE mediated food allergies. Immunotherapy is not typically curative but aims to provide temporary desensitization, or an increase in the threshold of a food that can be consumed without triggering an allergic reaction. Success depends on continuous treatment expo sure. An FDA approved peanut oral immunotherapy (OIT) agent is commercially available for use in children. Combining OIT with anti IgE treatment (omalizumab) or other biologic agents is under study and may improve safety or efficacy compared to OIT alone. Furthermore, extensively heated milk or egg in baked products are tolerated by the majority of milk and eggallergic children. Regular ingestion of baked products with milk and egg may accelerate reso lution of milk and egg allergy. PREVENTION It was once thought |
6,703 | that avoidance of allergenic foods and delayed introduction to the diet would prevent allergy, but the opposite is probably true; delayed introduction of these foods may increase the risk of allergy, especially in children with atopic dermatitis. A trial of early introduction of dietary peanut randomized 640 infants age 4 11 months with severe eczema, egg allergy, or both to consume or avoid peanut until the age 60 months. The early introduction of peanut dramatically decreased the development of peanut allergy among children at high risk for this allergy. A theory behind this approach is that early oral introduction of peanut induces oral tol erance that precedes the potential sensitization to peanut that can occur with environmental exposure to peanut via the inflamed, disrupted skin barrier seen in infants with eczema. Infants with severe eczema or egg allergy in the first 4 6 months of life might benefit from evaluation by an allergist or physician trained in man agement of allergic diseases to diagnose any food allergy and assist in promptly implementing appropriate early peanut introduction. For this high risk group, the clinician can perform an observed peanut challenge for those with evidence of a positive peanut skin test response or serum peanut specific IgE 0.35 kUAL to deter mine whether they are clinically reactive before initiating at home introduction of infant safe forms of peanut. Additional details for the early introduction of peanut are available from the National Institute of Allergy and Infectious Diseases (NIAID). Analyses of several early introduction studies have shown that early egg intro duction may be associated with reduced egg allergy, while review of data for other allergenic foods is not conclusive. There is however no evidence that delaying the introduction of typically allergenic foods prevents food allergy or other allergic diseases. There is no compelling evidence to support the practice of restricting the maternal diet during pregnancy or while breast feeding, or for delaying introduction of various allergenic foods to infants from atopic families. Exclusive breastfeeding for the first 4 6 months of life is strongly encouraged but has not been shown to reduce the development of food allergies. Potentially allergenic foods (eggs, milk, wheat, soy, peanuttree nut products, fish) should be introduced and maintained in the diet in infant appropriate forms after this period of exclusive breastfeeding and may prevent the development of allergies later in life. Recent meta analyses have not supported the use of hydrolyzed infant formulas in cases where breastfeeding cannot be continued for 4 6 months or after weaning to prevent eczema or food allergies in high risk families. Modula tion of the microbiome with probiotics has been an area of inter est, where it may affect oral tolerance induction; however, specific interventions have not been proven effective. Probiotic supple ments in the third trimester and to the newborn infant may reduce the incidence and severity of eczema, but have not demonstrated effects on food allergy prevention. Other potential influences on the infantchild microbiome are currently being studied, including |
6,704 | mode of delivery (vaginal vs C section), diet diversity, vitamin D supplementation, and household pet exposure. With the recogni tion that infantile eczema increases the risk of allergic sensitiza tion and food allergy, attention has also focused on early skin care and aggressive treatment of infantile eczema as potential preven tive measures. Because some skin preparations contain peanut or nut oils, which may sensitize young infants, especially those with cutaneous inflammation, such preparations should be avoided. Table 192.6 summarizes approaches to food allergy prevention. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. https:www.niaid.nih.govdiseases conditionsguidelines clinicians and patients food allergy.. Table 192.6 Approaches to Prevention of Food Allergy RECOMMENDED Infant safe forms of peanut, egg introduced around age 6 mo, not before 4 mo Other allergens may be introduced around this time as well Allergy testing before introduction not usually needed (see text) Infants with severe eczema or egg allergy may benefit from evaluation for early peanut introduction at 4 6 mo Diverse infant diet UNPROVENNOT RECOMMENDED Hydrolyzed formulas Maternal allergen avoidance during pregnancy or lactation Purposeful delay in introducing allergens to infants Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1448 Part XIII u Allergic Disorders 192.1 Non IgE Gastrointestinal Food Allergy Disorders Anna H. Nowak Wegrzyn, Hugh A. Sampson, Amanda L. Cox, and Scott H. Sicherer CLINICAL MANIFESTATIONS GI food allergies are often the first form of allergy to affect infants and young children, and typically manifest as chronic irritability, vomiting or spitting up, diarrhea, and poor weight gain. Cell mediated hypersensitivities without IgE involvement (non IgE) predominate, making standard allergy tests such as skin prick tests and in vitro tests for food specific IgE antibodies of little diagnostic value (Table 192.7). FPIES is a non IgE, cell mediated food allergy that can have dramatic GI symptoms and in its severe form is considered an allergic emergency. FPIES can present as acute or chronic phenotypes (Fig. 192.2). EPIDEMIOLOGY Prevalence: The prevalence of FPIES ranges between 0.34 and 0.7 of infants in Israel and Spain; in a population based survey, physician diagnosed FPIES was reported in 0.51 (95 confidence interval CI; 0.420.62) of U.S. children. Food triggers: Globally, cows milk is the most common trigger of FPIES, although in countries with higher rates of breastfeeding rather than formula feeding, complementary foods introduced into infants diets early are also reported. Commonly reported triggers include soy, oat, rice, vegetables (avocado, sweet potato), fruits (banana), egg, fish, chicken, turkey, peanut, tree nuts, and fish. Most infants (5075) react to one food; however, about 1015 report more than three food triggers. Pathophysiology: FPIES is characterized by a strong inflammato ry response with significant elevation of CRP, neutrophils, and platelets. There is evidence of innate immune compartment ac tivation (monocytes, neutrophils) along with the pan activation of T lymphocytes and significant elevation in levels of various cytokines and chemokines in |
6,705 | the peripheral blood, including IL 17A, IL 22, IL 17C, and tumor necrosis factor (TNF) , and a preferential activation of nonconventional T cell populations, including T cells. Clinical manifestations: FPIES typically manifests in the first year of life in an acute form as projectile, repetitive vomiting within 1 4 hours of food ingestion, frequently accompanied by lethargy, pallor (or dusky appearance), and low muscle tone; in a smaller subset, vomiting is followed by watery diarrhea in 5 10 hours (see Fig. 192.2). Prolonged ingestion of the causal allergen may result in abdominal distention, bloody diarrhea, anemia, and failure to thrive, referred to as chronic FPIES. Acute FPIES is considered to be an allergic emergency because hypotension occurs in approximately 510 of patients after allergen ingestion, which initially may be attributed to sepsis. Diagnosis: Acute FPIES is diagnosed based on the recognition of a constellation of symptoms, (Table 192.8; see Fig. 192.2) and allergy tests detecting food specific IgE are typically negative. OFCs are rarely required for the confirmation of the initial diagnosis, but are utilized for evaluating resolution of FPIES. Chronic FPIES is diag nosed based on the chronic GI symptoms that resolve within days to weeks following elimination of the allergen and recur acutely within 1 2 hours following a subsequent feeding. Differential diagnosis: The differential diagnosis includes GI infec tions (viral, bacterial), sepsis, necrotizing enterocolitis, metabolic disorders that induce emesis and lethargy (hyperammonemias, organic acidemias, congenital adrenal hyperplasia), very early on set inflammatory bowel disease and other immune enteropathies (IPEX), gastroesophageal reflux (GER) disease, ileus, anatomical small bowel obstruction, celiac disease, anaphylaxis, cyclic vomiting syndrome, poisoning, pyloric stenosis, seizures, and primary immu nodeficiencies. Emergency management: Severe FPIES reactions are considered allergic emergencies due to the risk of hypotension (in extreme cases, hypovolemic shock), dehydration, and metabolic derange ments including acidemia and methemoglobinemia (Fig. 192.3). Acute management entails vigorous intravenous hydration. Ad ditional therapies include intravenous or intramuscular ondan setron as an antiemetic, and a single dose of steroid (e.g., methyl prednisolone) may be administered due to a strong inflammatory response. Mild to moderate reactions can be managed with oral rehydration and oral ondansetron. Epinephrine autoinjectors and oral antihistamines are not prescribed for home manage ment; however, vasopressors may be used for treatment of shock in the medical setting. Dietary management: Breastfeeding mothers rarely need to restrict the foods that trigger symptoms in an infant following direct feeding, unless the infant exhibits symptoms of acute or chronic FPIES during breast milk feeding or has impaired growth. Hy poallergenic infant formulas (extensively hydrolyzed or amino acid) are recommended in non breastfed infants to avoid cows milk and soy. Timely introduction of solids is important for nu trition and for the development of oromotor skills. Following acute FPIES reactions to a solid food, foods from an unrelated food group can be chosen for introduction. Tolerance to one food from a food group usually indicates a favorable likelihood of tolerance to the related foods. Table 192.9 discusses practical guidelines for dietary |
6,706 | management of FPIES. Monitoring for resolution: The natural history of infantile FPIES is favorable, with the majority becoming tolerant by 3 5 years of age; persistent FPIES is rare. FPIES to fish and shellfish may start in older children and in adults; the natural history of adult FPIES is unknown. Reintroduction of foods that have caused FPIES is usually done during a physician supervised OFC. Timing of reintroduction varies based on the nutritional and social importance of the foods; usually attempts are done 6 24 months following the most recent FPIES reaction to the offending food. FPIES induced by cows milk may (10) evolve into IgE mediated food allergy. Comorbidities: FPIES is associated with an increased risk of IgE mediated food allergy to other foods, atopic dermatitis, allergic rhi nitis, asthma, and EoE. FPIAP presents in the first few months of life as blood streaked stools in otherwise healthy infants that are breastfed andor formula fed (see Table 192.7). Blood loss is typically mild, but can occasionally result in anemia. The most commonly implicated dietary triggers are cows milk and soy proteins, followed by egg; their elimination, either by maternal dietary restriction if breastfeeding or by use of hypoal lergenic formulas, leads to symptom and gross blood resolution within 48 72 hours in most infants. FPIAP is diagnosed clinically based on the presence of blood in the stool; sigmoidoscopy with biopsy, confirm ing an eosinophilic inflammatory response, is no longer done in rou tine practice for diagnosis of FPIAP. Blood in the infants stool can be attributed to multiple causes other than food allergy (see Table 192.7). Therefore diagnosis based on clinical observation carries the risk of overdiagnosis (especially when FPIAP is diagnosed based on detection of microscopic blood in stool) and unnecessary dietary restrictions resulting in delayed introduction of foods and an associated increased risk of developing IgE sensitization. Therefore, considering benign, nonspecific nature of the symptoms and favorable natural history, in cases of mild to moderate FPIAP, many authorities recommend a trial of the culprit food 2 3 months following symptom resolution to deter mine whether the infant has outgrown the sensitivity. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 192 u Food Allergy and Adverse Reactions to Foods 1449 Table 192.7 Food ProteinInduced Gastrointestinal Syndromes FPIES FPIAP FPE EOSINOPHILIC GASTROENTEROPATHIES Age at onset 1 day to 1 year, later for fish and shellfish 1 day to 6 months Dependent on age of exposure to antigen, cows milk and soy up to 2 yr Infant to adolescent FOOD PROTEINS IMPLICATED Most common Cows milk, egg, oat, rice Cows milk, soy Cows milk, soy Cows milk, wheat, egg white, soy, peanut, seafood Less common Soy, chicken, turkey, fish, pea, peanut, avocado, sweet potato Egg Wheat, egg Meats, corn, rice, fruits, vegetables, legumes Multiple food hypersensitivities 50 both cows milk and soy if |
6,707 | younger than 6 mo; 4050 react to more than one grain, 30 react to more than one fish 40 both cows milk and soy Rare Common Feeding at the time of onset Formula 50 exclusive breastfeeding Formula Formula ATOPIC BACKGROUND Family history of atopy 4070 25 Unknown 50 (often history of EoE) Personal history of atopy 30 22 22 50 SYMPTOMS Emesis Projectile, repetitive, severe No Intermittent Intermittent Diarrhea Severe in chronic FPIES No Moderate Moderate Bloody stools Occasionally severe Moderate Rare Moderate Edema Acute, severe No Moderate Moderate Shock 15 No No No Failure to thrive Moderate No Moderate Moderate Differential diagnosis Infection: viral, bacterial Necrotizing enterocolitis, GI obstruction (ileus, pyloric stenosis, Meckel diverticulum); gastro esophageal reflux disease; very early onset inflammatory bowel disease, seizure disorder, metabolic disorder, cardiac disease, anaphylaxis Rectal fissure, bleeding disorder, vit K deficiency, GI infection e.g., Shigella, inflammatory bowel disease Celiac disease, primary immunodeficiency, inflammatory bowel disease Gastroesophageal reflux disease, recurrent vomiting due to other causes, parasitic and fungal infections, congenital rings, Crohn disease, periarteritis, allergic vasculitis, connective tissue diseases, bullous pemphigoid, pemphigoid vegetans, graft versus host disease, achalasia, drug hypersensitivity, celiac disease, vasculitis, carcinoma, hypereosinophilic syndrome LABORATORY FINDINGS Anemia Moderate Mild Moderate Mild moderate Hypoalbuminemia Acute Rare Moderate Mild severe Methemoglobinemia May be present No No No ALLERGY EVALUATION Food skin prick test Majority negative Negative Negative Positive in 50 Serum food allergen IgE Majority negative Negative Negative Positive in 50 Total IgE Normal Negative Normal Normal to elevated Peripheral blood eosinophilia No Occasional No Present in 50 BIOPSY FINDINGS Colitis Prominent Focal No May be present Lymph nodular hyperplasia No Common No Yes Eosinophils Prominent Prominent Few Prominent; also neutrophilic infiltrates, papillary elongation, and basal zone hyperplasia Food challenge Emesis in 1 4 hr; diarrhea in 5 8 hr (in a subset) Rectal bleeding in 6 72 hr Vomiting, diarrhea, or both in 40 72 hr Vomiting and diarrhea in hours to days Treatment Protein elimination, 80 respond to casein hydrolysate and symptoms clear in 3 10 days; rechallenge under supervision in 0.5 2 yr Protein elimination, symptoms clear in 3 days with casein hydrolysate; resume continue breastfeeding on maternal antigen restricted diet; reintroduce at home after 9 12 mo of age Protein elimination, symptoms clear in 1 3 wk; rechallenge and biopsy in 1 2 yr Protein elimination, good response to casein hydrolysate, excellent (90) response to elemental diet; symptoms clear in 2 3 wk, excellent acute response to oral steroids but with high rate of relapse following discontinuation; in EoE 3050 response to proton pump inhibitors, 70 to swallowed corticosteroids; rechallenge by introducing food at home and biopsy in 1 2 yr Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1450 Part XIII u Allergic Disorders Fig. 192.2 Diagnostic algorithm for food proteininduced enterocolitis syndrome (FPIES). ED, Emergency department; IV, intravenous; OFC, oral |
6,708 | food challenge. Chronic FPIES is described almost exclusively with cows milk or soy in young infants. Without a confirmatory OFC or other ingestion with emesis onset in 1 4 hours, diagnosis of chronic FPIES is presumptive. Based on Nowak Wgrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food proteininduced enterocolitis syndrome: Executive summary Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma Immunology. J Allergy Clin Immunol. 2017;139:11111126. (From Sicherer SH, Nowak Wgrzyn A. Enterocolitis, proctocolitis, and enteropathies. In: Leung DYM, Akdis CA, Bacharier LB, et al., eds. Pediatric Allergy Principles and Practice. 4th ed. Philadelphia: Elsevier; 2021: Fig. 33.2.) Consider other causes Yes Yes Yes Yes Yes Yes No No No No No No After strict avoidance of suspect food, did symptoms improve within several days? Has the patient ingested a serving of the suspect food after period of avoidance of at least several weeks? Iswas ingestion followed 14 h later by acute FPIES symptoms? Meets criteria for Chronic FPIES Is there intermittent and progressive watery diarrhea and progressive vomiting with regular ingestion of the suspect food? Chronic FPIES: Usually in infancy Minor criteria: Are 3 present? 2nd episode after same suspect food Repetitive vomiting 14 h after other food Extreme lethargy Marked pallor Hypotension Hypothermia Diarrhea within 24 h Need for ED visit Need for IV fluids Meets criteria for Acute FPIES For acute FPIES: At any age Major criterion: Is there repetitive vomiting 14 hours after ingestion of suspect food absence of respiratory or cutaneous (urticaria, pruritus, angioedema) symptoms? Consider supervised OFC With any suspected reaction FPIES FPIAP FPE EOSINOPHILIC GASTROENTEROPATHIES Natural history Cows milk: 60 resolved by 2 yr Soy: 25 resolved by 2 yr Resolved by 9 12 mo Most cases resolve in 2 3 yr Typically a prolonged, relapsing course Reintroduction of the food Supervised food challenge At home, gradually advancing from 1 oz to full feedings over 2 wk Home, gradually advancing Home, gradually advancing Eosinophilic gastroenteropathies encompass esophagitis, gastritis, and gastroenterocolitis. If positive, may be a risk factor for persistent disease, referred to as atypical FPIES. FPIES, Food proteininduced enterocolitis syndrome; FPIAP, food proteininduced allergic proctocolitis; FPE, food proteininduced enteropathy; GI, gastrointestinal; EoE, eosinophilic esophagitis. Table 192.7 Food ProteinInduced Gastrointestinal Syndromescontd Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 192 u Food Allergy and Adverse Reactions to Foods 1451 Table 192.8 FPIES Diagnostic Criteria ACUTE FPIES MAJOR CRITERIA (BOTH MUST BE MET), PLUS MINOR CRITERIA (3 OCCURRING WITH EPISODE) Vomiting 1 4 hr after suspect food ingestion Absence of immediate, IgE mediated allergic symptoms (hives, itching, swelling, wheezing, cough) 2 episodes with same food One episode with a different food Lethargy Pallor Need for ER visit Need for IV fluid support Diarrhea within 24 hr (usually 5 10 hr) Hypotension Hypothermia |
6,709 | CHRONIC FPIES SYMPTOMS AND SEVERITY CRITERIA Milder (lower doses with intermittent ingestion): Intermittent vomiting andor diarrhea Growth faltering No dehydration or metabolic acidosis Severe (higher doses with chronic ingestion): Intermittent but progressive vomiting and watery diarrhea (occasionally with blood) Poor weight gain or failure to thrive Possible dehydration and metabolic acidosis, anemia, hypoproteinemia, neutrophilia, thrombocytosis Resolution of symptoms within days to weeks after elimination of offending food(s) Acute recurrence of symptoms (vomiting in 1 4 hr, diarrhea in 24 hr, usually 5 10 hr) when the food is reintroduced, following a period of elimination Confirmatory OFC required for conclusive diagnosis; if OFC not performed diagnosis remains presumptive Major criterion must be met (both) plus at least three minor criteria. General criteria because of paucity of available data. FPIES, Food proteininduced enterocolitis syndrome; ER, emergency room; IV, intravenous; OFC, oral food challenge. Adapted from Nowak Wgrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food protein induced enterocolitis syndrome: Executive summary Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma Immunology. J Allergy Clin Immunol. 2017;139(4):11111126.e4. Food proteininduced enteropathy (FPE) often manifests in the first several months of life as diarrhea, often with steatorrhea and poor weight gain (see Table 192.7). Symptoms include protracted diarrhea, vomiting in up to 65 of cases, failure to thrive, abdominal distention, early satiety, and malabsorption. Anemia, edema, and hypoproteinemia occur occasionally. Cows milk sensitivity is the most common cause of FPE in young infants, but it has also been associated with sensitivity to soy, egg, wheat, rice, chicken, and fish in older children. Celiac dis ease, the most severe form of FPE, occurs in about 1 per 100 of the U.S. population, although it may be silent in many patients (see Chapter 384). The classic form is characterized by extensive loss of absorptive villi and hyperplasia of the crypts, leading to malabsorption, chronic diarrhea, steatorrhea, abdominal distention, flatulence, and weight loss or failure to thrive. Oral ulcers and other extraintestinal symptoms sec ondary to malabsorption may occur. Genetically susceptible individu als (HLA DQ2 or HLA DQ8) demonstrate a cell mediated response to tissue transglutaminase deamidated gliadin (a fraction of gluten), which is found in wheat, rye, and barley. EoE may present from infancy through adolescence, more frequently in boys (see Chapter 370). EoE is a cell mediated disorder, which is often associated with IgE mediated food allergies in infants and young children, and manifests as chronic GER, intermittent emesis, food refusal, abdominal pain, dysphagia, food impaction, irritability, sleep disturbance, and failure to respond to conventional GER medications. EoE is a clinicopathologic diagnosis. The diagnosis is confirmed when 15 eosinophils per high power field are seen on esophageal biopsies. Treatment is possible with elimination of dietary allergens but man agement with medications is typically included (see Chapter 370). Eosinophilic gastritis and gastroenteritis are additional eosinophilic GI disorders that are far less common and can occur at any age. Eosin ophilic gastritis often presents |
6,710 | with nausea and abdominal pain or bloating, while eosinophilic enteritis may also present with nausea, abdominal pain or bloating with additional diarrhea, anemia, or pro tein loss. Eosinophilic colitis may present with loose stool or blood in stool associated with abdominal crampingpain. More than 50 of patients with these disorders are atopic; however, food induced IgE mediated reactions have been implicated only in a minority of patients. Generalized edema secondary to hypoalbuminemia may occur in some infants with marked protein losing enteropathy. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1452 Part XIII u Allergic Disorders 1. Manage acute reactions Current reaction with 3 episodes of emesis; OR moderatesevere lethargy; OR history of severe reaction 1. Educate parent on reaction management 2. Provide emergency letter explaining FPIES and basics of emergency care at medical facility Offer alternatives: Encourage breastfeeding eHF, some require AAF Andor supervised OFC to soy (or cow milk) Cows milk (or soy) FPIES? Provide plan for dietary advancement Infant (or restricted diet)? Nutrition consultation Seek immediate medical attention 3 episodes of emesis OR any lethargy Monitor vital signs Transfer to EDICU for persistent or severe hypotension, extreme lethargy, shock, or respiratory distress Monitor for resolution 46 h from onset Discharge if back to baseline, tolerating oral fluids, and 46 h have elapsed since reaction onset Mild: 1. Attempt oral rehydration 2. Age 6 mo, consider IM ondansetron 3. Monitor for resolution 46 h from reaction onset Moderate: 1. Age 6 mo, administer ondansetron IM 2. Consider placing IV access, and administering 20 mLkg NS bolus Attempt oral rehydration at home 2. Prepare for reactions 3. Avoid suspect foods; address nutrition and development 4. Offer interval food challenges 1218 months from last reaction, ANDOR patientfamily interested in adding food to diet? Consider testing for sIgE sensitization Yes Yes No Evidence of sIgE sensitization? May predict more protracted course; risk of sIgE mediated symptoms Consider supervised OFC, informed by and modified based on: Understanding of typical age of resolution Past reaction severity Family preference Prognostic value of sIgE sensitization if present Risks of OFC procedure in atypical FPIES with sIgE: Provide incremental dosing to account for the possibility of immediate reactions 0.15 mgkgdose; maximum, 16 mg AAF, amino acidbased formula ED, emergency department FPIES, food proteininduced enterocolitis syndrome ICU, intensive care unit IM, intramuscular IV, intravenous mo, months OFC, oral food challenge sIgE, specific immunoglobulin E WHO, World Health Organization NS, normal saline Template may be downloaded at https:www.fpies.orgwpcontentuploads201808IFPIESERLetter2018.pdf Interval can be modified at the discretion of the treating physician. Outside medical facility At medical facility Present Present Present Absent Absent Absent Modify based on individual circumstances Start first (low risk) High iron foods Lamb, fortified quinoa or millet cereal Beef, fortified gritscorn, wheat, or barley cereal Fortified infant rice and oat cereal Sweet potato Banana |
6,711 | Green pea, soy Cows milk, poultry, egg, fish Squash, carrot, white potato Apple, pear, orange Green bean, peanut, legumes other than green pea Broccoli, cauliflower, parsnip, pumpkin Berries, plum, watermelon, peach Tree nut and seed butters Foods should be offered in ageappropriate forms and textures. 46 months (AAP) or at 6 months (WHO): Begin with thin purees, choosing ironrich foods first, and gradually advancing to thicker 8 months: Biteanddissolve textures and soft cooked foods 12 months: Modified (choppedsoftened) foods from family table Vegetables Fruits Legumes Other Introduce next (moderate risk) Wait for guidance (high risk) Any of the below also present? Severe lethargy Hypotonia Ashencyanotic appearance Severe: 1. Place IV access, administer NS bolus 20 mLkg, repeat as needed 2. Age 6 mo, administer ondansetron IV 3. Consider methylprednisolone IV 1 mgkg 4. Monitor and correct acidemia, electrolyte abnormalities, methemoglobinemia Fig. 192.3 Treatment algorithm for food proteininduced enterocolitis syndrome (FPIES). Modified from Nowak Wegrzyn A, Chehade M, Gro etch ME, et al. International consensus guidelines for the diagnosis and management of food proteininduced enterocolitis syndrome: Executive summaryWorkgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma Immunology. J Allergy Clin Immunol. 2017;139:11111126. Template may be downloaded at https:www.fpies.orgwp contentuploads201808IFPIES ER Letter 2018.pdf. Interval can be modified at the discretion of the treating physician. (From Sicherer SH, Nowak Wgrzyn A. Enterocolitis, proctocolitis, and enter opathies. In: Leung DYM, Akdis CA, Bacharier LB, et al., eds. Pediatric Allergy Principles and Practice. 4th ed. Philadelphia: Elsevier; 2021: Fig. 33.3.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 193 u Adverse and Allergic Reactions to Drugs 1453 Table 192.9 Empiric Guidelines for Selecting Weaning Foods in Infants with FPIES AGES AND STAGESa,b LOWER RISK FOODS MODERATE RISK FOODS HIGHER RISK FOODS 4 6 MO (AS PER AAP, CON) If developmentally appropriate and safe and nutritious foods are available Begin with smooth, thin, purees and progress to thicker purees Choose foods that are high in iron Add vegetables and fruits 6 MO (AS PER WHO) Complementary feeding should begin no later than 6 mo of age In the breastfed infant, high iron foods or supplemental iron (1 mgkg day) is suggested by 6 mo of age Continue to expand variety of fruits, vegetables, legumes, grains, meats and other foods as tolerated 8 MO OF AGE OR WHEN DEVELOPMENTALLY APPROPRIATE Offer soft cooked and bite and dissolve textures from around 8 mo of age or as tolerated by infant 12 MO OF AGE OR WHEN DEVELOPMENTALLY APPROPRIATE Offer modified tolerated foods from the family table, chopped meats, soft cooked vegetables, grains, and fruits VEGETABLES Broccoli, cauliflower, parsnip, turnip, pumpkin, kale Squash, carrot, white potato, green bean (legume) Sweet potato, green pea (legume) FRUITS Blueberries, strawberries, plum, watermelon, peach Apple, pear, orange Avocado, banana HIGH IRON FOODS Lamb, beef, pork, fortified quinoa cereal, millet, amaranth Fortified |
6,712 | grits and corn cereal, wheat (whole wheat and fortified), fortified barley cereal Fortified, infant rice and oat cereals. OTHER Tree nuts and seed butters (sesame, sunflower, etc.) Thinned with water or infant puree for appropriate infant texture and to prevent choking Peanut, other legumes (other than green pea) Milk, soy, poultry, egg, fish, shellfish Risk assessment is based on the clinical experience and the published reports of FPIES triggers. This is not an exhaustive list and feeding should not be limited to this list of lower and moderate risk foods. Many other foods are appropriate for infant feeding. One may consider delaying the introduction of higher risk foods until there is a nutritional need for the food, the infant already has a diverse diet, or other lower and moderate risk foods are tolerated. aExclusive breastfeeding until 4 6 mo of age and continuing breastfeeding through the first year of life or longer as long as mutually desired by both mother and child. bIf an infant tolerates a variety of early foods, subsequent introduction may be more liberal. Additionally, tolerance to one food in a food group (green pea) is considered as a favorable prognostic indicator for tolerance of other foods from the same group (legumes). AAP, CON, American Academy of Pediatrics, Committee on Nutrition; WHO, World Health Organization. Adapted from Nowak Wegrzyn A, Chehade M, Groetch ME, et al. International consensus guidelines for the diagnosis and management of food proteininduced enterocolitis syndrome: Executive SummaryWorkgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma Immunology. J Allergy Clin Immunol. 2017;139(4):11111126.e4 Adverse drug reactions (ADRs) can be divided into predictable (type A) and unpredictable (type B) reactions. Predictable drug reactions, including drug toxicity, drug interactions, and adverse effects, are dose dependent, are related to known pharmacologic actions of the drug, and occur in patients without any unique sus ceptibility. Unpredictable drug reactions are generally dose inde pendent, often are not related to the pharmacologic actions of the drug, and occur in patients who are genetically or otherwise predis posed. These include idiosyncratic reactions, allergic (hypersensi tivity) reactions, and pseudoallergic reactions. Allergic reactions are immune mediated and require prior sensitization. They mani fest as signs and symptoms characteristic of an underlying allergic mechanism (Table 193.1). Anaphylaxis is due to production of drug specific IgE antibodies, and delayed cutaneous reactions are due to drug specific T cells. Pseudoallergic reactions resemble allergic reactions but are caused by nonIgE mediated release of media tors from mast cells and basophils, such as vancomycin induced flushing. Drug independent cross reactive antigens can induce sensitization manifesting as drug allergy. Patients with cetuximab induced anaphylaxis have IgE antibodies in pretreatment samples specific for galactose 1,3 galactose. This antigen is present on the antigen binding portion of the cetuximab heavy chain and is similar to structures in the ABO blood group. Sensitization to galactose 1,3 galactose may occur from tick bites caused by cross reactive tick salivary antigens. EPIDEMIOLOGY The incidence of ADRs in the general as |
6,713 | well as pediatric populations remains unknown, although data from hospitalized patients show it to be 6.7, with a 0.32 incidence of fatal ADRs. Databases such as the U.S. Food and Drug Administration (FDA) MedWatch program (https: www.fda.govsafetymedwatch fda safety information and adverse event reporting program) likely suffer from underreporting. Cutane ous reactions are the most common form of ADRs, with ampicillin, amoxicillin, penicillin, and trimethoprimsulfamethoxazole (TMP SMX) being the most frequently implicated drugs (Tables 193.2 and 193.3). Although the majority of ADRs do not appear to be allergic in nature, 610 can be attributed to an allergic or immunologic mecha nism. Importantly, given the high probability of recurrence of allergic reactions, these reactions should be preventable, and information tech nologybased interventions may be especially useful to reduce risk of re exposure. Chapter 193 Adverse and Allergic Reactions to Drugs Roland Solensky and Scott H. Sicherer Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1454 Part XIII u Allergic Disorders Table 193.1 Classification of Drug Allergies TYPE TYPE OF IMMUNE RESPONSE PATHOPHYSIOLOGY CLINICAL SYMPTOMS TYPICAL CHRONOLOGY OF THE REACTION 1 IgE Mast cell and basophil degranulation Anaphylactic shock Angioedema Urticaria Bronchospasm Within 1 6 hr after the last intake of the drug 2 IgG and complement IgG and complement dependent cytotoxicity Cytopenia 5 15 days after the start of the eliciting drug 3 IgM or IgG and complement or FcR Deposition of immune complexes Serum sickness Urticaria Vasculitis 7 8 days for serum sicknessurticaria 7 21 days after the start of the eliciting drug for vasculitis 4a Th1 (IFN ) Monocytic inflammation Eczema 1 21 days after the start of the eliciting drug 4b Th2 (IL 4 and IL 5) Eosinophilic inflammation Maculopapular exanthem, DRESS 1 to several days after the start of the eliciting drug for MPE 2 6 wk after the start of the eliciting drug for DRESS 4c Cytotoxic T cells (perforin, granzyme B, FASL) Keratinocyte death mediated by CD4 or CD8 Maculopapular exanthem, SJSTEN, pustular exanthem 1 2 days after the start of the eliciting drug for fixed drug eruption 4 28 days after the start of the eliciting drug for SJSTEN 4d T cells (IL 8CXCL8) Neutrophilic inflammation Acute generalized exanthematous pustulosis Typically 1 2 days after the start of the eliciting drug (but could be longer) CXCL8, C X C motif chemokine ligand 8; DRESS, drug reaction with eosinophilia and systemic symptoms; FASL, FAS ligand; FcR, Fc receptor; IFN , interferon gamma; IgE, immunoglobulin E; IL, interleukin; MPE, malignant pleural effusion; SJS , Stevens Johnson syndrome; TEN, toxic epidermal necrolysis; Th1, Th2, T helper cell type 1 and type 2. From Demoly P, Adkinson NF, Brockow K, et al. International Consensus on drug allergy. Allergy. 2014;69(4):420437. Table 193.2 Heterogeneity of Drug Induced Allergic Reactions ORGAN SPECIFIC REACTIONS CLINICAL FEATURES EXAMPLES OF CAUSATIVE AGENTS CUTANEOUS Exanthems Diffuse fine macules and |
6,714 | papules evolve over days after drug initiation Delayed type hypersensitivity Allopurinol, aminopenicillins, cephalosporins, antiepileptic agents, antibacterial sulfonamides Urticaria, angioedema Onset within minutes of drug initiation Potential for anaphylaxis Usually IgE mediated Lactam antibiotics Platinum agents Fixed drug eruption Hyperpigmented plaques Recur at same skin or mucosal site Tetracycline, sulfonamides, NSAIDs, carbamazepine Pustules Acneiform Acute generalized exanthematous pustulosis (AGEP) Acneiform: corticosteroids, sirolimus AGEP: antibiotics, calcium channel blockers Bullous Tense blisters Flaccid blisters Furosemide, vancomycin Captopril, penicillamine SJS Fever, erosive stomatitis, ocular involvement, purpuric macules on face and trunk with 10 epidermal detachment Antibacterial sulfonamides, anticonvulsants, oxicam NSAIDs, allopurinol TEN Similar features as SJS but 30 epidermal detachment Mortality as high as 50 Same as SJS Cutaneous lupus Erythematousscaly plaques in photodistribution Hydrochlorothiazide, calcium channel blockers, ACEIs Hematologic Hemolytic anemia, thrombocytopenia, granulocytopenia Penicillins, quinine, sulfonamides Hepatic Hepatitis, cholestatic jaundice Para aminosalicylic acid, sulfonamides, phenothiazines Pulmonary Pneumonitis, fibrosis Nitrofurantoin, bleomycin, methotrexate Renal Interstitial nephritis, membranous glomerulonephritis Penicillin, sulfonamides, gold, penicillamine, allopurinol MULTIORGAN REACTIONS Anaphylaxis Urticariaangioedema, bronchospasm, gastrointestinal symptoms, hypotension IgE and nonIgE dependent reactions Lactam antibiotics, platins DRESS Cutaneous eruption, fever, eosinophilia, hepatic dysfunction, lymphadenopathy Anticonvulsants, sulfonamides, minocycline, allopurinol Serum sickness Urticaria, arthralgias, fever Heterologous antibodies, infliximab Systemic lupus erythematosus Arthralgias, myalgias, fever, malaise Hydralazine, procainamide, isoniazid Vasculitis Cutaneous or visceral vasculitis Hydralazine, penicillamine, propylthiouracil ACEI, Angiotensin converting enzyme inhibitor; DRESS, drug reaction with eosinophilia and systemic symptoms; NSAID, nonsteroidal antiinflammatory drug; SJS, Stevens Johnson syndrome; TEN, toxic epidermal necrolysis. Adapted from Khan DA, Solensky R. Drug allergy. J Allergy Clin Immunol. 2010;125:S126S137. Table 1, p. S127. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 193 u Adverse and Allergic Reactions to Drugs 1455 PATHOGENESIS AND CLINICAL MANIFESTATIONS Immunologically mediated ADRs have been classified according to the Gell and Coombs classification: immediate hypersensitivity reactions (type I), cytotoxic antibody reactions (type II), immune complex reactions (type III), and delayed type hypersensitivity reactions (type IV) (see Table 193.1). Immediate hypersensitivity reactions occur when a drug or drug metabolite interacts with pre formed drug specific IgE antibodies that are bound to the surfaces of tissue mast cells andor circulating basophils. The cross link ing of adjacent receptor bound IgE by antigen causes the release of preformed and newly synthesized mediators, such as histamine and leukotrienes, that contribute to the clinical development of urticaria, bronchospasm, or anaphylaxis. Cytotoxic antibody reac tions involve IgG or IgM antibodies that recognize drug antigen on the cell membrane. In the presence of serum complement, the antibody coated cell is either cleared by the monocyte macrophage system or is destroyed. Examples are drug induced hemolytic ane mia and thrombocytopenia. Immune complex reactions are caused by soluble complexes of drug or metabolite in slight antigen excess with IgG or IgM antibodies. The immune complex is deposited in blood vessel walls and causes injury by activating the complement cascade, as seen in serum sickness. Clinical manifestations include |
6,715 | fever, urticaria, rash, lymphadenopathy, and arthralgias. Symptoms typically appear 1 3 weeks into the course of the offending drug and persist for days to weeks after the drug is discontinued. Delayed type hypersensitivity reactions are mediated by cellular immune mechanisms. They are subdivided into four categories involving activation and recruitment of monocytes (type IVa), eosinophils (type IVb), CD4 or CD8 T cells (type IVc), and neutrophils (type IVd). Examples include drug reaction with eosinophilia and sys temic symptoms (DRESS), acute generalized exanthematous pus tulosis (AGEP) and Stevens Johnson syndrome (SJS) (see Chapter 686.2). Not all allergic drug reactions can be easily classified using the Gell and Coombs system. NonIgE mediated immediate type reactions mimic Gell and Coombs type I reactions, with indistinguishable symptoms and signs. The most common drugs associated with these reactions are vancomycin, fluoroquinolones, and opiates, which cause non specific mast cell degranulation via interaction with the surface receptor MrgprX2. Because these reactions do not require prior sensitization (unlike IgE mediated reactions), they may occur with first exposure. The pharmacologic interaction with immune receptors concept (p i concept) is another type of drug hypersensitivity classification. In this scheme, a drug binds noncovalently to a T cell receptor, which leads to an immune response through interaction with a major histocompat ibility complex (MHC) receptor. In this scenario, no sensitization (i.e., previous exposure) is required because there is direct stimulation of memory and effector T cells analogous to the concept of superantigens. Although the various mechanistic schemes of drug induced allergic reactions are useful, not all drug allergic reactions can be categorized using these various classification systems. Stevens Johnson Syndrome and Toxic Epidermal Necrolysis Blistering mucocutaneous disorders induced by drugs encompass a spectrum of reactions, including SJS and toxic epidermal necrolysis (TEN; see Chapters 686.2, 695.2 and 695.3). Although their patho physiology remains incompletely understood, HLA associations including HLA B1502 with carbamazepine induced TEN have been recognized, and the pathogenic roles of drug specific cyto toxic T cells and granulysin have been reported. SJS is defined as the epidermal detachment of 10, TEN is 30 detachment, and overlap syndrome is 1030 detachment. The features of SJS include confluent purpuric macules on face and trunk and severe, explosive mucosal erosions, usually at more than one mucosal sur face, accompanied by fever and constitutional symptoms. Ocular involvement may be particularly severe, and the liver, kidneys, and lungs may also be involved. TEN, which appears to be related to keratinocyte apoptosis, manifests as widespread areas of conflu ent erythema followed by epidermal necrosis and detachment with severe mucosal involvement. Skin biopsy differentiates subepider mal cleavage characteristic of TEN from intraepidermal cleavage characteristic of the scalded skin syndrome induced by staphylo coccal toxins. The risks of infection and mortality remain high, but improved outcomes have been demonstrated by immediate with drawal of the implicated drug, early transfer to a burn unit, and aggressive supportive care. Additional management is reviewed in Chapter 695.3. Table 193.3 Delayed Hypersensitivity Drug Rashes by Category MACULOPAPULAR EXANTHEMS: ANY DRUG |
6,716 | CAN PRODUCE A RASH SEVERAL DAYS INTO THE COURSE Allopurinol Antibiotics: penicillins, ampicillin, sulfonamides Antiepileptics: phenytoin, phenobarbital Antihypertensives: thiazide diuretics, calcium channel blockers Radiocontrast material Gold salts Hypoglycemic drugs Meprobamate Phenothiazines Quinine DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS) Anticonvulsants: phenytoin, phenobarbital, valproate, lamotrigine, carbamazepine Antibiotics: sulfonamides, minocycline, dapsone, ampicillin, ethambutol, isoniazid, linezolid, metronidazole, rifampin, streptomycin, vancomycin Allopurinol NSAIDs: celecoxib, ibuprofen, diclofenac Phenothiazines STEVENS JOHNSON SYNDROMETOXIC EPIDERMAL NECROLYSIS Sulfonamides, phenytoin, barbiturates, carbamazepine, allopurinol, amikacin, phenothiazines, acetazolamide, gold, nitrofurantoin, pentazocine, tetracycline, quinidine ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS Antibiotics: penicillins, macrolides, cephalosporins, clindamycin, imipenem, fluoroquinolones, isoniazid, vancomycin, minocycline, doxycycline, linezolid, gentamicin, sulfonamides Antimalarials: chloroquine, hydroxychloroquine Antifungals: terbinafine, nystatin, amphotericin B, fluconazole, itraconazole Anticonvulsants: carbamazepine Calcium channel blockers Furosemide, thiazides Systemic corticosteroids Protease inhibitors COLLAGEN VASCULAR OR LUPUS LIKE REACTIONS Procainamide, hydralazine, phenytoin, penicillamine, trimethadione, methyldopa, carbamazepine, griseofulvin, nalidixic acid, oral contraceptives, propranolol ERYTHEMA NODOSUM Oral contraceptives, penicillins, sulfonamides, diuretics, gold, clonidine, propranolol, opiates FIXED DRUG REACTIONS Phenolphthalein, barbiturates, gold, sulfonamides, penicillins, tetracycline, quinolones, carbamazepine, NSAIDs Note: See Chapter 686 and Table 686.5. NSAID, Nonsteroidal antiinflammatory drug. Adapted from Duvic M. Urticaria, drug hypersensitivity rashes, nodules and tumors, and atrophic diseases. In: Goldman L, Schafer AI, eds. Goldman Cecil Medicine. 25th ed. Philadelphia: Elsevier; 2016: Table 440.3. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1456 Part XIII u Allergic Disorders Drug Reaction with Eosinophilia and Systemic Symptoms DRESS (i.e., drug induced hypersensitivity syndrome) is a potentially life threatening reaction that has been described primarily with anti convulsants, although many other medications have been implicated (see Tables 193.2 and 193.3; see Chapter 686.2). It is likely less common in children compared with adults. DRESS is characterized by fever, maculopapular rash, facial edema, eosinophilia, generalized lymph adenopathy, and potentially life threatening damage of one or more organs, usually hepatic or renal. Onset is delayed, usually 2 8 weeks after initiation of the medication. It has been associated with reactiva tion of human herpesvirus 6. Treatment is withdrawal of the medica tion, systemic steroids, and supportive care, but symptoms can worsen or persist for weeks to months after the drug has been discontinued. Drug Metabolism and Adverse Reactions Most drugs and their metabolites are not immunologically detect able until they have become covalently attached to a macromolecule. This multivalent hapten protein complex forms a new immunogenic epitope that can elicit T and B lymphocyte responses. Penicillins are highly reactive with proteins and can directly haptenate protein carri ers, without prior metabolism, possibly accounting for the higher fre quency of immune mediated hypersensitivity reactions with this class of antibiotics. Incomplete or delayed metabolism of some drugs can give rise to toxic metabolites. Hydroxylamine, a reactive metabolite produced by cytochrome P450 oxidative metabolism, may mediate adverse reac tions to sulfonamides. Patients who are slow acetylators appear to be at increased risk. In addition, cutaneous reactions in patients with AIDS treated with |
6,717 | TMPSMX, rifampin, and other drugs may be caused by glutathione deficiency resulting in toxic metabolites. Serum sickness like reactions due to cefaclor may result from an inherited propensity for hepatic biotransformation of drugs into toxic or immunogenic metabolites. Risk Factors for Hypersensitivity Reactions Risk factors for ADRs include prior exposure, previous reactions, age (20 49 years), route of administration (parenteral or topical), dose (high), and dosing schedule (intermittent), and genetic predisposi tion. Atopy does not appear to predispose patients to allergic reactions to low molecular weight compounds, but asthmatics who experience allergic reactions are likely at increased risk of more serious reactions, analogous to food allergic patients. Atopic patients also appear to be at greater risk for pseudoallergic reactions induced by radiocontrast media (RCM). Pharmacogenomics has an important role in identify ing individuals at risk for certain drug reactions. DIAGNOSIS Skin testing is the most rapid and sensitive method of demonstrat ing the presence of IgE antibodies to a specific allergen. It can be performed with high molecular weight compounds, such as foreign antisera, hormones, enzymes, and toxoids. Reliable skin testing can also be performed with penicillin, but not with most other antibiot ics. Most immunologically mediated ADRs are caused by metabo lites rather than by parent compounds, and the metabolites for most drugs other than penicillin have not been defined. In addition, many metabolites are unstable or must combine with larger proteins to be useful for diagnosis. Testing with nonstandardized reagents requires caution in interpretation of both positive and negative results, because some drugs can induce nonspecific irritant reactions. Whereas a wheal and flare reaction is suggestive of drug specific IgE antibodies, a nega tive skin test result does not exclude the presence of such antibodies because the relevant immunogen may not have been used as the testing reagent. In vitro tests (radioallergosorbent test or enzyme linked immu noassay) for IgE mediated penicillin allergy have lower sensitivity and comparable specificity compared with skin testing. The positive and negative predictive values (NPVs) of skin testing for antibiotics other than penicillin are not well established. Nevertheless, positive immediate hypersensitivity skin test responses using nonirritant con centrations of nonpenicillin antibiotics may be interpreted as a pre sumptive risk of an immediate reaction to such agents. Results of direct and indirect Coombs tests are often positive in drug induced hemolytic anemia. Assays for specific IgG and IgM have been shown to correlate with a drug reaction in immune cytopenia, but in most other reactions, such assays are not diagnostic. In general, many more patients express humoral or T cell immune responses to drug determinants than express clinical disease. Serum tryptase is elevated with systemic mast cell degranulation and can be seen with drug associated reactions such as anaphylaxis; however, not all patients with well defined anaphylaxis show increased serum tryptase levels. Patch testing is the most reliable technique for diagnosis of contact dermatitis caused by topically applied drugs. Graded drug challenge is an incremental (usually two step) administration of a drug under medical |
6,718 | supervision and is used in patients who are deemed unlikely to be allergic to the drug. Unlike desensitization, there is no attempt to modify the underlying immune response. Patients who pass a graded challenge are proven to not be allergic to the drug. TREATMENT Drug desensitization alters the immune response to a medication and allows allergic patients to receive it safely. However, the induced tol erance is temporary and if treatment is interrupted, hypersensitiv ity returns, and patients are again at risk of reacting to the drug. Drug desensitization has classically been used for IgE mediated allergy, such as penicillin, but the procedure has been successfully applied to immedi ate nonIgE mediated reactions, such as taxanes. Rapid desensitization is indicated in patients who are either proven or are strongly suspected to have an immediate type drug allergy and for whom an alternate drug is not available or appropriate. The procedure warrants close monitoring and preparedness to treat possible anaphylaxis. Depending on the clini cal stability of the patient and the severity of the previous reaction (or symptoms during a previous desensitization), it may be performed in outpatient or inpatient settings. Premedications are used for nonIgE mediated hypersensitivity (such as taxanes and biologic agents), but not for IgE mediated allergy (such as antibiotics). Desensitization can be performed via parenteral or oral routes. The starting dose is typically 110,000 of the full dose, and the dose is doubled every 15 minutes until the full dose is reached. Desensitization has a very high success rate and breakthrough allergic reactions occur about 2030 of the time, but they are usually mild and do not necessitate aborting the procedure. Penicillin Allergy Penicillin allergy is self reported by approximately 10 of patients, but following evaluation, about 95 of these individuals are shown to not be allergic and able to tolerate penicillins. This incongruity is due to the reaction being the result of the underlying infection (or interac tion between the infectious agent and the antibiotic), mislabeling a pre dictable reaction as allergic, and the waning of penicillin specific IgE. Being labeled as penicillin allergic is not benign, because patients are more likely to be treated with less effective, more toxic, or more expen sive antibiotics such as fluoroquinolones, vancomycin, later generation cephalosporins, and clindamycin. This prescribing practice compro mises optimal medical care and increases costs. Penicillin allergy has been associated with increased antimicrobial resistance (such as vancomycin resistant Enterococcus and methicillin resistant Staphylo coccus aureus), increased Clostridium difficile colitis, increased surgical site infections, prolonged length of hospital stays, increased intensive care admissions, increased hospital readmissions, and increased mor tality. Removal of the penicillin allergy label leads to improved anti biotic selection with decreased use of broad spectrum antibiotics and decreased healthcare utilization (fewer outpatient visits, fewer emer gency department ED visits, and fewer hospital days). Therefore a proactive effort should be made to de label penicillin allergy when ever possible. Ideally, this is done electively such as when patients are well and not in immediate need |
6,719 | of antibiotic treatment. De labeling of penicillin allergy is endorsed by the CDC, allergyimmunology, and infectious disease societies. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 193 u Adverse and Allergic Reactions to Drugs 1457 The penicillin lactam ring opens to form various reactive inter mediates, which then interact with self proteins to stimulate immune reactions. Penicillin skin test reagents are based on the immunochem istry, and they are broadly grouped into major and minor allergenic determinants. (Table 193.4) The positive predictive value of penicillin skin testing is 80 for immediate type reactions. Alternatively, 95 or more of penicillin skin testnegative patients tolerate these antibiotics. The major determinant (penicilloyl polylysine PPL) should always be used for skin testing, but there is controversy regarding the relative importance of various minor determinants (penicillin G, penicilloate, penilloate and ampicillinamoxicillin) and what effect this has on the NPV. Although PPL is commercially available in the United States as Pre Pen, the minor determinants are not. Penicillin G and IV ampicil lin can be diluted and used off label for skin testing, but penicilloate and penilloate require synthesis; therefore they are more difficult to obtain. Patients who are positive on penicillin skin testing should avoid penicillins but consider being reevaluated at a later time, because penicillin allergy wanes and resolves in most (but not all) individu als. If administration of penicillin is deemed necessary, desensitization can be performed. Skin testnegative patients should ideally undergo an amoxicillin challenge, to unequivocally prove lack of allergy. This alleviates the fear and reluctance on the part of the patient, patients family, or future prescribing clinicians to treat with penicillins. Addi tionally, effort should be made to remove the penicillin allergy label in all electronic medical systems (hospitals, clinics, private offices, phar macies, etc.). The traditional approach to de label penicillin allergy has been to first perform penicillin skin testing in all patients with suggestive penicillin allergy histories and then challenge with amoxicillin (if skin testing is negative). However, in recent years several publications have challenged this standard, particularly in the pediatric population, by instead directly challenging low risk patients with amoxicillin (with out preceding skin testing). Patients deemed appropriate for direct amoxicillin challenge are those with maculopapular and urticaria eruptions, without other respiratory, cardiovascular, oropharyngeal symptoms, angioedema, and vesicular or exfoliative eruptions. Using this strategy, the rate of observed reactions ranged from 5 to 10 and were no more severe than the historical reactions. For comparison, up to 7 of children (without a previous history of allergy) treated with aminopenicillins develop cutaneous eruptions. The cause of these rashes is presumed to be the underlying infection (typically viral) or an interaction between the infectious agent and the antibiotic. The best characterized example is patients with Epstein Barr infection, almost 100 of whom develop a nonpruritic morbilliform rash when treated with ampicillin. Pediatric patients |
6,720 | who undergo direct amoxi cillin challenge should be observed in a clinical setting for at least 1 hour, with preparedness to treat potential allergic reactions including anaphylaxis. Resensitization is the redevelopment of penicillin allergy after initial resolution. Resensitization after oral treatment with penicillins is rare in both pediatric and adult patients, including after repeated courses, and comparable to the rate of sensitization. Therefore repeat penicil lin skin testing is not indicated in patients with a history of penicillin allergy who have tolerated one or more courses of oral penicillin. Data on resensitization after parenteral treatment with penicillins is more limited, but routine repeat penicillin skin testing is likely not neces sary in patients with a history of penicillin allergy who have tolerated one or more courses of parenteral penicillin. Consideration may be given to retesting individuals with recent or particularly severe previ ous reactions. Lactam Cross Reactivity Penicillins, cephalosporins, carbapenems, and aztreonam share a com mon lactam ring and hence the potential for allergic cross reactiv ity. Additionally, some penicillins and cephalosporins share identical R group side chains, and these are another source of potential allergic cross reactivity (Table 193.5). Combining published reports of patients proven to be allergic via positive penicillin skin testing and then chal lenged with cephalosporins, only about 2 experienced allergic reac tions. This is similar to the incident rate of new drug reactions to structurally dissimilar medications in patients with prior drug allergies (because patients with a history of drug allergy are more likely to react to structurally unrelated drugs). If cephalosporin skin testing (using nonirritating concentrations) is performed in penicillin skin testposi tive subjects before challenging with cephalosporins, the reaction rate decreased to 0. In general, the preferred approach to patients with a history of pen icillin allergy is to electively de label the allergy because this greatly simplifies all future lactam administration recommendations by allowing treatment with any lactam antibiotics. Given that less than 5 of patients with an unverified penicillin allergy are truly allergic and 2 of those who are allergic cross react with cephalosporins, the chance Table 193.4 Penicillin Skin Test Reagents REAGENT CONCENTRATION USED FOR SKIN TESTING Penicilloyl polylysine (PPL) 6 105 M Penicillin G 10,000 unitsmL Penicilloate 0.01 M Penilloate 0.01 M Ampicillinamoxicillin 3 25 mgmL PPL is the major allergenic determinant; all the other reagents are minor determinants. Table 193.5 Groups of Lactam Antibiotics That Share Identical Side Chains IDENTICAL R1 GROUP SIDE CHAINS Amoxicillin Ampicillin Ceftriaxone Cefoxitin Cefamandole Ceftazidime Cefadroxil Cefaclor Cefotaxime Cephaloridine Cefonicid Aztreonam Cefprozil Cephalexin Cefpodoxime Cephalothin Cefatrizine Cephradine Cefditoren Cephaloglycin Ceftizoxime Loracarbef Cefmenoxime IDENTICAL R2 GROUP SIDE CHAINS Cephalexin Cefotaxime Cefuroxime Cefotetan Cefaclor Ceftibuten Cefadroxil Cephalothin Cefoxitin Cefamandole Loracarbef Ceftizoxime Cephradine Cephaloglycin Cefmetazole Cephapirin Cefpiramide Each column represents a group with identical side chains. From Solensky R, Khan DA. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105:273e1273e78. Tables 16, 17, p. 273e49. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For |
6,721 | personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1458 Part XIII u Allergic Disorders of a cephalosporin reaction is extremely low at approximately 0.1 (5 2 0.1). Therefore most experts and guidelines recommend that for patients with a history of nonanaphylactic penicillin allergy, cephalospo rins may be administered without prior testing or additional precautions. In patients with a history of penicillin anaphylaxis (or those positive on penicillin skin testing), cephalosporin graded challenge is preferred because the chance of reaction is still very low. There are rare patients who have selective IgE mediated allergy to aminopenicillins but tolerate penicillin VK and penicillin G. The allergic determinant is an R group side chain, rather than the core lactam portion of the molecule. In these patients, the positive challenge rate to cephalosporins sharing identical side group chains (such as ampicillincephalexin or amoxicillincefadroxil; see Table 193.5) is higher, or about 16. Therefore, in such patients, admin istration of cephalosporins with identical side group chains should be avoided, given via two step graded challenge or desensitization, whereas treatment with other cephalosporins does not require a more cautious approach. The data on allergic cross reactivity between penicillins and car bapenems mirror the discussion on penicillincephalosporin cross reactivity. Patients with unconfirmed penicillin allergy treated with carbapenems showed a higher reaction rate compared to patients without a history of penicillin allergy. In studies of penicillin skin testpositive patients challenged with carbapenems, none of 680 reacted; four carbapenem skin testpositive patients were not chal lenged. Therefore it is recommended that patients with a history of penicillin allergy may receive carbapenems in usual fashion or via two step graded challenge. Aztreonam is the only monobactam and the only lactam antibiotic that contains a monocyclic ring structure, in contrast to the bicyclic core of other lactams. In vitro, skin testing and challenge studies have demonstrated no evidence of allergic cross reactivity between penicillins and aztreonam, including no positive aztreonam challenges in penicillin skin testpositive patients. Therefore patients with a his tory of penicillin allergy may receive aztreonam in the usual fash ion. The only lactam that shows cross reactivity with aztreonam is ceftazidime, because these two antibiotics share an identical R group side chain. Hence, patients allergic to aztreonam or ceftazidime should avoid the other antibiotic. Sulfonamides The most common type of reaction to sulfonamide antibiotics is a maculopapular eruption that occurs about a week into treatment. The incidence of immediate reactions, such as urticariaangioedema or anaphylaxis, is rare and less frequent than with lactam antibiotics. On the other hand, sulfonamides are the most common antibiotic to cause severe cutaneous delayed reactions (SCARs), such as SJS, TEN, and DRESS. Hypersensitivity reactions to sulfonamides occur with greater frequency in HIV infected individuals. For patients with his tory of typical delayed maculopapular rashes, both graded one or two step challenge and desensitization protocols have been shown to be effective in HIV positive and nonHIV positive patients. Because the success rate of graded challenge and desensitization appears |
6,722 | com parable, it is not clear that the various desensitization protocols truly modify the immune response. These regimens are not intended for individuals with a history of SJS or TEN. There is no evidence of aller gic cross reactivity between sulfonamide antibiotics and nonantibiotic sulfonamides (such as celecoxib, thiazides, furosemide, acetazolamide, sumatriptan, and others). Macrolides Macrolides cause allergic reactions less frequently than penicillins, cephalosporins, or sulfonamides. The most common reactions are delayed onset maculopapular eruptions and urticaria, and they occur in about 1 of patients. IgE mediated reactions are uncommon, limited to case series, and anaphylactic reactions are extremely rare. When pediatric patients with convincing histories of allergic reactions undergo formal evaluation, less than 10 are confirmed to be aller gic. Skin testing with a nonirritating concentration of macrolides may provide useful information in those patients with immediate reaction histories. However, in patients with an anticipated clinical need for macrolides, graded challenge without preceding testing is used most commonly, given the high likelihood of success and rare nature of anaphylaxis. Antiretroviral Agents There are several categories of antiretroviral drugs to treat HIV (reverse transcriptase inhibitors, protease inhibitors, entry inhibitors, and inte grase inhibitors) and all have been implicated in hypersensitivity reac tions, which usually present as delayed onset and range from mild self limited maculopapular eruptions to life threatening SJSTEN or DRESS. Hypersensitivity to abacavir is a well recognized, multiorgan, potentially life threatening reaction that occurs in HIV infected chil dren and adults. Rechallenge is strictly contraindicated, because subse quent reactions may be more rapid and severe than the initial reaction. Importantly, these reactions have been associated with the presence of the MHC class I allele HLA B5701, and HLA testing has shown very high sensitivity and NPV. Therefore genetic screening for HLA B5701 is part of guideline based therapy when abacavir is initially prescribed. Chemotherapeutic Agents Hypersensitivity reactions to chemotherapeutic drugs have been described, most notably to platinum agents and taxanes. The clini cal pattern of immediate reactivity to platinum agents, along with skin test findings, is consistent with an IgE mediated mechanism. Hence reactions occur after patients tolerated several previous treat ments. In contrast, immediate reactions to paclitaxel and docetaxel usually occur with first exposure and the risk lessens with repeated exposure. They are believed to be due to emulsifying agents such as Cremophor EL, which result in complement activation and gen eration of anaphylatoxins. Rapid desensitization (most typically a 12 step protocol) is effective for both IgE and nonIgE mediated type reactions. Biologics An increasing number of biologic agents have become available for the treatment of autoimmune, allergic, cardiovascular, infectious, and neo plastic diseases. Their use may be associated with a variety of ADRs, including hypersensitivity reactions. Given the occurrence of anaphy laxis, including cases with delayed onset and protracted progression in spontaneous postmarketing adverse event reports, the FDA issued a black box warning regarding risk of anaphylaxis and need for patient monitoring with use of omalizumab (see Chapter 185). Vaccines Anaphylactic reactions to vaccines are very |
6,723 | rare, occurring at a rate of approximately one event per million administrations, and they may be due to various vaccine components such as antibiotics, pre servatives, stabilizers, virus inactivating compounds, residual ani mal proteins, and latex. Measles mumps rubella (MMR) vaccine has been shown to be safe in egg allergic patients (although rare reac tions to gelatin or neomycin can occur). Egg allergic patients are not at higher risk of reacting to both inactivated and live influenza vac cine than those without egg allergy. Skin testing with the influenza vaccine is no longer recommended for egg allergic patients but may be helpful if allergy to the vaccine itself is suspected. The American Academy of Allergy, Asthma, and Immunology (AAAAI)Ameri can College of Allergy, Asthma, and Immunology (ACAAI) Joint Task Force on Practice Parameters recommend that Influenza vac cines should be administered to individuals with egg allergy of any severity, just as they would be to individuals without egg allergy. The incidence of anaphylactic reactions following mRNA COVID 19 vaccines may be higher (2.5 4.7 events per million). However, following evaluation by allergistsimmunologists, most patients reporting immediate type reactions to the first vaccine dose are able to tolerate the second dose, arguing against an IgE mediated mechanism. Therefore the true rate of anaphylaxis is likely lower. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 193 u Adverse and Allergic Reactions to Drugs 1459 It is uncertain whether patients with underlying atopic conditions or other allergies are at increased risk of reacting to these vac cines. Although polyethylene glycol (PEG) (a component of mRNA COVID vaccines) has been proposed to be a possible culprit, there is limited evidence for the relationship. Perioperative Agents In North America, perioperative anaphylaxis is most frequently due to antibiotics, whereas in European series, neuromuscular blockers are the most common culprit. Other potential causes include induc tion agents, opioids, colloids and plasma expanders, chlorhexidine, sugammadex, and latex. The mechanism responsible may be IgE mediated or nonIgE mediated. Previous surgeries are a risk factor for IgE mediated reactions because they require prior sensitization. Patients who have experienced perioperative anaphylaxis should be screened for possible mast cell disease. Skin testing with agents known to cause IgE mediated reactions is useful and can help pre vent recurrent reactions during subsequent surgeries. Sometimes, despite a thorough evaluation, an underlying cause for periopera tive anaphylaxis is not detected. Local Anesthetics ADRs associated with local anesthetic agents are primarily nonaller gic and include vasovagal, psychomotor, sympathetic stimulation, and toxic reactions. IgE mediated reactions are exceedingly rare. Patients with suspected local anesthetic allergy should be referred to an aller gistimmunologist for skin testing followed by a graded challenge. This procedure invariably finds a local anesthetic the patient is able to tol erate, in the rare individuals who are allergic to one of these agents. Although local anesthetics can |
6,724 | be broadly grouped into esters (group I) and amides (group II), allergic cross reactivity within these groups is only relevant for delayed Gell and Coombs type IV reactions, not type I reactions. Insulin Insulin use has been associated with a spectrum of ADRs, includ ing local and systemic IgE mediated reactions, hemolytic anemia, serum sickness reactions, and delayed type hypersensitivity. In gen eral, human insulin is less allergenic than porcine insulin, which is less allergenic than bovine insulin, but for individual patients, por cine or bovine insulin may be the least allergenic. Patients treated with nonhuman insulin have had systemic reactions to recombi nant human insulin even on the first exposure. More than 50 of patients who receive insulin develop antibodies against the insulin preparation, although there may not be any clinical manifestations. Local cutaneous reactions usually do not require treatment and resolve with continued insulin administration, possibly because of IgG blocking antibodies. More severe local reactions can be treated with antihistamines or by splitting the insulin dose between sepa rate administration sites. Local reactions to the protamine com ponent of neutral protamine Hagedorn insulin may be avoided by switching to lente insulin. Immediate type reactions to insulin, including urticaria and anaphylactic shock, are unusual and almost always occur after reinstitution of insulin therapy in sensitized patients. Insulin therapy should not be interrupted if a systemic reaction to insulin occurs, and continued insulin therapy is essential. Skin test ing may identify a less antigenic insulin preparation. The dose follow ing a systemic reaction is usually reduced to one third, and successive doses are increased in 2 to 5 unit increments until the dose resulting in glucose control is attained. Insulin skin testing and desensitization are required if insulin treatment is subsequently interrupted for 24 48 hours. Radiocontrast Media Immediate type allergic reactions to RCM may occur after intravascu lar administration, and during myelograms or retrograde pyelograms. The pathogenic mechanism has classically been thought to be non IgE mediated mast cell activation (anaphylactoid). However, there is growing evidence that some immediate reactions are IgE mediated. This may be because use of older high osmolar RCM agents has been replaced by low and iso osmolar agents. One approach to patients with previous RCM reactions who require another diagnostic study is to choose an alternate agent and premedicate with prednisone and diphenhydramine. Another approach is to perform skin testing with the culprit and alternate RCM agents, with the results guiding the choice of treatment. The latter method appears to be more useful when the historical reactions are severe (i.e., anaphylactic). There is no evi dence that seafood or iodine allergy is associated with or predisposes to RCM reactions. Aspirin and Nonsteroidal Antiinflammatory Drugs Acetylsalicylic acid (ASA) and other NSAIDs have been associated with several types of allergic reactions. Reactions that are caused by modifying effects on arachidonic acid metabolism, namely respiratory reactions (in patients with underlying aspirin exacerbated respiratory disease AERD) and urticarial reactions (in patients with underlying chronic idiopathic urticaria), show cross |
6,725 | reactivity with other NSAIDs, as one would expect. Patients with AERD and aspirin sensitive patients with chronic idiopathic urticaria tolerate drugs that selectively block the cyclooxygenase 2 (COX 2) enzyme, such as celecoxib. On the other hand, acute urticarial or anaphylactic reactions in otherwise nor mal individuals are medication specific. There are no skin or in vitro tests to identify patients allergic to ASA or other NSAIDs. Except for respiratory reactions in asthmatics, there are no data on the incidences of reactions to ASANSAIDs in children; however, clini cal experience suggests that it is much lower than in adults. Further more, only 20 of children reporting NSAID allergy are confirmed to be allergic when challenged. The incidence of AERD in children with asthma has been investigated in six prospective studies, the rate varied from 0 to 28, and there was a trend for more respiratory reactions in adolescents compared with younger children. Overall, the data indi cate that ASA sensitivity in asthmatic children under the age of 10 is rare and increases thereafter. Patients with AERD whose nasal disease or asthma is poorly con trolled with use of medications are candidates for ASA desensitization. This procedure, unlike antibiotic or chemotherapy desensitization, involves administration of the drug to cautiously induce a respira tory reaction (rather than prevent it), following which patients enter a refractory phase that can be maintained with continued administra tion of ASA. Long term studies of adults maintained on chronic ASA desensitization demonstrated improved clinical outcomes for both upper and lower respiratory diseases. ASA desensitization is rarely performed in children because severe, poorly controlled AERD is encountered very infrequently in the pediatric population, and aspirin is not routinely recommended for children because of the risk of Reyes syndrome. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) PART XIV 1460 Rheumatic diseases are defined by the constellation of results of the physical examination, autoimmune markers and other serologic tests, tissue pathology, and imaging. Defined diagnostic criteria exist for most rheumatic diseases. Recognition of clinical patterns remains essential for diagnosis because there is no single diagnostic test, and tests may be positive in the absence of disease. Further complicating diagnosis, children sometimes present with partial criteria that evolve over time or with features of more than one rheumatic disease (over lap syndromes). The primary mimics of rheumatic diseases are infec tion and malignancy but also include metabolic, orthopedic, immune deficiencies, autoinflammatory diseases, and chronic pain conditions. Exclusion of possible mimicking disorders is essential before initiation of treatment for a presumptive diagnosis, especially corticosteroids. After careful evaluation has excluded nonrheumatic causes, referral to a pediatric rheumatologist for confirmation of the diagnosis and treat ment should be considered. SYMPTOMS SUGGESTIVE OF RHEUMATIC DISEASE There are no classic symptoms of |
6,726 | rheumatic diseases, but common symptoms include joint pain, fever, fatigue, and rash. Presenting signs and symptoms help direct the evaluation and limit unnecessary testing. Once a differential diagnosis is developed based on history and physi cal findings, a directed assessment assists in determining the diagnosis. Arthralgias are common in childhood and are a frequent reason for referral to pediatric rheumatologists. Arthralgias without physical findings for arthritis suggest infection, malignancy, orthopedic con ditions, benign syndromes, or pain syndromes such as fibromyalgia (Table 194.1). Although rheumatic diseases may manifest as arthral gias, arthritis is a stronger predictor of the presence of rheumatic disease and a reason for referral to a pediatric rheumatologist. The timing of joint pain along with associated symptoms, including poor sleep and interference with normal activities, provides important clues. Poor sleep, debilitating generalized joint pain that worsens with activ ity, school absences, and normal physical and laboratory findings in an adolescent suggest an amplified pain syndrome (see Chapter 212). If arthralgia is accompanied by a history of dry skin, hair loss, fatigue, growth disturbance, or cold intolerance, testing for thyroid disease is merited. Nighttime awakenings because of severe pain along with decreased platelet or white blood cell (WBC) count or, alternatively, a very high WBC count, may lead to the diagnosis of malignancy, espe cially marrow occupying lesions such as acute lymphocytic leukemia and neuroblastoma. Pain with physical activity suggests a mechani cal problem such as an overuse syndrome or orthopedic condition. An adolescent presenting with knee pain aggravated by walking up stairs and on patellar distraction likely has patellofemoral syndrome. Children age 3 10 years with a history of episodic pain occurring at night, especially after increased daytime physical activity, that is relieved by rubbing but who have no limp or complaints in the morn ing likely have growing pains. There is often a positive family history for growing pains, which may aid in this diagnosis. Intermittent pain in a child, especially a girl 3 10 years old, that is increased with activity and is associated with hyperextensible joints on examination likely has benign hypermobility syndrome. Many febrile illnesses cause arthral gias that improve when the temperature normalizes, and arthralgias are part of the diagnostic criteria for acute rheumatic fever (ARF; see Chapter 229.1). Arthralgia may also be a presenting symptom of pediatric systemic lupus erythematosus (SLE) and chronic childhood arthritis such as juvenile idiopathic arthritis (JIA). Interestingly, many children with JIA do not complain of joint symptoms at presentation. Other symp toms more suggestive of arthritis include morning stiffness, joint swell ing, limited range of motion, pain with joint motion, gait disturbance, fever, and fatigue or stiffness after physical inactivity (gelling phenom enon). A diagnosis of JIA cannot be made without the finding of arthri tis on physical examination (see Chapters 196 and 197). No laboratory test is diagnostic of JIA. Fatigue is a nonspecific symptom that may point to the presence of a rheumatic disease but is also common in nonrheumatic causes, such as viral infections, |
6,727 | pain syndromes, depression, and malignancy. Fatigue, rather than the specific complaints of muscle weakness, is a common presenting complaint in juvenile dermatomyositis (JDM). It is also frequently present in SLE, vasculitis, and chronic childhood arthritis. Overwhelming fatigue with inability to attend school is more sug gestive of chronic fatigue syndrome, pediatric fibromyalgia, or other amplified pain syndrome. SIGNS SUGGESTIVE OF RHEUMATIC DISEASE A complete physical examination is essential in any child with sus pected rheumatic disease, because subtle physical findings may further refine the differential diagnosis. In addition, many rheumatic diseases have multisystem effects, and a stepped assessment should focus on delineating the extent of organ system involvement (e.g., skin, joints, muscle, hepatic, renal, cardiopulmonary). Presence of a photosensitive malar rash that spares the nasolabial folds is suggestive of SLE (Table 194.2; see Fig. 199.1A). Diffuse facial rash is more indicative of JDM. A hyperkeratotic rash on the face or around the ears may represent discoid lupus (see Fig. 199.1D). A palpable pur puric rash on the extensor surfaces of the lower extremities points to IgA vasculitis (HenochSchnlein purpura) (see Fig. 210.2A). Less local ized purpuric rashes and petechiae are present in systemic vasculitis or blood dyscrasias, including coagulopathies. Nonblanching erythematous papules on the palms are seen in vasculitis, SLE, and endocarditis. Got tron papules (see Fig. 200.3) and heliotrope rashes (see Fig. 200.2) along with erythematous rashes on the elbows and knees are pathognomonic Chapter 194 Evaluation of Suspected Rheumatic Disease C. Egla Rabinovich Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 194 u Evaluation of Suspected Rheumatic Disease 1461 of JDM. Dilated capillary loops in the nail beds (periungual telangiec tasias; see Fig. 200.4) are common in JDM, scleroderma, and second ary Raynaud phenomenon. An evanescent macular rash associated with fever is part of the diagnostic criteria for systemic onset arthritis (see Fig. 196.12). Sun sensitivity or photosensitive rashes are indicative of SLE or JDM but can also be caused by antibiotics. Mouth ulcers are part of the diagnostic criteria for SLE and Behet disease (see Fig. 199.1C); painless nasal ulcers and erythematous macules on the hard palate are also common in SLE. Cartilage loss in the nose, causing a saddle nose deformity, is classically present in granulomatosis with polyangiitis (formerly Wegener granulomatosis; see Fig. 210.8) but is also seen in relapsing polychondritis and syphi lis. Alopecia can be associated with SLE but is also found in localized scleroderma (see Fig. 201.4) and JDM. Raynaud phenomenon may be a primary benign idiopathic disorder or can be a presenting complaint in the child with scleroderma, lupus, mixed connective tissue disease (MCTD), or an overlap syndrome. Diffuse lymphadenopathy is pres ent in many rheumatic diseases, including SLE, polyarticular JIA, and systemic JIA. Irregular pupils may represent the insidious and unrec ognized onset of uveitis associated with JIA. Erythematous conjunc tivae may be a |
6,728 | result of uveitis or episcleritis associated with JIA, SLE, sarcoidosis, spondyloarthropathies, or vasculitis. A pericardial rub and orthopnea are suggestive of pericarditis, often seen in systemic JIA, SLE, and sarcoid. Coronary artery dilation is strongly suggestive of Kawasaki disease and multisystem inflammatory syndrome in children (MIS C) but may also be a finding in systemic arthritis and other forms of systemic vasculitis. Interstitial lung disease, suggested by dyspnea on exertion or the finding of basilar rales with decreased carbon monoxide diffusion capacity, occurs in SLE, MCTD, and systemic sclerosis. Signs consistent with pulmonary hemorrhage point to granulomatosis with polyangiitis, microscopic angiitis, or SLE. Pulmonary vascular aneurysms are indicative of Behet disease. Arthritis is defined by the presence of intraarticular swelling or two or more of the following findings on joint examination: pain on motion, loss of motion, erythema, and heat. Arthritis is present in all the chronic childhood arthritis syndromes, along with SLE, JDM, vasculitis, Behet disease, sarcoidosis, Kawasaki disease, and Henoch Schnlein purpura. Nonrheumatic causes of arthritis include malig nancy, septic arthritis, Lyme disease, osteomyelitis, viral infections (e.g., rubella, hepatitis B, parvovirus B19, chikungunya), and postin fectious etiologies such as Epstein Barr virus (EBV), ARF, and reactive arthritis. ARF typically involves a migratory (lasting hours to days), painful arthritis. Pain on palpation of long bones is suggestive of malig nancy. Specific muscle testing for weakness should be performed in a child presenting with fatigue or difficulty with daily tasks, because both these symptoms may be manifestations of muscle inflammation. LABORATORY TESTING There are no specific screening tests for rheumatologic disease. Once a differential diagnosis is determined, appropriate testing can be per formed (Tables 194.3 and 194.4). Initial studies are generally performed in standard local laboratories. Screening for specific autoantibodies can be performed in commercial laboratories, but confirmation of results in a tertiary care center immunology laboratory is often necessary. Table 194.2 Signs Suggestive of Rheumatic Disease SIGN RHEUMATIC DISEASES COMMENTS NONRHEUMATIC CAUSES Malar rash SLE, JDM SLE classically spares nasolabial folds Sunburn, parvovirus B19 (fifth disease), Kawasaki disease Oral ulcers SLE, Behet disease Behet disease also associated with genital ulcers HSV infection, PFAPA syndrome Purpuric rash Vasculitis (e.g., ANCA associated vasculitis), HSP HSP typically starts as small lesions on lower extremities and buttocks that coalesce Meningococcemia, thrombocytopenia, clotting disorders Gottron papules JDM Look for associated heliotrope rash, periungual telangiectasias Psoriasis, eczema Arthritis Juvenile idiopathic arthritis, SLE, vasculitis, HSP, MCTD, scleroderma, acute rheumatic fever, reactive arthritis Chronic joint swelling (6 wk) required for diagnosis of JIA; MCTD associated with diffuse puffiness of hands Postviral arthritis, reactive arthritis, trauma, infection, Lyme disease, Kawasaki disease, malignancy, overuse syndromes ANCA, Antineutrophil cytoplasmic antibody; HSP, Henoch Schnlein purpura; HSV, herpes simplex virus; JIA, juvenile idiopathic arthritis; JDM, juvenile dermatomyositis; MCTD, mixed connective tissue disease; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis; SLE, systemic lupus erythematosus. Also know as IgA vasculitis. Table 194.1 Symptoms Suggestive of Rheumatic Disease SYMPTOM RHEUMATIC DISEASE(S) POSSIBLE NONRHEUMATIC DISEASES CAUSING SIMILAR SYMPTOMS Fevers Systemic JIA, SLE, vasculitis, acute rheumatic |
6,729 | fever, sarcoidosis, MCTD Malignancies, infections and postinfectious syndromes, inflammatory bowel disease, periodic fever (autoinflammatory) syndromes, Kawasaki disease, HSP Arthralgias JIA, SLE, rheumatic fever, JDM, vasculitis, scleroderma, sarcoidosis Hypothyroidism, trauma, endocarditis, other infections, pain syndromes, growing pains, malignancies, overuse syndromes Weakness JDM, myositis secondary to SLE, MCTD, and deep localized scleroderma Muscular dystrophies, metabolic and other myopathies, hypothyroidism Chest pain Juvenile idiopathic arthritis, SLE (with associated pericarditis or costochondritis) Costochondritis (isolated), rib fracture, viral pericarditis, panic attack, hyperventilation Back pain Enthesitis related arthritis, juvenile ankylosing spondylitis Vertebral compression fracture, diskitis, intraspinal tumor, spondylolysis, spondylolisthesis, bone marrowoccupying malignancy, pain syndromes, osteomyelitis, muscle spasm, injury Fatigue SLE, JDM, MCTD, vasculitis, JIA Pain syndromes, chronic infections, chronic fatigue syndrome, depression HSP, Henoch Schnlein purpura; JDM, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; MCTD, mixed connective tissue disease; SLE, systemic lupus erythematosus. Also know as IgA vasculitis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1462 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) For initial workup of rheumatic disease, a CBC with differential, alanine transaminaseaspartate transaminase (ALTAST), albumin, BUNcreatinine, urinalysis, creatine phosphokinaselactate dehydro genase (CPKLDH), and inflammatory markers (sedimentation rate and CRP) are recommended. Further appropriate testing depends on clinical concern (see Table 194.4). One essential laboratory test for rheumatic disease assessment is the complete blood count (CBC), because it yields many diagnostic clues. Elevated WBC count is compatible with malignancy, infection, systemic JIA, and vasculitis. Leukopenia can be postinfectious, espe cially viral, or caused by SLE or malignancy. Lymphopenia is more specific for SLE than is leukopenia. Platelets are acute phase reactants and are therefore elevated with inflammatory markers. Exceptions are a bone marrowoccupying malignancy, such as leukemia or neu roblastoma, SLE, and early Kawasaki disease. Anemia is nonspecific and may be caused by any chronic illness, but hemolytic anemia (pos itive Coombs test result) may point to SLE or MCTD. Rheumatoid factor (RF) is present in 10 of children with JIA and thus has poor sensitivity as a diagnostic tool; RF may be elevated by infections such as endocarditis, tuberculosis, syphilis, and viruses (parvovirus B19, hepatitis B and C, mycoplasma), as well as primary biliary cirrhosis and malignancies. In a child with chronic arthritis, RF serves as a prognostic indicator. Inflammatory markers (erythrocyte sedimentation rate, CRP, fer ritin, procalcitonin) are nonspecific and are elevated in infections, malignancies, and rheumatic diseases (Table 194.5). Their levels may also be normal in rheumatic diseases such as arthritis, sclero derma, and dermatomyositis. The advantages of a CRP include rapid response to inflammatory stimuli, wide range of clinically relevant values, the fact that it is unaffected by age or gender, it is precise and reproducible, and it can be measured on stored sera. Sedimen tation rates have classically been used as markers of inflammation, but they can be affected by anemia, red cell morphology, and drugs such |
6,730 | as intravenous immunoglobulin (IVIG); they require a fresh blood sample; and they are slow to respond to clinical changes. Inflammatory marker measurements in general are more useful in rheumatic diseases for following response to treatment than as diagnostic tests. Muscle enzymes include AST, ALT, CPK, aldolase, and LDH, any of which may be elevated in JDM and in other diseases causing muscle breakdown. Muscle building supplements, medications, and extreme physical activity may also cause muscle breakdown and enzyme eleva tions. AST, ALT, and aldolase may also be elevated in liver disease, and a glutamyltransferase (GGT) measurement may help differentiate muscle or liver source. The use of an antinuclear antibody (ANA) measurement as a screen ing test is not recommended because it has low specificity. A positive ANA test result may be induced by infection, especially EBV infec tion, endocarditis, and parvovirus B19 infection. The ANA test result is also positive in up to 30 of normal children, and ANA level is Table 194.3 Autoantibody Specificity and Disease Associations ANTIBODY DISEASE PREVALENCE () SPECIFICITY Antinuclear antibody (ANA) SLE, juvenile rheumatoid arthritis, dermatomyositis, scleroderma, psoriatic arthritis, MCTD Associated with increased risk of uveitis in JIA and psoriatic arthritis Up to 30 of children testing positive for ANAs have no underlying rheumatic disease Double stranded DNA (dsDNA) SLE 60 70 High specificity for SLE; associated with lupus nephritis Smith (Sm) SLE 20 30 Highly specific for SLE; associated with lupus nephritis Smooth muscle (Sm) Autoimmune hepatitis Pm Scl (polymyositis scleroderma) Sclerodermatomyositis SSA (Ro) SLE, Sjgren syndrome 25 30 Associated with neonatal lupus syndrome, subacute cutaneous lupus, thrombocytopenia SSB (La) SLE, Sjgren syndrome 25 30 Usually coexists with anti SSA antibody Ribonuclease protein (RNP) MCTD, SLE 30 40 Suggestive of MCTD unless meets criteria for SLE Histone Drug induced lupus, SLE Centromere Limited cutaneous systemic sclerosis 70 Nonspecific for systemic sclerosis Topoisomerase I (Scl 70) Systemic sclerosis Rare in childhood Antineutrophil cytoplasmic antibodies (ANCAs) Vasculitis Cytoplasmic (cANCAs)PR3 ANCA cANCAs associated with granulomatosis with polyangiitis (Wegener), cystic fibrosis Perinuclear (pANCAs)MPO ANCA pANCAs associated with microscopic polyangiitis, polyarteritis nodosa, SLE, inflammatory bowel disease, cystic fibrosis, primary sclerosing cholangitis, Henoch Schnlein purpura, Kawasaki disease, Churg Strauss syndrome Anticitrullinated protein (ACPA); also called anticyclic citrullinated protein (anti CCP) RF positive JIA 50 90 Specific for JIA (RF), may be positive before RF MCTD, Mixed connective tissue disease; MPO ANCA, antimyeloperoxidase; PR3 ANCA, antiproteinase 3; RF, rheumatoid factor; SLE, systemic lupus erythematosus. Adapted from Aggerwal A. Clinical application of tests used in rheumatology. Indian J Pediatr 2002;69:889892. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 194 u Evaluation of Suspected Rheumatic Disease 1463 Table 194.4 Evaluation Based on Suspected Diagnosis of Rheumatic Disease SUSPECTED RHEUMATIC DISEASE(S) INITIAL EVALUATION FURTHER EVALUATION SUBSPECIALTY EVALUATION Systemic lupus erythematosus (SLE) Mixed connective tissue disease (MCTD) CBC, ESR, ANA, ALT, AST, CPK, creatinine, albumin, total protein, urinalysis, |
6,731 | BP, thyroid profile If ANA test result is positive: anti SSA (Ro), anti SSB (La), anti Smith, and anti RNP Abs; anti dsDNA Ab, C3, C4, Coombs, spot urine protein creatinine ratio, CXR Antiphospholipid Abs, lupus anticoagulant, anti2 glycoprotein, echocardiogram; consider renal biopsy, PFTs, bronchoscopy with lavage, HRCT of chest; consider lung biopsy Juvenile dermatomyositis (JDM) CBC, CPK, ALT, AST, LDH, aldolase, ANA; check gag reflex Consider MRI of muscle Consider electromyography and possible muscle biopsy, PFTs, swallowing study, serum neopterin Juvenile idiopathic arthritis (JIA) CBC, ESR, creatinine, ALT, AST, consider antistreptolysin O antiDNAase B for streptococcus induced arthritis, Epstein Barr virus titers, Lyme titer, parvovirus B19 titer, plain radiograph of joints Consider Ab titers to unusual infectious agents, purified protein derivative, RF, ANA, HLA B27, anti CCP MRI Granulomatosis with polyangiitis (Wegener granulomatosis) CBC, ANCA, AST, ALT, albumin, creatinine, ESR, urinalysis, CXR, BP Spot urine proteincreatinine ratio, antimyeloperoxidase and antiproteinase 3 Abs, PFTs Bronchoscopy with lavage, HRCT chest; consider lung and kidney biopsies Sarcoidosis CBC, electrolytes, AST, ALT, albumin, creatinine, calcium, phosphorous, ACE, BP CXR, PFTs Consider testing for Blau syndrome in infants (see Chapter 200); HRCT of chest; consider renal and lung biopsy Localized scleroderma Skin biopsy, CBC, ESR Serum IgG, ANA, RF, single stranded DNA Ab, antihistone Ab, CPK Systemic scleroderma ANA, CBC, ESR, BP, AST, ALT, CPK, creatinine, CXR Anti Scl70, PFTs HRCT of chest, echocardiogram, upper GI radiography series Ab, Antibody; ACE, angiotensin converting enzyme (normally elevated in childhood; interpret with caution); ALT, alanine transaminase; ANA, antinuclear antibody; anti dsDNA Ab, antidouble stranded DNA antibody; AST, aspartate transaminase; BP, blood pressure; CBC, complete blood count; CCP, cyclic citrullinated protein; CPK, creatine phosphokinase; CXR, chest x ray; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HRCT, high resolution CT; LDH, lactate dehydrogenase; PFTs, pulmonary function tests; RF, rheumatoid factor; RNP, ribonucleoprotein. increased in those with a first degree relative with a known rheumatic disease. In the majority of children with a positive ANA without signs of a rheumatic disease on initial evaluation, autoimmune disease does not develop over time, so this finding does not necessitate referral to a pediatric rheumatologist. A positive ANA test result is found in many rheumatic diseases, including JIA, in which it serves as a predic tor of the risk for inflammatory eye disease (see Chapter 196). Once a positive ANA test result is discovered in a child, the need for specific autoantibody testing is directed by the presence of clinical signs and symptoms (see Table 194.3). IMAGING STUDIES Plain radiographs are useful in evaluation of arthralgias and arthritis, as they offer reassurance in benign pain syndromes and their findings may be abnormal in malignancies, osteomyelitis, and long standing chronic juvenile arthritis. Musculoskeletal ultrasound can be useful in evaluation of synovitis and joint effusion. MRI findings are abnor mal in inflammatory myositis and suggest the optimal site for biopsy. MRI is more sensitive than plain radiographs in detecting the presence of early erosive arthritis and demonstrates increased joint fluid, synovial enhancement, and sequela of |
6,732 | trauma with internal joint derangement. MRI is also helpful in ruling out infection or malignancy. Cardiopul monary evaluation is suggested for diseases commonly affecting the heart and lung, including SLE, systemic scleroderma, MCTD, JDM, and sarcoid, as clinical manifestations may be subtle. This evaluation, which may include echocardiogram, pulmonary function tests, and high resolution CT of the lungs along with consideration of bronchoal veolar lavage, is generally performed by a pediatric rheumatologist to whom the patient is referred (see Table 194.4). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 194.5 Conditions Associated with Elevated C Reactive Protein Levels NORMAL OR MINOR ELEVATION (1 mgdL) Vigorous exercise Common cold Pregnancy Gingivitis Seizures Depression Insulin resistance and diabetes Several genetic polymorphisms Obesity MODERATE ELEVATION (1 10 mgdL) Myocardial infarction Malignancies Pancreatitis Mucosal infection (bronchitis, cystitis) Most systemic autoimmune diseases Rheumatoid arthritis Influenza and adenovirus infections MARKED ELEVATION (10 mgdL) Acute bacterial infection (8085) Major trauma, surgery Systemic vasculitis MIS C MIS C, Multisystem inflammatory syndrome in children. From Firestein GS, Budd RC, Gabriel SE, et al., eds. Kelley Firesteins Textbook of Rheumatology, 10th ed. Philadelphia: Elsevier; 2017, Table 57 4, p. 849. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 195 u Treatment of Rheumatic Diseases 1465 qualitatively different from that observed with treatment of neo plasms. Adverse effects include elevated liver enzyme values (15); GI toxicity (13); stomatitis (3); headache (12); and leukope nia, interstitial pneumonitis, rash, and alopecia (1). Hepatotox icity observed among adults with rheumatoid arthritis (RA) treated with MTX has raised concern about similar problems in children. Analysis of liver biopsy specimens in children with JIA undergoing long term MTX treatment has revealed occasional mild fibrosis but no evidence of even moderate liver damage. Patients receiving MTX should be counseled to avoid alcohol, smoking, and pregnancy. Folic acid (1 mg daily) is given as an adjunct to minimize adverse effects. Lymphoproliferative disorders have been reported in adults treated with MTX, primarily in association with Epstein Barr virus (EBV) infection. Regression of lymphoma may follow withdrawal of MTX. Monitoring laboratory tests for MTX toxicity include CBC and LFTs at regular intervals, initially every 8 12 weeks for the first 3 6 months of treatment, then every 12 weeks, with more frequent intervals after dosing adjustments or in response to abnormal values. Hydroxychloroquine Hydroxychloroquine sulfate is an antimalarial drug important in the treat ment of SLE and dermatomyositis, particularly cutaneous manifestations of disease and to reduce lupus flares. It is not indicated to treat JIA because of lack of efficacy. The most significant potential adverse effect is retinal toxicity, which occurs rarely but results in irreversible color blindness or loss of central vision. Complete ophthalmologic examinations, including assessment of peripheral vision and color fields, are conducted at baseline and every 6 12 months to screen for retinal toxicity. Retinal toxicity is rare (15,000 |
6,733 | patients) and is associated with weight based dosing exceed ing 6.5 mgkgday; therefore recommended dosing is 5 mgkgday, not to exceed 400 mgday. Other potential adverse effects include rash, skin discoloration, gastric irritation, bone marrow suppression, central nervous system (CNS) stimulation, and myositis. Leflunomide Leflunomide is a DMARD approved for treatment of RA and also offers an alternative to MTX for treatment of JIA. MTX outperformed leflunomide for treatment of JIA in a randomized trial (at 16 weeks, 89 of patients receiving MTX achieved a 30 response rate vs 68 of those receiving leflunomide), although both drugs were effective. Dosing is oral, once daily, and weight based: 10 mg for children 10 to 20 kg, 15 mg for chil dren 20 40 kg, and 20 mg for children 40 kg. Adverse reactions include paresthesias and peripheral neuropathy, GI intolerance, elevated liver transaminases and hepatic failure, cytopenias, alopecia, and teratogenesis. Leflunomide has a long half life, and in cases in which discontinuation of the agent is required, a drug elimination protocol with cholestyramine may be indicated. Avoidance of pregnancy is essential. Laboratory tests (e.g., CBC, LFTs) are monitored every 4 weeks for the first 6 months of treatment, then every 8 12 weeks. Sulfasalazine Sulfasalazine is used to treat children with polyarticular JIA, oligoarticu lar JIA, and the peripheral arthritis and enthesitis associated with juvenile ankylosing spondylitis. In JIA, sulfasalazine 50 mgkgday (adult maxi mum: 3,000 mgday, divided bid) achieves greater improvement in joint inflammation, global assessment parameters, and laboratory parameters than placebo. More than 30 of sulfasalazine treated patients withdraw from the treatment because of adverse effects, primarily GI irritation and skin rashes. Sulfasalazine is associated with severe systemic hypersensi tivity reactions, including Stevens Johnson syndrome. Sulfasalazine is generally considered contraindicated in children with active systemic JIA because of increased hypersensitivity reactions. Sulfasalazine should not be used in patients with sulfa or salicylate hypersensitivity or porphyria. Monitoring laboratory tests for sulfasalazine toxicity include CBC, LFTs, serum creatinineblood urea nitrogen (BUN), and urinalysis, every other week for the first 3 months of treatment, monthly for 3 months, then every 3 months. Mycophenolate Mofetil Mycophenolate mofetil (MMF) is an immunosuppressive drug approved by the FDA for organ transplant rejection. MMF is used primarily for treatment of lupus, uveitis, and autoimmune skin manifestations. In adult clinical trials, MMF was noninferior to cyclophosphamide for induction therapy of lupus nephritis, with a potential for fewer adverse effects (infec tion, gonadal toxicity). Dosing is based on body surface area (BSA): 600 mgm2 orally twice daily, with maximum dosage limits varying by for mulation and BSA. The most common adverse reaction is GI intolerance; infections, cytopenias, and secondary malignancies are also reported. Glucocorticoids Glucocorticoids are given through oral, intravenous (IV), ocular, topi cal, and intraarticular administration as part of treatment of rheumatic disease. Oral corticosteroids are foundational treatment for moderate to severe lupus, dermatomyositis, and most forms of vasculitis; their long term use is associated with many well described, dose dependent complications, including linear growth suppression, cushingoid |
6,734 | fea tures, osteoporosis, avascular necrosis, hypertension, impaired glucose tolerance, mood disturbance, and increased infection risk. Glucocor ticoids should be tapered to the lowest effective dose over time and DMARDs introduced as steroid sparing agents. Table 195.1 Multidisciplinary Treatment of Rheumatic Diseases in Childhood Accurate diagnosis and education of family Pediatric rheumatologist Pediatrician Nurse Disease related education Medication administration (injection teaching) Safety monitoring Social worker Facilitation of school services Resource identification (community, government, financial, advocacy groups, vocational rehabilitation) Physical medicine and rehabilitation Physical therapy Addressing deficits in joint or muscle mobility, limb length discrepancies, gait abnormalities, and weakness Occupational therapy Splinting to reduce joint contractures deformities and lessen stress on joints; adaptive devices for activities of daily living Consultant team Ophthalmology Eye screening for uveitis Screening for medication related ocular toxicity (hydroxychloroquine, glucocorticoids) Nephrology Orthopedics Dermatology Gastroenterology Physical and psychosocial growth and development Nutrition Addressing undernourishment from systemic illness and obesity overnourishment from glucocorticoids School integration Individualized educational plan (IEP) or 504 plan Peer group relationships Individual and family counseling Coordination of care Involvement of patient and family as active team members Communication among healthcare providers Involvement of school (school nurse) and community (social worker) resources Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1 4 6 6 P art X IV u R heum atic D iseases of C hild hood (C onnective Tissue D isease, C ollag en Vascular D iseases) Table 195.2 Therapeutics for Childhood Rheumatic Diseases CLASSIFICATION THERAPEUTIC DOSE INDICATION ADVERSE REACTIONS MONITORING Nonsteroidal antiinflammatory drugs (NSAIDs) Etodolaca PO once daily dose: 20 30 kg: 400 mg 31 45 kg: 600 mg 46 60 kg: 800 mg 60 kg: 1,000 mg JIA Spondyloarthropathy Pain Serositis Cutaneous vasculitis Uveitis GI intolerance (abdominal pain, nausea), gastritis, hepatitis, tinnitus, anemia, pseudoporphyria, aseptic meningitis, headache, renal disease CBC, LFTs, BUNcreatinine, urinalysis at baseline, then every 6 12 mo Ibuprofena 40 mgkgday PO in 3 divided doses Max 2,400 mgday Naproxena 15 mgkgday PO in 2 divided doses Max 1,000 mgday Celecoxiba 10 25 kg: 50 mg PO bid 25 kg: 100 mg PO bid Meloxicama 0.125 mgkg PO daily Max 7.5 mg Disease modifying antirheumatic drugs (DMARDs) Methotrexatea 10 20 mgm2wk (0.35 0.65 mgkg wk) PO 20 30 mgm2wk (0.65 1 mgkgwk) SC; higher doses better absorbed by SC injection JIA Uveitis GI intolerance (nausea, vomiting), hepatitis, myelosuppression, mucositis, teratogenesis, lymphoma, interstitial pneumonitis CBC, LFTs at baseline, monthly 3, then every 8 12 wk Leflunomide PO once daily: 10 to 20 kg: 10 mg 20 40 kg: 15 mg 40 kg: 20 mg JIA Hepatitis, hepatic necrosis, cytopenias, mucositis, teratogenesis, peripheral neuropathy CBC, LFTs, at baseline, monthly 6, then every 8 12 wk Hydroxychloroquine 5 mgkg PO daily; do not exceed 5 mgkgdaily Max 400 mg daily SLE JDMS Antiphospholipid antibody syndrome Retinal toxicity, GI intolerance, rash, skin discoloration, anemia, cytopenias, myopathy, CNS stimulation, death |
6,735 | (overdose) Ophthalmologic screening every 6 12 mo Sulfasalazinea 30 50 mgkgday in 2 divided doses Adult max 3 gday Spondyloarthropathy, JIA GI intolerance, rash, hypersensitivity reactions, Stevens Johnson syndrome, cytopenias, hepatitis, headache CBC, LFTs, BUNcreatinine, urinalysis at baseline, every other wk 3 mo, monthly 3, then every 3 mo Janus kinase inhibitor Tofacitiniba Oral solution (1 mgmL) Use for 2 yr and 10 kg; 10 to 20 kg: 3.2 mg twice daily 20 to 40 kg: 4 mg twice daily 40 kg: 5 mg twice daily or Immediate release tablet (5 mg), 5 mg twice daily Polyarticular JIA Infection, headache, increased HDL, cytopenias, potential increased malignancy risk, potential increased thrombosis risk CBC, LFTs at baseline, then every 3 mo; lipids 4 8 wk after initiation, then periodically D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. C hap ter 1 9 5 u Treatm ent o f R heum atic D iseases 1 4 6 7 Table 195.2 Therapeutics for Childhood Rheumatic Diseasescontd CLASSIFICATION THERAPEUTIC DOSE INDICATION ADVERSE REACTIONS MONITORING Tumor necrosis factor (TNF) antagonists Adalimumaba SC once every other wk: 10 to 15 kg: 10 mg 15 to 30 kg: 20 mg 30 kg: 40 mg JIA Spondyloarthropathy Psoriatic arthritis Uveitis Injection site reaction, infection, rash, cytopenias, lupus like syndrome, potential increased malignancy risk TB test; anti dsDNA, CBC Etanercepta 0.8 mgkg SC once weekly (max 50 mgdose) or 0.4 mgkg SC twice weekly (max 25 mgdose) JIA Injection site reactions, infections, rash, demyelinating disorders, cytopenias, potential increased malignancy risk TB test; CBC Golimumaba 80 mgm2 IV at 0 and 4 wk, then every 8 wk Polyarticular JIA Spondyloarthropathy Psoriatic arthritis Infusion reactions, hepatitis, potential increased malignancy risk TB test; anti dsDNA, LFTs Infliximab 5 10 mgkg IV every 4 8 wk JIA Spondyloarthropathy Uveitis Sarcoidosis Infusion reactions, hepatitis, potential increased malignancy risk TB test; anti dsDNA, LFTs Modulate T cell activation Abatacepta IV every 2 wk 3 doses, then monthly for 6 yr of age: 75 kg: 10 mgkg 75 100 kg: 750 mg 100 kg: 1,000 mg JIA Infection, headache, potential increased malignancy risk SC once weekly: 10 to 25 kg: 50 mg 25 to 50 kg: 87.5 mg 50 kg: 125 mg Anti CD20 (B cell) antibody Rituximab 575 mgm2, max 1,000 mg, IV on days 1 and 15 SLE Infusion reactions, lymphopenia, reactivation hepatitis B, rash, serum sickness, arthritis, PML CBC, BMP; consider monitoring quantitative IgG Anti BLyS antibody Belimumabe 10 mgkg IV every 2 wk 3 doses, then every 4 wk SLE Infusion reactions, infection, depression Interleukin (IL) 1 antagonist Anakinra 1 2 mgkgdaily Adult max 100 mg Systemic JIA CAPS Injection site reactions, infection CBC Canakinumabb Given SC every 8 wk (CAPS) every 4 wk (systemic JIA): 15 |
6,736 | 40 kg: 2 mgkg (up to 3 mgkg if needed) 40 kg: 150 mg CAPS Systemic JIA Injection site reaction, infection, diarrhea, nausea, vertigo, headache IV: 30 kg: 10 mgkgdose every 4 wk 30 kg: 8 mgkgdose every 4 wk; maximum dose: 800 mgdose SC: 30 kg: 162 mgdose once every 3 wk 30 kg: 162 mgdose once every 2 wk Polyarticular JIA Continued D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1 4 6 8 P art X IV u R heum atic D iseases of C hild hood (C onnective Tissue D isease, C ollag en Vascular D iseases) Table 195.2 Therapeutics for Childhood Rheumatic Diseasescontd CLASSIFICATION THERAPEUTIC DOSE INDICATION ADVERSE REACTIONS MONITORING IL 6 antagonist Tocilizumaba 2 yr and 30 kg: 8 mgkgdose every 2 wk 2 yr and 30 kg: 12 mgkgdose every 2 wk Systemic JIA Infusion reactions, elevated LFTs, elevated lipids, thrombocytopenia, infections CBC, LFTs, platelet count, serum lipid profile Intravenous immune globulin IVIGc 1,000 2,000 mgkg IV infusion For JDMS, give monthly Kawasaki disease JDMS SLE Infusion reaction, aseptic meningitis, renal failure Serum creatinine, BUN, IgG level Cytotoxic Cyclophosphamide 0.5 1 gm2 IV (max 1.5 g) monthly for 6 mo induction, then every 2 3 mo Oral regimen: 1 2 mgkgdaily; max 150 mgdaily SLE Vasculitis JDMS Pulmonary hemorrhage Nausea, vomiting, myelosuppression, mucositis, hyponatremia, alopecia, hemorrhagic cystitis, gonadal failure, teratogenesis, secondary malignancy CBC Immunosuppressive Mycophenolate mofetil Oral suspension: max 1,200 mgm2 day PO (up to 2 gday) divided bid Capsules: max 1,500 mgday PO for BSA 1.25 1.5 m2, 2 gday PO for BSA 1.5 m2 divided bid SLE Uveitis GI intolerance (diarrhea, nausea, vomiting), renal impairment, neutropenia, teratogenesis, secondary malignancy, PML CBC, BMP Glucocorticoids Prednisonea,d f 0.05 2 mgkgday PO given in 1 4 divided doses; max varies by individual (80 mgdaily) Adverse effects are dose dependent; lowest effective dose should be used SLE JDMS Vasculitis JIA Uveitis Sarcoidosis Cushing syndrome, osteoporosis, increased appetite, weight gain, striae, hypertension, adrenal suppression, hyperglycemia, infection, avascular necrosis Blood glucose, potassium Blood pressure Methylprednisolonea,d g 0.5 1.7 mgkgday or 5 25 mgm2 day IMIV in divided doses every 6 12 hr For severe manifestations: 30 mg kgdose (max 1 g) daily for 1 5 days SLE JDMS Vasculitis Sarcoidosis Localized scleroderma Intraarticular Dose varies by joint and formulation JIA Subcutaneous atrophy, skin hypopigmentation, calcification, infection Prednisolone ophthalmic suspension 1 2 drops into eye up to every hr while awake Needs monitoring by ophthalmologist Uveitis Ocular hypertension, glaucoma, nerve damage, cataract, infection Ophthalmologic exam Consult a clinical pharmacology reference for current dosing and monitoring guidelines and complete list of known adverse effects. Therapeutics used in practice may not have an FDA approved indication. Individual therapeutics annotated with FDA approved indication as |
6,737 | follows: a, JIA; b, CAPS; c, Kawasaki disease; d, sarcoidosis; e, SLE; f, uveitis; g, dermatomyositis. Many more products are available in this class. bid, Twice daily; BLys, B lymphocyte stimulator; BMP, basic metabolic panel; BSA, body surface area; BUN, blood urea nitrogen; CAPS, cryopyrin associated periodic syndrome; CBC, complete blood count; CNS, central nervous system; dsDNA, double stranded DNA; GI, gastrointestinal; IM, intramuscular(ly); IV, intravenous(ly); IVIG, intravenous immune globulin; JDMS, juvenile dermatomyositis; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; PML, progressive multifocal leukoencephalopathy; PO, by mouth; SC, subcutaneous(ly); SLE, systemic lupus erythematosus; TB, tuberculosis D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. Chapter 195 u Treatment of Rheumatic Diseases 1469 Intravenous corticosteroids have been used to treat severe, acute manifestations of systemic rheumatic diseases such as SLE, dermato myositis, and vasculitis. The IV route allows for higher doses to obtain an immediate, profound antiinflammatory effect. Methylprednisolone 10 30 mgkgdose up to a maximum of 1 g, given over 1 hour daily for 1 5 days is the IV preparation of choice. Although generally associ ated with fewer adverse effects than oral corticosteroids, IV steroids are associated with significant and occasionally life threatening toxicities, such as cardiac arrhythmia, acute hypertension, hypotension, hyper glycemia, shock, pancreatitis, and avascular necrosis. Ocular corticosteroids are prescribed by ophthalmologists as oph thalmologic drops or injections into the soft tissue surrounding the globe (subTenon capsule injection) for active uveitis. Long term ocular corticosteroid use leads to cataract formation and glaucoma. Current ophthalmologic management with methotrexate and biologic therapy, especially TNF inhibitors, have significantly decreased the fre quency of eye complications of JIA associated uveitis. Intraarticular corticosteroids are frequently used as initial therapy for children with oligoarticular JIA or as bridge therapy while await ing efficacy of a DMARD in polyarticular disease. Most patients have significant clinical improvement within 3 days. Duration of response depends on steroid preparation used, joint affected, and arthritis sub type; the anticipated response rate to knee injection is 6080 at 6 months. Intraarticular administration may result in subcutaneous atrophy and hypopigmentation of the skin at the injection site, as well as subcutaneous calcifications along the needle track. JANUS KINASE INHIBITORS Another effective class of DMARDs is the Janus kinase inhibitors, col lectively known as JAKinibs. In immune cells, these drugs inhibit intra cellular signaling through the JAK STAT pathway in immune cells by binding to various Janus kinases (in humans, JAK 1, JAK 2, JAK 3, and TYK2), thereby negating the response to extracellular cytokine liga tion of immune cell receptors. Inhibition affects lymphocyte activation, function, and survival. Many JAKinibs are currently available, includ ing tofacitinib, baricitinib, ruxolitinib, and upadacitinib. Currently, only tofacitinib has FDA approval in pediatric rheumatic disease. Tofacitinib is a small molecule, |
6,738 | oral JAKinib of the JAK1, JAK3, and, to a lesser extent, JAK2 enzymes. Tofacitinib has FDA approval for treatment of polyarticular JIA (age 2 years and weight 10 kg) with twice daily dosing: 3.2 mg bid for 10 20 kg, 4 mg bid for 20 40 kg, and 5 mg bid for 40 kg. It is available as an oral solution (1 mgmL) and as oral tablets (5 mg). Adverse reactions include increased risk of serious infections, thrombosis including pulmonary and deep venousarterial, and gastrointestinal perforations; the most common adverse reactions are upper respiratory infections, diarrhea, and headache. Biologic Agents Biologic agents are proteins that have been engineered to target and modulate specific components of the immune system, with the goal of decreasing the inflammatory response. Antibodies have been developed to target specific cytokines such as IL 1 and IL 6 or to interfere with specific immune cell function through depletion of cells or suppres sion of T cell activation (Table 195.3). Biologic agents have increased the therapeutic options for treating rheumatic disease recalcitrant to nonbiologic therapies, and in some cases biologics are first line inter ventions. A primary concern is the increased risk of malignancy when biologics are combined with other immunosuppressants. Tumor Necrosis Factor Antagonists Three TNF antagonists have an FDA indication for treatment of children with moderate to severe polyarticular JIA (etanercept, adalimumab, and golimumab). Etanercept is a genetically engineered fusion protein consist ing of two identical chains of the recombinant extracellular TNF receptor monomer fused with the Fc domain of human immunoglobulin G1. Etan ercept binds both TNF and lymphotoxin (formerly called TNF ) and inhibits their activity. Three fourths of children with active polyarticular JIA that fails to respond to MTX demonstrate response to etanercept after 3 months of therapy. Dosing is 0.8 mgkg subcutaneously weekly (max 50 mgdose) or 0.4 mgkg SC twice weekly (max 25 mgdose). Adalimumab is a fully human anti TNF monoclonal antibody (mAb) used alone or in combination with MTX. In a placebo controlled withdrawal design study, children continuing to receive adalimumab were less likely to experience disease flares (43 vs 71) even if they were also taking MTX (37 vs 65). Adalimumab is administered subcutaneously every other week at a dose of 10 mg for children weighing 10 to 15 kg, 20 mg for children weighing 15 to 30 kg, and 40 mg for those weighing 30 kg. Golimumab is a human mAb that binds to both soluble and transmembrane bioactive forms of TNF. It has FDA approval for use in polyarticular JIA at dosing of 80 mgm2 IV with initial doses at 0 and 4 weeks and then every 8 weeks thereafter. Non FDA approved uses include psoriatic arthritis. Infliximab, a chimeric mouse human mAb, was tested in a randomized controlled trial (RCT) for use in JIA but did not achieve study end points. However, it is FDA approved for pediatric inflammatory bowel disease and has been used off label for treatment of polyarticular JIA, uveitis, Behet syndrome, |
6,739 | and sarcoidosis. Certolizumab pegol, a pegylated humanized antibody against TNF, is approved by the FDA for RA, psoriatic arthritis, and ankylosing spondylitis in adults and is currently in pediatric trials for treatment of polyarticular JIA. The most common adverse effects are injection site reactions that diminish over time. TNF blockade is associated with an increased fre quency of serious systemic infections, including sepsis, dissemination of latent tuberculosis (TB), and invasive fungal infections in endemic areas. TNF blockade should not be initiated in patients with a history of chronic or frequent recurrent infections. TB testing should be done before initia tion of therapy with TNF antagonists. If test results are positive, antituber cular treatment must be administered before anti TNF treatment can be started. Theoretically, the risk of malignancy increases with TNF antago nists. Case reports describe the development of lupus like syndromes, leu kocytoclastic vasculitis, interstitial lung disease, demyelinating syndromes, antibody formation to the drug, rashes, cytopenias, anaphylaxis, serum sickness, and other reactions. The benefitrisk profile appears favorable after a decade of experience with this therapeutic class; the safety of longer term suppression of TNF function is unknown. Modulator of T Cell Activation Abatacept is a selective inhibitor of T cell costimulation resulting in T cell anergy. It is FDA approved for treatment of moderate to severe polyar ticular JIA. In a double blind withdrawal RCT in children whose disease had not responded to DMARDs, 53 of placebo treated patients vs 20 of abatacept treated patients experienced disease flares during the with drawal period. The frequency of adverse events did not differ between the Table 195.3 Method of Action of Biologic Therapies Studied in Juvenile Idiopathic Arthritis DRUG METHOD OF ACTION Etanercept Soluble TNF p75 receptor fusion protein that binds to and inactivates TNF Infliximab Chimeric humanmouse monoclonal antibody that binds to soluble TNF and its membrane bound precursor, neutralizing its action Adalimumab A humanized IgG1 monoclonal antibody that binds to TNF Abatacept Soluble, fully human fusion protein of the extracellular domain of CTLA 4, linked to a modified Fc portion of the human IgG1. It acts as a costimulatory signal inhibitor by binding competitively to CD80 or CD86, where it selectively inhibits T cell activation Tocilizumab A humanized antihuman IL 6 receptor monoclonal antibody Anakinra An IL 1 receptor antagonist (IL 1RA) CTLA, Cytotoxic T lymphocyteassociated antigen; IL, interleukin; TNF, tumor necrosis factor. From Beresford MW, Baildam EM. New advances in the management of juvenile idiopathic arthritis. Part 2. The era of biologicals. Arch Dis Child Educ Pract Ed. 2009;94:151156. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1470 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) groups. Abatacept is administered IV every other week for three doses (75 kg: 10 mgkgdose; 75 100 kg: 750 mgdose; 100 kg: 1,000 mgdose; maximum 1,000 mgdose at 0, 2, and |
6,740 | 4 weeks) and then monthly there after. Abatacept administered by SC injection was given FDA approval in March 2017 for children 4 years old for treatment of polyarticular JIA at doses given weekly: 50 mg for 10 25 kg, 87.5 mg for 25 to 50 kg, and 125 mg for 50 kg. B Cell Depletion Rituximab is a chimeric mAb to the antigen CD20, a transmembrane pro tein on the surface of B cell precursors and mature B lymphocytes. This antibody induces B cell apoptosis and causes depletion of circulating and tissue based B cells. Antibody production is not completely abrogated because plasma cells are not removed. Rituximab has FDA approval for treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in children greater than 2 years of age. It is approved for treatment of adult RA and may also have a role in treatment of SLE, particularly its hematologic manifestations. Adverse events include seri ous infusion reactions, cytopenias, hepatitis B virus reactivation, hypo gammaglobulinemia, infections, serum sickness, vasculitis, and a rare but fatal side effect, progressive multifocal leukoencephalopathy. Resistance to rituximab may develop over time in patients being treated for lymphoma. Belimumab is a human mAb to B lymphocyte stimulator (BLys) that negatively affects B cell proliferation, differentiation, and long term sur vival by inhibiting binding of BLys to its receptors on B cells. It is FDA approved for treatment of pediatric SLE in children age 5 years and older. For this indication, it is given as an IV infusion (10 mgkg) every 2 weeks for the first three doses, then every 4 weeks thereafter. Side effects associ ated with belimumab include increased risk of serious infections, allergic (hypersensitivity) reactions, and changes in mood. Interleukin 1 Antagonists Anakinra, a recombinant form of the human IL 1 receptor antagonist, competitively inhibits binding of IL 1 and IL 1 to the natural recep tor, interrupting the cytokine proinflammatory cascade. Anakinra has been approved for RA in adults. In meta analyses of treatments for RA, anakinra was outperformed by TNF antagonists but has a special niche in pediatric rheumatology for treatment of systemic JIA (sJIA) and other autoinflammatory syndromes, such as cryopyrin associated periodic syn drome (CAPS). The medication is dosed SC, 1 2 mgkg, once daily. An IL 1 mAb, canakinumab, is FDA approved for use in CAPS, dosed SC every 8 weeks, and sJIA, dosed SC every 4 weeks. Adverse reactions include sig nificant injection site reactions and increased bacterial infections. Interleukin 6 Receptor Antagonist Tocilizumab is an antiIL 6 receptor antibody binding to both soluble and membrane associated receptors. Tocilizumab has FDA approval for treat ment of sJIA and polyarticular JIA. Adverse reactions include transami nase and lipid elevations. Tocilizumab is given as an IV infusion every 2 weeks (sJIA) to 4 weeks (polyarticular JIA), and SC for polyarticular JIA 162 mg every 3 weeks for those 30 kg and every 2 wk for 30 kg. Intravenous Immune Globulin Intravenous immunoglobulin (IVIG) is thought to be beneficial in |
6,741 | various clinical conditions. IVIG significantly improves the short and long term natural history of Kawasaki disease. Open studies have sup ported benefit for juvenile dermatomyositis, lupus associated throm bocytopenia, and polyarticular JIA. IVIG is given as 1 2 gkgdose, administered once monthly. It has been occasionally associated with severe, systemic allergy like reactions and postinfusion aseptic menin gitis (headache, stiff neck) (Table 195.4). Cytotoxics Cyclophosphamide Cyclophosphamide requires metabolic conversion in the liver to its active metabolites, which alkylate the guanine in DNA, leading to immunosup pression by inhibition of the S2 phase of mitosis. The subsequent decrease in numbers of T and B lymphocytes results in diminished humoral and cellular immune responses. Cyclophosphamide infusions (500 1,000 mg m2) given monthly for 6 months, then every 3 months for 12 18 months, have been shown to reduce the frequency of renal failure in patients with lupus and diffuse proliferative glomerulonephritis. Open trials suggest efficacy in severe CNS lupus. Oral cyclophosphamide (1 2 mgkgday) is effective as induction treatment of severe antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis and other forms of systemic vas culitis, as well as interstitial lung disease or pulmonary hemorrhage associ ated with rheumatic disease. Cyclophosphamide is a potent cytotoxic drug associated with sig nificant toxicities. Potential short term adverse effects include nausea, vomiting, anorexia, alopecia, mucositis, hemorrhagic cystitis, and bone marrow suppression. Long term complications include an increased risk for sterility and cancer, especially leukemia, lymphoma, and blad der cancer. In adult women with lupus treated with IV cyclophospha mide, 3040 become infertile; the risk of ovarian failure appears to be significantly lower in adolescent and premenarchal girls. Ovarian suppression with an inhibitor of gonadotropin releasing hormone to preserve fertility is currently being studied. Other Drugs Azathioprine is sometimes used to treat ANCA associated vasculitis after induction therapy or to treat SLE. Cyclosporine has been used occasionally in the treatment of dermatomyositis on the basis of uncontrolled studies and is helpful in the treatment of macrophage activation syndrome complicating sJIA (see Chapter 207). Case reports describe the successful use of thalidomide, or its analog lenalidomide, as treatment for sJIA, inflammatory skin disorders, and Behet disease. Several drugs commonly used in the past to treat arthritis are no lon ger part of standard treatment, including salicylates, gold compounds, and d penicillamine. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 195.4 Predisposing Factors for Immunoglobulin Induced Adverse Effects ADVERSE EFFECT PREDISPOSING FACTORS Flulike symptoms High dose, rapid infusion rate, accompanying infection, previous adverse effects Dermatologic adverse effects High dose, rapid infusion rate, accompanying infection, male patients with chronic inflammatory demyelinating polyneuropathy Arrhythmia and hypotension History of heart disease Transfusion related acute lung injury Rapid infusion rate Thrombotic events High dose, rapid infusion rate, advanced age, being bedridden, diabetes mellitus, hypertension, dyslipidemia, prior current thrombosis, preexisting atherosclerotic disease, elevated serum viscosity, oral contraceptive use, hereditary hypercoagulable state, idiopathic thrombocytopenic purpura Aseptic meningitis High dose Renal impairment Rapid infusion rate, advanced age, renal insufficiency, nephrotic syndrome, diabetes mellitus, dehydration, sepsis paraproteinemia, nephrotoxic drugs, |
6,742 | hemolysis, sucrose containing preparations Hemolysis High dose, rapid infusion rate, non O blood group, underlying inflammatory state From Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Frontiers Immunol. 2018;9:1299, Table 2. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 196 u Juvenile Idiopathic Arthritis 1471 Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and one of the more common chronic illnesses of childhood. JIA represents a heterogeneous group of disorders sharing the clinical manifestation of arthritis. The etiology and pathogenesis of JIA are largely unknown, and the genetic component is complex, making clear distinction among various subtypes difficult. As a result, several classification schemes exist, each with its own limitations. The former classification of the American College of Rheumatology (ACR) uses the term juvenile rheumatoid arthritis and categorizes the disease into three onset types (Table 196.1). Attempting to standardize nomenclature, the International League of Associations for Rheu matology (ILAR) proposed a different classification using the term juvenile idiopathic arthritis (Table 196.2), inclusive of all subtypes of chronic juvenile arthritis. We refer to the ILAR classification criteria; see Chapter 197 for enthesitis related arthritis (ERA) and psoriatic JIA (Tables 196.3 and 196.4). EPIDEMIOLOGY The worldwide incidence of JIA ranges from 0.8 to 22.6 per 100,000 children per year, with prevalence ranges from 7 to 401 per 100,000. These wide ranging numbers reflect population differences, particu larly environmental exposure and immunogenetic susceptibility, along with variations in diagnostic criteria, difficulty in case ascer tainment, and lack of population based data. An estimated 300,000 U.S. children have arthritis, including 100,000 with a form of JIA. Oligoarthritis is the most common subtype (4050), followed by polyarthritis (2530) and systemic JIA (515) (see Table 196.4). More females than males are affected in both oligoarticular (3:1) and polyarticular (5:1) JIA but are equally affected in systemic JIA (sJIA). The peak age at onset is 2 4 years for oligoarticular disease. Age of onset has a bimodal distribution in polyarthritis, with peaks at 2 4 years and 10 14 years. sJIA occurs throughout childhood, with a peak at 1 5 years. ETIOLOGY The etiology and pathogenesis of JIA are not completely understood, although both immunogenetic susceptibility and an external trigger are considered necessary. Twin and family studies suggest a substantial role for genetic factors. JIA is a complex genetic trait in which multiple genes may affect disease susceptibility. Variants in major histocompat ibility complex (MHC) class I and class II regions have indisputably been associated with different JIA subtypes. Non HLA candidate loci are also associated with JIA, including polymorphisms in the genes encoding protein tyrosine phosphatase nonreceptor 22 (PTPN22), tumor necrosis factor (TNF) , macrophage inhibitory factor, inter leukin (IL) 6 and its receptor, and IL 1. Possible nongenetic triggers include bacterial and viral infections, enhanced immune responses to bacterial or |
6,743 | mycobacterial heat shock proteins, abnormal reproductive hormone levels, and joint trauma. PATHOGENESIS JIA is an autoimmune disease associated with alterations in both humoral and cell mediated immunity. T lymphocytes have a central role, releasing proinflammatory cytokines favoring a type 1 helper T lymphocyte response. Studies of T cell receptor expression confirm recruitment of T lymphocytes specific for synovial nonself antigens. B cell activation, immune complex formation, and complement activa tion also promote inflammation. Inheritance of specific cytokine alleles may predispose to upregulation of inflammatory networks, resulting in systemic disease or more severe articular disease. sJIA is characterized by dysregulation of the innate immune system with a lack of autoreactive T cells and autoantibodies. It therefore may be more accurately classified as an autoinflammatory disorder, which may transition to an autoimmune process once actual arthritis devel ops (Fig. 196.1). The IL 1 family of cytokines is key to disease patho genesis, which is strongly supported by the marked responsiveness to IL 1 inhibitors. IL 18 in particular is a central driver, and serum IL 18 levels are markedly elevated in children with sJIA. All these immunologic abnormalities cause inflammatory synovitis, characterized pathologically by villous hypertrophy and hyperplasia with hyperemia and edema of the synovial tissue. Vascular endothelial hyperplasia is prominent and is characterized by infiltration of mono nuclear and plasma cells with a predominance of T lymphocytes (Fig. 196.2). Advanced and uncontrolled disease leads to pannus formation and progressive erosion of articular cartilage and contiguous bone (Figs. 196.3 and 196.4). CLINICAL MANIFESTATIONS Arthritis must be present 6 weeks to make a diagnosis of any JIA subtype. Arthritis is defined by intraarticular swelling or the presence of two or more of the following signs: limitation in range of motion (ROM), tenderness or pain on motion, and warmth. Initial symptoms may be subtle or acute and often include morning stiffness with a limp or gelling after inactivity. Easy fatigability and poor sleep quality may be present. Involved joints are often swollen, warm to the touch, and uncomfortable on movement or palpation with reduced ROM, but usually are not erythematous. Arthritis in large joints, especially knees, initially accelerates linear growth and causes the affected limb to be longer, resulting in a discrepancy in limb lengths. Continued inflam mation stimulates rapid and premature closure of the growth plate, resulting in shortened bones. Oligoarthritis is defined as involving four or fewer joints within the first 6 months of disease onset, and often only a single joint is involved (see Table 196.4). It predominantly affects the large joints of the lower extremities, such as the knees and ankles (Fig. 196.5). Isolated involve ment of upper extremity large joints is less common. Those in whom disease never develops in four or more joints are regarded as having persistent oligoarticular JIA, whereas evolution of disease in five or more joints after 6 months changes the classification to extended oligoarticular JIA and is associated with a worse prognosis. Isolated involvement of the hip is almost never a presenting sign and |
6,744 | suggests ERA (see Chapter 197) or a nonrheumatic cause. The presence of a positive antinuclear antibody (ANA) test confers increased risk for asymptomatic anterior uveitis, requiring periodic slit lamp examina tion (Table 196.5). ANA positivity may also be correlated with younger age at disease onset, females, asymmetric arthritis, and fewer involved joints over time. Chapter 196 Juvenile Idiopathic Arthritis Eveline Y. Wu and C. Egla Rabinovich Table 196.1 Criteria for the Classification of Juvenile Rheumatoid Arthritis Age at onset: 16 yr Arthritis (swelling or effusion, or the presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, increased heat) in one or more joints Duration of disease: 6 wk Onset type defined by type of articular involvement in the first 6 mo after onset: Polyarthritis: five or more inflamed joints Oligoarthritis: four or fewer inflamed joints Systemic onset disease: arthritis with rash and a characteristic quotidian fever Exclusion of other forms of juvenile arthritis Adapted from Cassidy JT, Levison JE, Bass JC, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum. 1986;29:274281. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1472 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases)Table 196.2 International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis (JIA) CATEGORY DEFINITION EXCLUSIONS Systemic JIA Arthritis in one or more joints with, or preceded by, fever of 2 wk in duration that is documented to be daily (quotidian) for at least 3 days and accompanied by one or more of the following: 1. Evanescent (nonfixed) erythematous rash 2. Generalized lymph node enlargement 3. Hepatomegaly or splenomegaly or both 4. Serositis a. Psoriasis or a history of psoriasis in patient or first degree relative b. Arthritis in an HLA B27positive male beginning after the sixth birthday c. Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, Reiter syndrome, or acute anterior uveitis, or history of one of these disorders in a first degree relative d. Presence of IgM RF on at least two occasions at least 3 mo apart Oligoarthritis Arthritis affecting one to four joints during the first 6 mo of disease; two subcategories are recognized: 1. Persistent oligoarthritisaffecting four or fewer joints throughout the disease course 2. Extended oligoarthritisaffecting five or more joints after the first 6 mo of disease a, b, c, d (above) plus e. Presence of systemic JIA in the patient Polyarthritis (RF negative) Arthritis affecting five or more joints during the first 6 mo of disease; a test for RF is negative a, b, c, d, e Polyarthritis (RF positive) Arthritis affecting five or more joints during the first 6 mo of disease; two or more tests for RF at least 3 mo apart during the first 6 mo of disease are positive a, b, c, e |
6,745 | Psoriatic arthritis Arthritis and psoriasis or arthritis and at least two of the following: b, c, d, e 1. Dactylitis 2. Nail pitting and onycholysis 3. Psoriasis in first degree relative Enthesitis related arthritis Arthritis and enthesitis or arthritis or enthesitis with at least two of the following: a, d, e 1. Presence of or history of sacroiliac joint tenderness or inflammatory lumbosacral pain, or both 2. Presence of HLA B27 antigen 3. Onset of arthritis in a male 6 yr old 4. Acute (symptomatic) anterior uveitis 5. History of ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with IBD, Reiter syndrome, or acute anterior uveitis in first degree relative Undifferentiated arthritis Arthritis that fulfills criteria in no category or two or more of the above categories Quotidian fever is defined as a fever that rises to 39C (102.2F) once daily and returns to 37C (98.6F) between fever peaks. Serositis refers to pericarditis, pleuritis, or peritonitis or some combination of the three. Dactylitis is swelling of one or more digit(s), usually in an asymmetric distribution, that extends beyond the joint margin. A minimum of two pits on any one or more nails at any time. Enthesitis is defined as tenderness at the insertion of a tendon, ligament, joint capsule, or fascia to bone. Inflammatory lumbosacral pain refers to lumbosacral pain at rest with morning stiffness that improves on movement. IBD, Inflammatory bowel disease; RF, rheumatoid factor. From Firestein GS, Budd RC, Harris ED Jr, et al., eds. Kelleys Textbook of Rheumatology, 8th ed. Philadelphia: Saunders; 2009. Table 196.3 Characteristics of ACR and ILAR Classifications of Childhood Chronic Arthritis PARAMETER ACR (1977) ILAR (1997) Term Juvenile rheumatoid arthritis (JRA) Juvenile idiopathic arthritis (JIA) Minimum duration 6 wk 6 wk Age at onset 16 yr 16 yr Four or fewer joints in first 6 mo after presentation Pauciarticular Oligoarthritis: Persistent: four or fewer joints for course of disease Extended: four or more joints after 6 mo Four or more joints in first 6 mo after presentation Polyarticular Polyarthritis, RF negative Polyarthritis, RF positive Fever, rash, arthritis Systemic onset Systemic Other categories included Exclusion of other forms Psoriatic arthritis Enthesitis related arthritis Undifferentiated: Fits no other category Fits more than one category Inclusion of psoriatic arthritis, inflammatory bowel disease, ankylosing spondylitis No (see Chapter 197) Yes ACR, American College of Rheumatology; ILAR, International League of Associations for Rheumatology; RF, rheumatoid factor. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. C hap ter 1 9 6 u Juvenile Id io p athic A rthritis 1 4 7 3 Table 196.4 Overview of Main Features of Subtypes of Juvenile Idiopathic Arthritis (JIA) ILAR SUBTYPE PEAK AGE AT ONSET (yr) FEMALE:MALE RATIO OF ALL JIA CASES ARTHRITIS PATTERN EXTRAARTICULAR FEATURES LABORATORY INVESTIGATIONS NOTES ON THERAPY Systemic arthritis 1 5 1:1 5 15 Polyarticular, often affecting knees, wrists, and ankles; also fingers, neck, |
6,746 | and hips Daily fever; evanescent rash; pericarditis; pleuritis Anemia; WBC ; ESR ; CRP ; ferritin ; platelets (normal or in MAS) Less responsive to standard treatment with MTX and anti TNF agents; consider IL 1 or IL 6 inhibitors in resistant cases or as first line therapy Oligoarthritis 2 4 3:1 40 50 (but ethnic variation) Knees ; ankles, fingers Uveitis in 30 of cases ANA positive in 60; other test results usually normal; may have mildly ESRCRP NSAIDs and intraarticular corticosteroids; MTX occasionally required Polyarthritis: RF negative 2 4 and 10 14 3:1 and 10:1 20 35 Symmetric or asymmetric; small and large joints; cervical spine; temporomandibular joint Uveitis in 10 ANA positive in 40; RF negative; ESR or ; CRP or normal; mild anemia Standard therapy with MTX and NSAIDs; then, if nonresponsive, anti TNF agents or other biologics, including abatacept, indicated as first line therapy RF positive 9 12 9:1 10 Aggressive symmetric polyarthritis Rheumatoid nodules in 10; low grade fever RF positive; ESR ; CRP normal; mild anemia Long term remission unlikely; early aggressive therapy is warranted Psoriatic arthritis 2 4 and 9 11 2:1 5 10 Asymmetric arthritis of small or medium sized joints Uveitis in 10; psoriasis in 50 ANA positive in 50; ESR ; CRP or normal; mild anemia NSAIDs and intraarticular corticosteroids; MTX, anti TNF agents Enthesitis related arthritis 9 12 1:7 5 10 Predominantly lower limb joints affected; sometimes axial skeleton (but less than in adult, ankylosing spondylitis) Acute anterior uveitis; association with reactive arthritis and inflammatory bowel disease 80 of patients positive for HLA B27 NSAIDs and intraarticular corticosteroids; consider sulfasalazine as alternative to MTX; anti TNF agents ILAR, International League of Associations for Rheumatology; ANA, antinuclear antibody; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; MAS, macrophage activation syndrome; MTX, methotrexate; NSAIDs, nonsteroidal antiinflammatory drugs; RF, rheumatoid factor; TNF, tumor necrosis factor; WBC, white blood cell count. From Firestein GS, Budd RC, Harris ED Jr, et al., eds. Kelleys Textbook of Rheumatology, 8th ed. Philadelphia: Saunders; 2009. D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1474 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Innate Febrile sJIA Arthritic sJIA Innately adaptive Adaptive CD4 T cell fate? IFNlow environment? IFNlow environment? IFNlow TCR T cells Ag Presentation? TCR Th1 faterole? Th17 faterole? (i)NKT cells IL18R i.e. IPP IL18R IL6 others IL1R DAMPs (S100A8A9) DAMPs (S100A8A9A12) DAMPs (S100A8A9A12) NK cell Necrotic granulocyte PAMPs Granulocyte Monocyte IL17 IL18 IL18 IL1 5 2 5 6 4 4 7 7 7 2 3 1 1 1 HLADRB111 Intracellular role? Proliferation IL17 expression 2 IFNlow 3 Disease progression X Fig. 196.1 Innately adaptive or truly autoimmune: a pathophysiologic model for disease progression in |
6,747 | systemic juvenile idiopathic arthritis (sJIA). Innate immune cells, such as myeloid cells (granulocytes, monocytes) and natural killer (NK) cells, are relevant during the acute febrile phase of systemic JIA. (1) Myeloid cells release interleukin 1 (IL 1) family cytokines (IL 1, IL 18) and other proinflammatory cytokines, which can either be trig gered by infection (pathogen associated molecular patterns PAMPs) or result from pattern recognition receptor activation by damage associated molecular patterns (DAMPs) released from stressed or necrotic cells. (2) Together with T cell receptor ( TCR) activation by endogenous ligands (i.e., isopentenyl pyrophosphate IPP) or bacterial ligands, IL 1 and IL 18 can trigger IL 17 expression from T cells, while (3) IL 18 fails to trigger interferon (IFN) expression from NK cells because of a defective IL 18 receptor (IL 18R). (4) Similarly, systemic JIA Th1 cells express only low levels of IFN. Both cell types may contribute to hypophysiologic IFN levels, potentially promoting IL 17 expression in disease. Although a genetic as sociation or alterations in frequencies have been reported, the pathomechanistic roles of (5) HLA DRB111 (whether antigen Ag presentation or intracellular function) or (6) invariant NKT (iNKT) and (7) CD4 T cells in disease progression are yet largely unclear. Thus current data imply that in nately adaptive immune cells bridging innate and adaptive immunity, rather than classic B or T lymphocytes, play a central role in promoting disease progression in systemic JIA. (From Kessel C, Hedrich CM, Foeil D. Innately adaptive or truly autoimmune: is there something unique about systemic juvenile idiopathic arthritis? Arth Rheumatol. 2020;72:210219, Fig. 2, p. 214) Polyarthritis is characterized by inflammation of five or more joints in both upper and lower extremities (Figs. 196.6 and 196.7). Rheu matoid factor (RF)positive polyarthritis resembles the characteristic symmetric presentation of adult rheumatoid arthritis. Rheumatoid nodules on the extensor surfaces of the elbows, spine, and over the Achilles tendons, although unusual, are associated with a more severe course and almost exclusively occur in RF positive individuals (Fig. 196.8). Micrognathia reflects chronic temporomandibular joint Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 196 u Juvenile Idiopathic Arthritis 1475 disease (Fig. 196.9). Cervical spine involvement (Fig. 196.10), mani festing as decreased neck extension, occurs with a risk of atlantoaxial subluxation and neurologic sequelae. Hip disease may be subtle, with findings of decreased or painful ROM on examination (Fig. 196.11). Systemic JIA is characterized by arthritis (may not be evident on initial presentation), fever, rash, and prominent visceral involvement, including hepatosplenomegaly, lymphadenopathy, and serositis (peri carditis). The characteristic fever, defined as spiking temperatures to 39C (102.2F), occurs on a daily or twice daily basis for at least 2 weeks, with a rapid return to normal or subnormal temperatures (Fig. 196.12). The fever is often present in the evening and is frequently accompanied by a characteristic faint, erythematous, macular rash. The evanescent |
6,748 | salmon colored lesions, classic for sJIA, are linear or circu lar and are usually distributed over the trunk and proximal extremities (Fig. 196.13). The classic rash is nonpruritic and migratory with lesions lasting 1 hour. Koebner phenomenon, a cutaneous hypersensitivity in which classic lesions are brought on by superficial trauma, is often present. Heat can also evoke rash. Fever, rash, hepatosplenomegaly, and lymphadenopathy are present in 70 of affected children. Without arthritis, the differential diagnosis includes the episodic fever (auto inflammatory) syndromes (see Chapter 204), infection (endocarditis, rheumatic fever, brucellosis, multisystem inflammatory syndrome in children MIS C), other rheumatic disorders (systemic lupus ery thematosus SLE, vasculitis syndromes, serum sickness, Kawasaki disease, sarcoidosis, Castleman disease), inflammatory bowel disease, hemophagocytic lymphohistiocytosis syndromes, and malignancy (leukemia, neuroblastoma, lymphoma). Some children initially pres ent with only systemic features and evolve over time, but definitive Fig. 196.2 Synovial biopsy specimen from a 10 yr old child with oli goarticular juvenile idiopathic arthritis. There is a dense infiltration of lymphocytes and plasma cells in the synovium. Fig. 196.3 Arthroscopy in the shoulder of a child with juvenile idi opathic arthritis showing pannus formation and cartilage erosions. (Courtesy Dr. Alison Toth.) Fig. 196.4 MRI with gadolinium of a 10 yr old child with juvenile idi opathic arthritis (same patient as in Fig. 196.2). The dense white signal in the synovium near the distal femur, proximal tibia, and patella reflects inflammation. MRI of the knee is useful to exclude ligamentous injury, chondromalacia of the patella, and tumor. Fig. 196.5 Oligoarticular juvenile idiopathic arthritis with swelling and flexion contracture of the right knee. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1476 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) diagnosis requires the presence of arthritis. Arthritis may affect any number of joints, but the course is classically polyarticular; may be very destructive; and can include hip, cervical spine, and temporomandibu lar joint involvement. Macrophage activation syndrome (MAS; see Chapter 207) is a rare but potentially fatal complication of sJIA that can occur at any time (onset, medication change, active or remission) during the disease course. It is also referred to as secondary hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) (see Chapter 556.2). There is increasing evidence that sJIAMAS and HLH share similar func tional defects in granule dependent cytotoxic lymphocyte activity. In addition, sJIA associated MAS and HLH share genetic variants in approximately 35 of patients with sJIAMAS. MAS classically mani fests as acute onset of high spiking fevers, lymphadenopathy, hepa tosplenomegaly, and encephalopathy. Laboratory evaluation shows thrombocytopenia and leukopenia with elevated liver enzymes, lactate dehydrogenase, ferritin, and triglycerides. Patients may have purpura and mucosal bleeding, as well as elevated fibrin split product values and prolonged prothrombin and partial thromboplastin times. The ESR falls because of hypofibrinogenemia and hepatic dysfunction, a feature use ful in distinguishing MAS from |
6,749 | a flare of systemic disease (Table 196.6). An international consensus panel developed a set of classification cri teria for sJIA associated MAS, including hyperferritinemia (684 ng mL) and any two of the following: thrombocytopenia (181 109L), elevated liver enzymes (aspartate transaminase 48 UL), hypertriglyc eridemia (156 mgdL), and hypofibrinogenemia (360 mgdL) (see Table 196.6). These criteria apply to a febrile patient suspected of sJIA and in the absence of disorders such as immune mediated thrombocy topenia, infectious hepatitis, familial hypertriglyceridemia, or visceral leishmaniasis. A relative change in laboratory values is likely more rel evant in making an early diagnosis than are absolute normal values. A bone marrow aspiration and biopsy may be helpful in diagnosis, but Table 196.5 Frequency of Ophthalmologic Examination in Patients with Juvenile Idiopathic Arthritis REFERRAL Patients should be referred at the time of diagnosis, or suspicion, of JIA INITIAL SCREENING EXAMINATION Should occur as soon as possible and no later than 6 wk from referral Symptomatic ocular patients should be seen within a week of referral ONGOING SCREENING Screening at 2 monthly intervals from onset of arthritis for 6 mo Followed by 3 4 monthly screening for time outlined below OLIGOARTICULAR JIA, PSORIATIC ARTHRITIS, AND ENTHESITIS RELATED ARTHRITIS IRRESPECTIVE OF ANA STATUS, ONSET UNDER 11 YR AGE AT ONSET (YR) LENGTH OF SCREENING (YR) 3 8 3 4 6 5 8 3 9 10 1 POLYARTICULAR, ANA POSITIVE JIA, ONSET 10 YR AGE AT ONSET (YR) LENGTH OF SCREENING (YR) 6 5 6 9 2 Polyarticular, ANA negative JIA, onset 7 yr 5 yr screening for all children Systemic JIA and rheumatoid factorpositive polyarticular JIA Uveitis risk very low; however, diagnostic uncertainty in the early stages and overlap of symptoms may mean initial screening is indicated All categories, onset 11 yr 1 yr screening for all children After stopping immunosuppression (e.g., methotrexate) Two monthly screening for 6 mo, then revert to previous screening frequency as above After discharge from screening Patients should receive advice about regular self monitoring by checking vision uniocularly once weekly and when to seek medical advice Screening may need to continue indefinitely in situations where a young person may be unable to detect a change in vision or be unwilling to seek re referral Annual check by optometrist as a useful adjunct Data from Clarke SLN, Sen ES, Ramanan AV. Juvenile idiopathic arthritis associated uveitis. Pediatr Rheumatol. 2016;14:27. Fig. 196.6 Hands and wrists of a child with polyarticular juvenile idi opathic arthritis, rheumatoid factor negative. Notice the symmetric in volvement of the wrists, metacarpophalangeal joints, and proximal and distal interphalangeal joints. In this photograph, there is cream with occlusive dressing on the patients right hand in preparation for place ment of an intravenous line for administration of a biologic agent. A B Fig. 196.7 Progression of joint destruction in a child with polyarticular juvenile idiopathic arthritis, rheumatoid factor positive, despite doses of corticosteroids sufficient to suppress symptoms in the interval be tween radiographs. A, Radiograph of the hand at onset. B, Radiograph |
6,750 | taken 4 years later, showing a loss of articular cartilage and destruc tive changes in the distal and proximal interphalangeal and metacar pophalangeal joints as well as destruction and fusion of wrist bones. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 196 u Juvenile Idiopathic Arthritis 1477 evidence of hemophagocytosis is not always evident. Emergency treat ment with high dose intravenous methylprednisolone, cyclosporine, or anakinra may be effective. Severe cases may require therapy similar to that for primary HLH (see Chapter 556.2). An inflammatory lung disease has also recently been recognized as a rare but life threatening complication in children with sJIA. Chil dren can present with little to no respiratory symptoms; acute clubbing can be an early indicator. The predominant pathology is pulmonary alveolar proteinosis andor endogenous lipoid pneumonia. Compared with children without lung disease, children with sJIA and lung disease are younger at diagnosis, have a history of MAS, have higher serum IL 18 levels, and have higher exposure and adverse reaction rates to cytokine inhibitors. Given the more severe disease course, lung disease in children with sJIA requires a high index of suspicion and prompt evaluation. Bone mineral metabolism and skeletal maturation are adversely affected in children with JIA, regardless of subtype. Children with JIA have decreased bone mass (osteopenia), which appears to be associated with increased disease activity. Increased levels of cytokines such as TNF and IL 6, both key regulators in bone metabolism, have delete rious effects on bone both within the joint and systemically in the axial and appendicular bones. Abnormalities of skeletal maturation become most prominent during the pubertal growth spurt. DIAGNOSIS JIA is a clinical diagnosis without any diagnostic laboratory tests. The meticulous clinical exclusion of other diseases and many mimics is therefore essential. Laboratory studies, including tests for ANA and RF, Fig. 196.8 Rheumatoid nodules overlying bony prominences in an adolescent with rheumatoid factorpositive polyarthritis. (From Rosen berg AM, Oen KG. Polyarthritis. In: Cassiday JT, Petty RE, Laxer RM, et al., eds. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia: Saunders; 2011: Fig 15 5, p. 257.) Fig. 196.9 CT scan of the temporomandibular joint of a child with juvenile idiopathic arthritis exhibiting destruction on the right. Fig. 196.10 Radiograph of the cervical spine of a child with active juvenile idiopathic arthritis showing fusion of the neural arch between joints C2 and C3, narrowing and erosion of the remaining neural arch joints, obliteration of the apophyseal space, and loss of the normal lor dosis. Fig. 196.11 Severe hip disease in 13 yr old male with active systemic juvenile idiopathic arthritis. Radiograph shows destruction of the femo ral head and acetabula, joint space narrowing, and subluxation of left hip. The child had received corticosteroids systemically for 9 years. 41 T em pe ra tu re ( C ) 40 39 38 37 36 0 2 4 |
6,751 | 6 8 10 12 Days 14 16 18 20 22 24 35 Fig. 196.12 High spiking intermittent fever in a 3 yr old child with systemic juvenile idiopathic arthritis. (From Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet 2007;369:767778.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1478 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) are only supportive or prognostic, and their results may be normal in patients with JIA (see Tables 196.1, 196.3, and 196.4). DIFFERENTIAL DIAGNOSIS The differential diagnosis for arthritis is broad, and a careful, thorough investigation for other underlying etiology is imperative (Table 196.7). History, physical examination, laboratory tests, and radiography may help exclude other possible causes. Arthritis can be a presenting manifestation for any of the multisystem rheumatic diseases of childhood, including SLE (see Chapter 199), juvenile dermatomyositis (see Chapter 200), sarcoidosis (see Chapter 209), and the vasculitic syndromes (see Chapter 210). In scleroderma (see Chapter 201), limited ROM caused by sclerotic skin overly ing a joint may be confused with sequelae from chronic inflamma tory arthritis. Acute rheumatic fever is characterized by exquisite joint pain and tenderness, remittent fever, and migratory polyar thritis. Autoimmune hepatitis can also be associated with an acute arthritis. Many infections are associated with arthritis, and a recent history of infectious symptoms may help make a distinction. Viruses, includ ing parvovirus B19, rubella, Epstein Barr virus, hepatitis B virus, and HIV, can induce a transient arthritis. Arthritis may follow enteric infec tions (see Chapter 198). Lyme disease should be considered in chil dren with oligoarthritis living in or visiting endemic areas (see Chapter 268). Although a history of tick exposure, preceding flulike illness, and subsequent rash should be sought, these are not always present. Mono articular arthritis unresponsive to antiinflammatory treatment may be the result of chronic mycobacterial or other infection, such as Kingella kingae, and the diagnosis is established by synovial fluid analysis (poly merase chain reaction PCR) or biopsy. Acute onset of fever and a painful, erythematous, hot joint suggests septic arthritis (see Chapter 726). Isolated hip pain with limited ROM suggests suppurative arthri tis, osteomyelitis (see Chapter 725), toxic synovitis, Legg Calv Perthes disease, slipped capital femoral epiphysis, and chondrolysis of the hip (see Chapter 719). Lower extremity arthritis and tenderness over insertion of liga ments and tendons, especially in a male child, suggest ERA (see Chap ter 197). Psoriatic arthritis can manifest as limited joint involvement in an unusual distribution (e.g., small joints of the hand and ankle) years before the onset of cutaneous disease. Inflammatory bowel dis ease may manifest as oligoarthritis, usually affecting joints in the lower extremities, as well as gastrointestinal symptoms, elevations in ESR, and microcytic anemia. Many conditions present solely with arthralgia (i.e., joint pain). Hypermobility may cause joint pain, especially in the lower extrem ities. Growing pains should |
6,752 | be suspected in a child age 4 12 years complaining of leg pain in the evening with normal investigative studies and no morning symptoms. Nocturnal pain that awakens the child also alerts to the possibility of a malignancy. An adoles cent with missed school days may suggest a diagnosis of fibromyal gia (see Chapter 211.3). Children with leukemia or neuroblastoma may have joint or bone pain resulting from malignant infiltration of the bone, synovium, or more often the bone marrow, sometimes months before demonstrating lymphoblasts on peripheral blood smear. Physical examination may reveal no tenderness, a deeper pain with palpation of the bone, or pain out of proportion to exam findings. Malignant pain often awakens the child from sleep and may cause cytopenias. Because platelets are an acute phase reactant, a high ESR with leukopenia and a low normal platelet count may also be a clue to underlying leukemia. In addition, the characteristic quotidian fever of sJIA is absent in malignancy. Bone marrow examination is necessary for diagnosis. Some diseases, such as cystic fibrosis, diabetes mellitus, and the glycogen storage diseases, have associated arthropathies. Swelling that extends beyond the joint can be a sign of lymphedema or IgA vasculitis (formerly Henoch Schnlein purpura; see Chapter 210.1). A peripheral arthritis indis tinguishable from JIA occurs in the humoral immunodeficiencies (see Chapter 165), such as common variable immunodeficiency and X linked agammaglobulinemia. Skeletal dysplasias associated with a degenerative arthropathy are diagnosed from their characteristic radiologic abnormalities. Systemic onset of JIA often presents as a fever of unknown origin (see Chapter 222). Important considerations in the differential diag nosis include infections (endocarditis, brucellosis, cat scratch disease, Q fever, mononucleosis), autoinflammatory disease (see Chapter 204), malignancy (leukemia, lymphoma, neuroblastoma), and HLH. Fig. 196.13 The rash of systemic juvenile idiopathic arthritis is salmon colored, macular, and nonpruritic. Individual lesions are tran sient and occur in crops over the trunk and extremities. (From American College of Rheumatology. Clinical Slide Collection on the Rheumatic Diseases. Atlanta, GA: ACR. Copyright 1991, 1995, 1997.) Table 196.6 Macrophage Activation Syndrome (MAS) LABORATORY FEATURES 1. Cytopenias 2. Abnormal liver function tests 3. Coagulopathy (hypofibrinogenemia) 4. Decreased erythrocyte sedimentation rate 5. Hypertriglyceridemia 6. Hyponatremia 7. Hypoalbuminemia 8. Hyperferritinemia 9. Elevated sCD25 and sCD163 CLINICAL FEATURES 1. Nonremitting fever 2. Hepatomegaly 3. Splenomegaly 4. Lymphadenopathy 5. Hemorrhages 6. Central nervous system dysfunction (headache, seizures, lethargy, coma, disorientation) HISTOPATHOLOGIC FEATURES 1. Macrophage hemophagocytosis in the bone marrow aspirate 2. Increased CD163 staining of the bone marrow PROPOSED CRITERIA FOR MAS IN SJIA 1. Serum ferritin 684 ngmL and 2. Any two of the following: Thrombocytopenia (181 109L) Elevated liver enzymes (aspartate transaminase 48 UL) Hypertriglyceridemia (156 mgdL) Hypofibrinogenemia (360 mgdL) From Ravelli A, Grom A, Behrens E, Cron R. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: Diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012;13:289298. From Ravelli A, Minoia F, Dav S, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against RheumatismAmerican College |
6,753 | of RheumatologyPaediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 2016;68:566576. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 196 u Juvenile Idiopathic Arthritis 1479 LABORATORY FINDINGS Hematologic abnormalities often reflect the degree of systemic or artic ular inflammation, with elevated white blood cell (WBC) and platelet counts and a microcytic anemia. Inflammation may also cause eleva tions in ESR and CRP, although it is not unusual for both to be normal in children with JIA. Elevated ANA titers are present in 4085 of children with oligoar ticular or polyarticular JIA but are rare with sJIA. ANA seropositivity is associated with increased risk of chronic uveitis in JIA. Approxi mately 515 of patients with polyarticular JIA are seropositive for RF. Anticyclic citrullinated peptide antibody, as with RF, is a marker of more aggressive disease. Both ANA and RF seropositivity can occur in association with transient events, such as viral infection. Table 196.7 Conditions Causing Arthritis or Extremity Pain RHEUMATIC AND INFLAMMATORY DISEASES Juvenile idiopathic arthritis Systemic lupus erythematosus Juvenile dermatomyositis Polyarteritis nodosa Scleroderma Sjgren syndrome Behet disease Overlap syndromes Antineutrophilic cytoplasmic antibody (ANCA)associated vasculitis Sarcoidosis Kawasaki syndrome IgA vasculitis (formerly Henoch Schnlein purpura) Chronic recurrent multifocal osteomyelitis SERONEGATIVE SPONDYLOARTHROPATHIES Juvenile ankylosing spondylitis Inflammatory bowel disease Psoriatic arthritis Reactive arthritis associated with urethritis, iridocyclitis, and mucocutaneous lesions INFECTIOUS ILLNESSES Bacterial arthritis (septic arthritis, Staphylococcus aureus, Kingella kingae, pneumococcal, gonococcal, Haemophilus influenzae) Lyme disease Viral illness (parvovirus, rubella, mumps, Epstein Barr, hepatitis B, chikungunya) Fungal arthritis Mycobacterial infection Spirochetal infection Endocarditis REACTIVE ARTHRITIS Acute rheumatic fever Reactive arthritis (postinfectious caused by Shigella, Salmonella, Yersinia, Chlamydia, poststreptococcal, or meningococcus) Serum sickness Toxic synovitis of the hip Postimmunization IMMUNODEFICIENCIES Hypogammaglobulinemia Immunoglobulin A deficiency Common variable immunodeficiency disease (CVID) Human immunodeficiency virus (HIV) CONGENITAL AND METABOLIC DISORDERS Gout Pseudogout Mucopolysaccharidoses Thyroid disease (hypothyroidism, hyperthyroidism) Hyperparathyroidism Vitamin C deficiency (scurvy) Hereditary connective tissue disease (Marfan syndrome, Ehlers Danlos syndrome) Fabry disease Farber disease Fucosidosis Amyloidosis (familial Mediterranean fever) BONE AND CARTILAGE DISORDERS Trauma Patellofemoral syndrome Hypermobility syndromes Osteochondritis dissecans Avascular necrosis (including Legg Calv Perthes disease) Hypertrophic osteoarthropathy Slipped capital femoral epiphysis Osteolysis Benign bone tumors (including osteoid osteoma) Langerhans cell histiocytosis Rickets Idiopathic multicentric osteolysis Camptodactyly arthropathy coxa vara pericarditis syndrome Progressive pseudorheumatoid dysplasia Pachydermodactyly NEUROPATHIC DISORDERS Peripheral neuropathies Carpal tunnel syndrome Charcot joints NEOPLASTIC DISORDERS Leukemia Neuroblastoma Lymphoma Bone tumors (osteosarcoma, Ewing sarcoma) Histiocytic syndromes Synovial tumors HEMATOLOGIC DISORDERS Hemophilia Hemoglobinopathies (including sickle cell disease) MISCELLANEOUS DISORDERS Autoinflammatory diseases Recurrent multifocal osteomyelitis Pigmented villonodular synovitis Plant thorn synovitis (foreign body arthritis) Myositis ossificans Eosinophilic fasciitis Tendinitis (overuse injury) Raynaud phenomenon Hemophagocytic syndromes PAIN SYNDROMES Fibromyalgia Growing pains Depression (with somatization) Complex regional pain syndrome Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights |
6,754 | reserved. 1480 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Children with sJIA usually have striking elevations in inflamma tory markers and WBC and platelet counts. Hemoglobin levels are low, typically 7 10 gdL, with indices consistent with anemia of chronic disease. The ESR is usually high, except in MAS. Although immuno globulin levels tend to be high, ANA and RF are uncommon. Ferritin values are typically elevated and can be markedly increased in MAS (10,000 ngmL). In the setting of MAS, all cell lines have the potential to decline precipitously because of the consumptive process. A low or normal WBC count andor platelet count in a child with active sJIA should raise concerns for MAS. Early radiographic changes of arthritis include soft tissue swelling, periarticular osteopenia, and periosteal new bone apposition around affected joints (Fig. 196.14). Continued active disease may lead to subchondral erosions, loss of cartilage with varying degrees of bony destruction, and fusion. Characteristic radiographic changes in the cervical spine, most frequently in the neural arch joints at C2 C3 (see Fig. 196.10), may progress to atlantoaxial subluxation. MRI is more sensitive than radiography to detect early changes (Fig. 196.15). TREATMENT The goals of treatment are to achieve disease remission, prevent or halt joint damage, and foster normal growth and development. All chil dren with JIA need individualized treatment plans, and management is tailored according to disease subtype and severity, presence of poor prognostic indicators, and response to medications. Disease manage ment also requires monitoring for potential medication toxicities (see Chapter 195). Children with oligoarthritis often show partial response to non steroidal antiinflammatory drugs (NSAIDs), with improvement in inflammation and pain (Table 196.8). Those who have no or partial response after 4 6 weeks of treatment with NSAIDs or who have func tional limitations such as joint contracture or leg length discrepancy benefit from injection of intraarticular corticosteroids. Triamcinolone hexacetonide is a long lasting preparation that provides a prolonged response. A substantial fraction of patients with oligoarthritis show no response to NSAIDs and injections and therefore require treatment with disease modifying antirheumatic drugs (DMARDs), including con ventional synthetic DMARDs (csDMARDs) like methotrexate, and, if no response, biologic DMARDs (bDMARDs) like TNF inhibitors. NSAIDs alone rarely induce remission in children with polyarthritis or sJIA. Methotrexate is the oldest and least toxic of the csDMARDs available for adjunctive therapy. It may take 6 12 weeks to see the effects of methotrexate. Failure of methotrexate monotherapy warrants the addition of a bDMARD. bDMARDs that inhibit proinflammatory cytokines, such as TNF , IL 1, and IL 6, demonstrate excellent disease control. TNF antagonists (e.g., etanercept, adalimumab, golimumab) are used to treat children with an inadequate response to methotrex ate, poor prognostic factors, or severe disease onset. Early aggressive therapy with a combination of methotrexate and a TNF antagonist may result in earlier achievement of clinically inactive disease. Abata cept, a selective inhibitor of T cell activation, and tocilizumab, an IL 6 Fig. 196.14 Early (6 month |
6,755 | duration) radiographic changes of juve nile idiopathic arthritis. Soft tissue swelling and periosteal new bone formation appear adjacent to the second and fourth proximal inter phalangeal joints. Fig. 196.15 MRI of the wrist in a child with wrist arthritis. A, Multiple erosions of carpal bones. B, After administration of gadolinium contrast agent, uptake is consistent with active synovitis. A B Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 196 u Juvenile Idiopathic Arthritis 1481 Table 196.8 Pharmacologic Treatment of Juvenile Idiopathic Arthritis (JIA) TYPICAL MEDICATIONS TYPICAL DOSES JIA SUBTYPE SIDE EFFECT(S) NONSTEROIDAL ANTIINFLAMMATORY DRUGS Naproxen 15 mgkgday PO divided bid (maximum dose 500 mg bid) Polyarthritis Systemic Oligoarthritis Gastritis, renal and hepatic toxicity, pseudoporphyria Ibuprofen 40 mgkgday PO divided tid (maximum dose 800 mg tid) Same as above Same as above Meloxicam 0.125 mgkg PO once daily (maximum dose 15 mg daily) Same as above Same as above DISEASE MODIFYING ANTIRHEUMATIC DRUGS Methotrexate 0.5 1 mgkg PO or SC weekly (maximum dose 25 mgwk) Polyarthritis Systemic Persistent or extended oligoarthritis Nausea, vomiting, oral ulcerations, hepatic toxicity, blood count dyscrasias, immunosuppression, teratogenicity Sulfasalazine Initial 12.5 mgkg PO daily; increase by 10 mgkgday Maintenance: 40 50 mgkg divided bid (maximum dose 2 gday) Polyarthritis GI upset, allergic reaction, pancytopenia, renal and hepatic toxicity, Stevens Johnson syndrome Leflunomide 10 20 mg PO daily Polyarthritis GI upset, hepatic toxicity, allergic rash, alopecia (reversible), teratogenicity (needs washout with cholestyramine) BIOLOGIC AGENTS AntiTumor Necrosis Factor Etanercept 0.8 mgkg SC weekly or 0.4 mgkg SC twice weekly (maximum dose 50 mgwk) Polyarthritis Systemic Persistent or extended oligoarthritis Immunosuppressant, concern for malignancy, demyelinating disease, lupus like reaction, injection site reaction Infliximab 3 10 mgkg IV q4 8wk Same as above Same as above, infusion reaction Adalimumab 10 to 15 kg: 10 mg SC every other week 15 to 30 kg: 20 mg SC every other week 30 kg: 40 mg SC every other week Same as above Same as above Golimumab 80 mgm2 IV wk 0 and 4 and then q8 wk Same as above Same as above Anticytotoxic T LymphocyteAssociated Antigen 4 Immunoglobulin Abatacept 75 kg: 10 mgkgdose IV q4wk 75 100 kg: 750 mgdose IV q4wk 100 kg: 1,000 mgdose IV q4wk SC once weekly: 10 to 25 kg: 50 mg 25 to 50 kg: 87.5 mg 50 kg: 125 mg Polyarthritis Immunosuppressant, concern for malignancy, infusion reaction Anti CD20 Rituximab 750 mgm2 IV 2 wk 2 (maximum dose 1,000 mg) Polyarthritis Immunosuppressant, infusion reaction, progressive multifocal encephalopathy Interleukin 1 Inhibitors Anakinra 1 2 mgkg SC daily Systemic Immunosuppressant, GI upset, injection site reaction Canakinumab 4 mgkgdose SC q4wk (maximum dose 300 mg) Systemic Immunosuppressant, headache, GI upset, injection site reaction Rilonacept 2.2 mgkgdose SC weekly (maximum dose 160 mg) Systemic Immunosuppressant, allergic reaction, dyslipidemia, injection site reaction Interleukin 6 Receptor Antagonist Tocilizumab 30 kg: 12 mgkgdose IV q2wk |
6,756 | (maximum dose 800 mg) 162 mg SC q2wk 30 kg: 8 mgkgdose IV q2wk (maximum dose 800 mg) 162 mg SC weekly Systemic Immunosuppressant, hepatic toxicity, dyslipidemia, cytopenias, GI upset, infusion reaction 30 kg: 10 mgkgdose IV q4wk (maximum dose 800 mg) 162 mg SC q3wk 30 kg: 8 mgkgdose IV q4wk 162 mg SC q2wk Polyarthritis Janus Kinase Inhibitors Tofacitinib 10 to 20 kg: 3.2 mg PO bid 20 to 40 kg: 4 mg PO bid 40 kg 5 mg PO bid Polyarthritis Immunosuppressant, GI perforation, thrombosis Not indicated by the U.S. Food and Drug Administration for use in JIA as of 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1482 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) receptor antagonist, have demonstrated efficacy in and are approved for treatment of polyarticular JIA (see Table 196.8). TNF inhibition is not as effective for the systemic symptoms found in sJIA. When systemic symptoms dominate, systemic corticosteroids are started, followed by the initiation of IL 1 or IL 6 antagonist therapy, which often induces a dramatic and rapid response. Patients with severe disease activity may go directly to anakinra. Canakinumab, an IL 1 inhibitor, and tocilizumab are Food and Drug Administration (FDA)approved treatments for sJIA in children older than 2 years (see Table 196.8). Stan dardized consensus guiding therapy for sJIA provide four treatment plans based on glucocorticoids, methotrexate, anakinra, or tocilizumab, with optional glucocorticoid use in the latter three plans as clinically indicated. With the use of DMARDs, the use of systemic corticosteroids can often be avoided or minimized. Systemic corticosteroids are recom mended only for management of severe systemic illness, for bridge therapy during the wait for therapeutic response to a DMARD, and for control of uveitis. Steroids impose risks of severe toxicities, including Cushing syndrome, growth retardation, and osteopenia, and they do not prevent joint destruction. Small molecule drugs, including Janus kinase (JAK) inhibitors, are an alternative to csDMARDs and bDMARDs. Oral JAK inhibitors (tofacitinib, ruxolitinib) inhibit JAK signaling pathways involved in immune activation and inflammation. Tofacitinib is FDA approved for children older than 2 years with polyarticular JIA. Management of JIA must include periodic slit lamp ophthalmologic examinations to monitor for asymptomatic uveitis (Figs. 196.16 and 196.17; see Table 196.4). Optimal treatment of uveitis requires collabo ration between the ophthalmologist and rheumatologist; initial man agement may include mydriatics and corticosteroids used topically, systemically, or through periocular injection. DMARDs allow for a decrease in exposure to steroids, and methotrexate and TNF inhibi tors (adalimumab and infliximab) are effective in treating severe uveitis. Dietary evaluation and counseling to ensure appropriate calcium, vitamin D, protein, and caloric intake are important for children with JIA. Physical therapy and occupational therapy are invaluable adjuncts to any treatment program. A social worker and nurse clinician can be important resources for families |
6,757 | to recognize stresses imposed by a chronic illness, to identify appropriate community resources, and to aid compliance with the treatment protocol. PROGNOSIS Although the course of JIA in an individual child is unpredictable, some prognostic generalizations can be made on the basis of disease type and course. Studies analyzing management of JIA in the preTNF era indicate that up to 50 of JIA patients had active disease persisting into early adulthood, often with severe limitations of physical function. Children with persistent oligoarticular disease fare well, with a majority achieving disease remission. Those with extended oligoarticular disease have a poorer prognosis. Children with oligoarthritis, particularly females who are ANA positive and with onset of arthritis before 6 years of age, are at greatest risk for development of chronic uveitis. There is no association between the activity or severity of arthritis and uveitis. Persistent, uncontrolled anterior uveitis (see Fig. 196.16) can cause posterior synechiae, cataracts, glaucoma, and band keratopathy, with resultant blindness. Morbidity can be averted with early diagnosis and implementation of systemic therapy. The child with polyarticular JIA often has a more prolonged course of active joint inflammation and requires early and aggressive therapy. Predictors of severe and persistent disease include young age at onset, RF seropositivity or rheumatoid nodules, presence of anticyclic citrul linated peptide antibodies, and many affected joints. Disease involving the hip and handwrist is also associated with a poorer prognosis and may lead to significant functional impairment. sJIA is often the most difficult to control in terms of both articular inflam mation and systemic manifestations. Poorer prognosis is related to poly articular distribution of arthritis, fever lasting 3 months, and increased inflammatory markers, such as platelet count and ESR, for 6 months. IL 1 and IL 6 inhibitors have changed the management and improved the out comes for children with severe and prolonged systemic disease. Orthopedic complications include leg length discrepancy and flexion contractures, particularly of the knees, hips, and wrists. Discrepancies in leg length can be managed with a shoe lift on the shorter side to pre vent secondary scoliosis. Joint contractures require aggressive medical control of arthritis, often in conjunction with intraarticular cortico steroid injections, appropriate splinting, and stretching of the affected tendons. Popliteal cysts may require no treatment if they are small or respond to intraarticular corticosteroids in the anterior knee. Psychosocial adaptation may be affected by JIA. Studies indicate that, compared with controls, a significant number of children with JIA have problems with lifetime adjustment and employment. Disability not directly associated with arthritis may continue into young adult hood in as many as 20 of patients, together with continuing chronic pain syndromes at a similar frequency. Psychological complications, including problems with school attendance and socialization, may respond to counseling by mental health professionals. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 196.16 Chronic anterior uveitis demonstrating posterior synechi ae and absence of significant scleral inflammation. (From Firestein GS, Budd RC, Gabriel SE, et al., eds. Kelley Firesteins Textbook of Rheu matology, 10th ed. |
6,758 | Philadelphia: Elsevier; 2017: Fig. 107 5, p. 1838.) Fig. 196.17 Slit lamp examination shows flare in the fluid of the anterior chamber (caused by increased protein content) and keratic precipitates on the posterior surface of the cornea, representing small collections of inflammatory cells. (Courtesy Dr. H.J. Kaplan. From Petty RE, Rosenbaum JT. Uveitis in juvenile idiopathic arthritis. In Cassidy JT, Petty RE, Laxer RM, et al., eds. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia: Saunders; 2011: Fig. 20 3, p. 309.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 197 u Ankylosing Spondylitis and Other Spondyloarthritides 1483 The diseases collectively referred to as spondyloarthritides include ankylosing spondylitis (AS), arthritis associated with inflamma tory bowel disease (IBD) or psoriasis, and reactive arthritis after gastrointestinal (GI) or genitourinary (GU) infections (Table 197.1 and Table 197.2). Spondyloarthritis is more common in adults, but all forms can present during childhood with varying symptoms and signs. Many children with spondyloarthritis are classified in the juvenile idiopathic arthritis (JIA) categories of enthesitis related arthritis (ERA) or psoriatic arthritis. Children and adoles cents with spondyloarthritis who may not meet JIA criteria include arthritis associated with IBD, juvenile ankylosing spondylitis (JAS), and reactive arthritis. EPIDEMIOLOGY JIA is diagnosed in 90 per 100,000 U.S. children every year (see Chapter 196). ERA accounts for 1020 of JIA and has a mean age at onset of 12 years. In India, ERA is the most common category of JIA, accounting for 35 of cases. Unlike other JIA categories, males are affected more often than females, accounting for 60 of ERA cases. AS occurs in 0.20.5 of adults, with approximately 15 of cases beginning in childhood. These disorders can be famil ial, largely as a result of the influence of human leukocyte antigen (HLA) B27, which is found in 90 of JAS and 50 of ERA patients compared to 7 of healthy individuals. Approximately 20 of chil dren with ERA have a family history of HLA B27associated dis ease, such as reactive arthritis, AS, or IBD with sacroiliitis. ETIOLOGY AND PATHOGENESIS Spondyloarthritides are complex diseases in which susceptibility is largely genetically determined. Only 30 of heritability has been defined, with HLA B27 responsible for two thirds of the total, and 100 additional genetic loci accounting for only one third. Genes that influence interleukin (IL) 23 responses (e.g., CARD9, IL23R, JAK2, TYK2, STAT3) and the function of HLA B27 (ERAP1) are particularly important. Unusual properties of HLA B27, such as its tendency to misfold and form abnormal cell surface structures, may have a role. Infection with certain GI or GU pathogens can trigger reactive arthri tis (see Table 197.2 and Chapter 198). Altered gut microbiota and an abnormal immune response to normal microbiota may also play a role in pathogenesis. Inflamed joints and entheses in spondyloarthritis con tain T and B cells, macrophages, osteoclasts, proliferating fibroblasts, and |
6,759 | osteoblasts, with activation of the IL 23IL 17 pathway. Bone loss and osteoproliferation in and around vertebral bodies and facet joints in long standing AS contribute to significant morbidity. CLINICAL MANIFESTATIONS AND DIAGNOSIS Clinical manifestations that help distinguish spondyloarthritis from other forms of juvenile arthritis include arthritis of the axial skeleton (sacroiliac joints or spine) and hips, enthesitis (inflamma tion at the site of a tendon, ligament, or joint capsule attachment to bone), symptomatic eye inflammation (acute anterior uveitis), and GI inflammation (even in the absence of IBD) (Table 197.3, but see also Table 197.1). Enthesitis Related Arthritis Children fulfill classification criteria for ERA if they have either arthritis and enthesitis or arthritis or enthesitis with at least two of the following characteristics: (1) sacroiliac joint tenderness or inflammatory lumbosacral pain, (2) presence of HLA B27, (3) onset of arthritis in a male older than 6 years, (4) acute anterior uveitis, and (5) a family history of an HLA B27associated disease (ERA, sacroiliitis with IBD, reactive arthritis, or acute anterior uveitis) in a first degree relative. Patients with psoriasis (or a family his tory of psoriasis in a first degree relative), a positiverheumatoid factor (RF) test result, or systemic arthritis are excluded from this group. During the first 6 months of disease the arthritis is typically Chapter 197 Ankylosing Spondylitis and Other Spondyloarthritides Pamela F. Weiss Table 197.1 Overlapping Characteristics of the Spondyloarthritides CHARACTERISTIC JUVENILE ANKYLOSING SPONDYLITIS JUVENILE PSORIATIC ARTHRITIS INFLAMMATORY BOWEL DISEASE REACTIVE ARTHRITIS Enthesitis Axial arthritis Peripheral arthritis HLA B27 positive Antinuclear antibody positive Rheumatoid factor positive SYSTEMIC DISEASE Eyes Skin Mucous membranes Gastrointestinal tract Frequency of characteristics: , absent; , 25; , 2550; , 5075; , 75. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1484 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) asymmetric and involves fewer than four joints, most frequently the knees, ankles, and hips. Inflammation of the small joints of the foot, or tarsitis, is highly suggestive of ERA. Enthesitis is typically sym metric and affects the lower limbs. Up to 40 of children develop clinical or radiographic evidence of sacroiliac joint arthritis as part of their disease; approximately 20 have evidence of sacroiliac joint arthritis at diagnosis. When the sacroiliac or other axial joints are involved, children may experience inflammatory back pain (Table 197.4), hip pain, and alternating buttock pain. Patients may also experience pain with palpation of the lower back or with pelvic compression. The risk of sacroiliac joint arthritis is highest in chil dren who are HLA B27 positive and have an elevated C reactive protein (CRP). Untreated sacroiliitis may, but does not always, evolve into AS; additional risk factors for progression are unclear. Psoriatic Arthritis Psoriatic arthritis accounts for |
6,760 | approximately 5 of JIA. Common clinical features of psoriatic arthritis are nail pitting (Fig. 197.1), ony cholysis, and dactylitis (sausage like swelling of fingers or toes). Children fulfill classification criteria for psoriatic arthritis if they have arthritis and psoriasis or arthritis and at least two of the follow ing: (1) dactylitis, (2) nail pitting or onycholysis, and (3) psoriasis in a first degree relative. The presence of psoriasis aids in diagnosis but is not required. Disease onset peaks during the preschool and early adolescent years. Children with onset during the preschool years are more often female, antinuclear antibody (ANA) positive, and at risk for asymptomatic ocular inflammation. Disease onset during adoles cence is equally common among males and females. In the majority Table 197.3 Assessment in SpondyloArthritis International Society (ASAS) Classification Criteria for Spondyloarthritis (SpA) AXIAL SpA PERIPHERAL SpA In patients with 3 months back pain and age at onset 45 years In patients with peripheral symptoms ONLY Sacroiliitis on imaging plus one or more SpA feature(s) or HLA B27 plus two or more other SpA features Arthritis or enthesitis or dactylitis plus SpA features Inflammatory back pain (IBP) Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn diseaseulcerative colitis Good response to NSAIDs Family history for SpA HLA B27 Elevated CRP One or more SpA feature(s): Uveitis Psoriasis Crohn diseaseulcerative colitis Preceding infection HLA B27 Sacroiliitis on imaging or Two or more other SpA features: Arthritis Enthesitis Dactylitis IBP ever Family history for SpA Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA. Definite radiographic sacroiliitis according to modified NY criteria. CRP, C reactive protein; NSAIDs, nonsteroidal antiinflammatory drugs. Adapted from Rudwaleit M, van der Heijde D, Landew R, et al. The development of Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis. Part II. Validation and final selection. Ann Rheum Dis. 2009;68(6):777783; and The Assessment of Spondyloarthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011;70(1):2531. Table 197.4 Symptoms Characteristic of Inflammatory Back Pain Pain at night with morning stiffness (and improvement on arising) No improvement with rest Improvement with exercise Insidious onset Good response to nonsteroidal antiinflammatory drugs Table 197.2 Etiologic Microorganisms of Reactive Arthritis PROBABLE Chlamydia trachomatis Shigella species Salmonella enteritidis Salmonella typhimurium Yersinia enterocolitica Yersinia pseudotuberculosis Campylobacter jejuni and coli POSSIBLE Neisseria gonorrhoeae Mycoplasma fermentans Mycoplasma genitalium Ureaplasma urealyticum Escherichia coli Cryptosporidium Entamoeba histolytica Giardia lamblia Brucella abortus Clostridium difficile Streptococcus pyogenes Chlamydia pneumoniae Chlamydia psittaci From Kim PS, Klausmeier TL, Orr DP. Reactive arthritis: a review. J Adolesc Health. 2009;44:309315, Table 2, p. 311. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 197 u Ankylosing Spondylitis and Other Spondyloarthritides 1485 of children, the arthritis is asymmetric and affects four or fewer joints at presentation. Large (knees and ankles) and small (fingers and toes) joints may be involved. Although |
6,761 | distal interphalangeal joint involve ment is uncommon, it is highly suggestive of the diagnosis. Enthesitis is detectable in 2075 of patients and seems to be more frequent in those who present at an older age (Table 197.5, Fig. 197.2). Axial (sacroiliac) and root (hip) joints may be affected in up to 30 of chil dren; the risk of axial arthritis is highest in those who are HLA B27 positive. Juvenile Ankylosing Spondylitis JAS frequently begins with oligoarthritis and enthesitis. The arthri tis occurs predominantly in the lower extremities and often involves the hips. In comparison to adult onset AS, axial disease and inflammatory back pain are less frequent at disease onset, whereas enthesitis and peripheral arthritis are more common. AS is diag nosed according to the modified New York (NY) criteria if there is sufficient radiographic evidence of sacroiliitis (sacroiliitis of grade 2 or greater bilaterally or at least grade 3 unilaterally) and if the patient meets at least one clinical criterion involving inflammatory back pain, limitation of motion in the lumbar spine (Fig. 197.3), or limitation of chest expansion. JAS is present if the patient is 16 years old. Juvenile onset AS is frequently used to describe adult AS when the symptoms began before 16 years of age but full criteria were not met until later. To fulfill the modified NY criteria for AS, patients must have radiographic changes in the sacroiliac joints and clinical sequelae of axial disease. Because radiographic sacroiliitis can take many years to develop in adults and even longer in children, and clini cal sequelae may lag further behind, criteria to identify preradio graphic axial spondyloarthritis were developed by the Assessment of SpondyloArthritis International Society. To meet criteria for axial spondyloarthritis (SpA), patients must have at least 3 months of back pain and sacroiliitis on imaging (acute inflammation on MRI or definite radiographic sacroiliitis by NY criteria) plus one feature of SpA (inflammatory back pain, arthritis, enthesitis heel, uveitis, dactylitis, psoriasis, Crohn diseaseulcerative colitis, good response to nonsteroidal antiinflammatory drugs NSAIDs, family history for SpA, HLA B27, or elevated CRP). Alternatively, patients can fulfill axial SpA criteria if they are HLA B27 positive and have at least two SpA features. These criteria have low sensitivity and specificity in the pediatric population but, in the absence of alterna tive pediatric criteria, may be useful as a guide to evaluating prera diographic axial SpA. Arthritis with Inflammatory Bowel Disease The presence of erythema nodosum, pyoderma gangrenosum, oral ulcers, abdominal pain, diarrhea, fever, weight loss, or anorexia in a child with chronic arthritis should raise suspicion of IBD. Two patterns of arthritis complicate IBD. Polyarthritis affecting large and small joints is most common and often reflects the activity of the intestinal inflammation. Less frequently, arthritis of the axial skeleton, includ ing the sacroiliac joints, occurs. As with psoriatic arthritis, the presence of HLA B27 is a risk factor for the development of axial disease. The severity of axial involvement is independent of the activity of the GI inflammation. |
6,762 | LABORATORY FINDINGS Laboratory evidence of systemic inflammation with elevation of the erythrocyte sedimentation rate (ESR) andor CRP value is vari able in most spondyloarthritides and may or may not be present at the onset of disease. RF and ANAs are absent, except in chil dren with psoriatic arthritis, as many as 50 of whom are ANA positive. HLA B27 is present in approximately 90 of children with JAS, compared with 7 of healthy individuals, but is less frequent in ERA and other SpA types. Imaging Conventional radiographs detect chronic bony changes and damage but not active inflammation and are unreliable in the assessment of pediatric disease. Early radiographic changes in the sacroiliac joints include indistinct margins and erosions. Sclerosis typically starts on the iliac side of the joint (Fig. 197.4). Peripheral joints may exhibit periarticular osteoporosis, with loss of sharp cortical mar gins in areas of enthesitis, which may eventually show erosions or bony spurs (enthesophytes). Squaring of the corners of the vertebral bodies and syndesmophyte formation resulting in the classic bam boo spine characteristic of advanced AS are rare in early disease, particularly in childhood. CT, like radiographs, can detect chronic bony changes but not active inflammation and has the disadvantage of more radiation exposure. The gold standard for early visualiza tion of sacroiliitis is evidence of bone marrow edema adjacent to the joint on MRI with fluid sensitive sequences such as short T1 inversion recovery (STIR) (Figs. 197.5 and 197.6). Gadolinium does not add value to the study of the sacroiliac joints if STIR is used. MRI will reveal abnormalities before the plain radiograph. Whole Fig. 197.1 Nail pitting in a 9 year old with JPsA. (From Srinivasalu H, Sikora KA, Colbert RA. Recent updates in juvenile spondyloarthritis. Rheum Dis Clin N Am. 2021;47:565583, Fig. 2, p. 569.) Table 197.5 Entheseal Sites Studied in Historical JSpA Cohorts ENTHESEAL SITES PERCENTAGE Insertion of infrapatellar tendon on patella 27 44 Achilles tendon 21 74 Interosseous ligaments of the sacroiliac joint 30.3 Plantar fascia insertion to calcaneus 12 39 Tibial tuberosity 23 30 Quadriceps insertion to upper poles of patella 22 46 Second MTP 21 Third MTP 16 First MTP 14 Greater trochanter 14 Iliac crest 14 JSpA, Juvenile spondyloarthritis; MTP, metatarsophalangeal. From Srinivasalu H, Sikora KA, Colbert RA. Recent updates in juvenile spondyloarthritis. Rheum Dis Clin N Am. 2021;47:565583, Table 1, p. 567. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1486 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) body MRI may also be used to evaluate the axial skeleton in adults with early disease because it can detect vertebral lesions in addition to sacroiliac changes. DIFFERENTIAL DIAGNOSIS The onset of arthritis after a recent history of diarrhea or symptoms of urethritis or conjunctivitis may suggest reactive arthritis (see Chapter 198). Lower back pain can be caused by |
6,763 | strain, infectious arthritis of the sacroiliac joint, osteomyelitis of the pelvis or spine, chronic nonbacterial osteomyelitis (CNO) of the pelvis or spine, osteoid osteoma of the posterior elements of the spine, pelvic muscle pyomyositis, or malignancies. In addition, mechanical conditions such as spondylolysis, spondylolisthesis, and Scheuermann disease should be considered. Back pain secondary to fibromyalgia usually affects the soft tissues of the upper back in a symmetric pattern and is associated with well localized tender points and sleep distur bance (see Chapter 211.3). Legg Calv Perthes disease (avascular necrosis of the femoral head), slipped capital femoral epiphysis, and chondrolysis may also manifest as pain over the inguinal ligament and loss of internal rotation of the hip joint, but without other SpA features, such as involvement of other entheses andor joints. Radi ography and MRI are critical for distinguishing these conditions. Fig. 197.2 Anatomic sites for as sessment of enthesitis in ERA and JAS. (From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Fig. 20.1, p. 254.) Anatomic region Enthesitis exam Foot and ankle Achilles tendon insertion to calcaneus Plantar fascia insertion to calcaneus Plantar fascia insertion to metatarsal heads Plantar fascia insertion to base of fifth metatarsal Quadriceps tendon insertion to patella (2 and 10 oclock) Infrapatellar ligament insertion to patella (6 oclock) and tibial tuberosity Hip extensor insertion at greater trochanter of femur Sartorius insertion at anterior superior iliac spine Posterior superior iliac spine Abdominal muscle insertions to iliac crest Gracilis and adduction insertion to pubis symphysis Hamstrings insertion to ischial tuberosity 5th lumbar spinous process Common flexor insertion at medial epicondyle of humerus Common extensor insertion at lateral epicondyle of humerus Supraspinatus insertion into greater tuberosity of humerus Costosternal junctions (1st and 7th) Knee Pelvis Spine Upper extremity Chest Fig. 197.3 Loss of lumbodorsal spine mobility in a boy with anky losing spondylitis. The lower spine remains straight when the patient bends forward. Fig. 197.4 Well developed sacroiliitis in a boy with ankylosing spon dylitis. Both sacroiliac joints show extensive sclerosis, erosion of joint margins, and apparent widening of the joint space. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 197 u Ankylosing Spondylitis and Other Spondyloarthritides 1487 TREATMENT The goals of therapy are to control inflammation, minimize pain, preserve function, and prevent ankylosis (fusion of adjacent bones) using a combination of antiinflammatory medications, physical therapy, and education. Treatment regimens for SpA include mono therapy or combination therapy with NSAIDs, disease modifying antirheumatic drugs (DMARDs), or biologic agents. NSAIDs, such as naproxen (15 20 mgkgday), are frequently used to help relieve symptoms and may slow the progression of structural damage (syndesmophyte formation and growth) if used continually. With relatively mild monoarticular disease, intraarticular corticosteroids (e.g., triamcinolone acetonidehexacetonide) may also help to con trol peripheral joint inflammation. DMARDs such as sulfasalazine (up |
6,764 | to 50 mgkgday; maximum 3 gday) or methotrexate (10 mg m2) may be beneficial for peripheral arthritis, but these medications have not been shown to improve axial disease in adults. For axial arthritis, it is typically necessary to add a biologic therapy. Tumor necrosis factor (TNF) inhibitors (e.g., etanercept, infliximab, adali mumab) have been efficacious in reducing symptoms and improv ing function in adults with AS. It remains unclear whether TNF inhibitors have an impact on structural damage in established AS, underscoring the need for earlier recognition and better therapies. Drugs that target IL 17 (secukinumabixekizumab), IL 23IL 12 (ustekinumab), and the JAKSTAT pathway (tofacitinibupadaci tinib) reduce clinical disease activity in adults with AS. Physical therapy and low impact exercise should be included in the treatment program for all children with spondyloarthritis. Exercise to maintain range of motion in the back, thorax, and affected joints should be instituted early in the disease course. Custom fitted insoles and heel cups are particularly useful in the management of painful entheses around the feet, and the use of pillows to position the lower extremities while the child is in bed can be helpful. PROGNOSIS Observational studies suggest that ongoing disease activity for 5 years in juvenile spondyloarthritis predicts disability. Disease remis sion occurs in 20 of children with spondyloarthritis 5 years after diagnosis. Factors associated with disease progression include tarsitis, HLA B27 positivity, hip arthritis within the first 6 months, and dis ease onset after age 8. Important questions, such as which patients with ERA will go on to have JASAS, have yet to be addressed. Outcomes for JAS compared with adult onset AS suggest that hip disease requir ing replacement is more common in children but axial disease is more severe in adults. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 197.5 Coronal MRI (STIR) of the pelvis in a 14 year old boy with ERA (HLA B27 positive). Fluid and pathology appear bright, spinal fluid also appears bright. Increased signal abnormality is observed around bilateral triradiate cartilages and greater trochanteric apophyses (arrow heads), common areas of involvement for ERA. Also, signal abnormality appears on the iliac side of the sacroiliac joints bilaterally around more curvilinear, dark, sclerotic subchondral areas representing erosions and sacroiliitis (arrows). (From Tse SM, Laxer RM. New advances in juvenile spondyloarthritis. Nat Rev Rheumatol. 2012;10;8:269279.) Fig. 197.6 Short T1 inversion recovery image from whole body MRI of a 15 yr old boy with HLA B27negative JSpA. The MRI shows ac tive corner inflammatory lesions of vertebral end plates at multiple levels (straight arrows) and more chronic appearing discovertebral unit changes (curved arrow). (From Srinivasalu H, Sikora KA, Colbert RA. Recent updates in juvenile spondyloarthritis. Rheum Dis Clin N Am. 2021;47:565583, Fig. 7, p. 574.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1488 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue |
6,765 | Disease, Collagen Vascular Diseases) In addition to causing arthritis by means of direct microbial infec tion (i.e., septic arthritis; see Chapter 726), microbes activate innate and adaptive immune responses, which can lead to the generation and deposition of immune complexes and antibody or T cellmedi ated cross reactivity with self. Furthermore, microbes may influence the immune system in ways that promote immune mediated inflam matory diseases such as systemic lupus erythematosus (SLE), inflam matory bowel disease (IBD), juvenile idiopathic arthritis (JIA), and spondyloarthritis. Reactive arthritis and postinfectious arthritis are defined as joint inflammation caused by a sterile inflammatory reac tion after a recent infection. The term reactive arthritis is used to refer to arthritis that occurs after enteropathic or urogenital infections and postinfectious arthritis to describe arthritis that occurs after infectious illnesses not classically considered in the reactive arthritis group, such as infection with group A streptococcus or viruses. In some patients, nonviable components of the initiating organism have been demon strated in affected joints, and the presence of viable, yet nonculturable, bacteria within the joint remains an area of investigation. The course of reactive arthritis is variable and may remit or progress to a chronic spondyloarthritis, including ankylosing spondylitis (see Chapter 197). In postinfectious arthritis, the pain or joint swelling is usually transient, lasting 6 weeks, and does not necessarily share the typical spondyloarthritis pattern of joint involvement. The distinction between postinfectious arthritis and reactive arthritis is not always clear, either clinically or pathophysiologically. PATHOGENESIS Reactive arthritis typically follows enteric infection with Salmonella species, Shigella flexneri, Yersinia enterocolitica, Campylobacter jejuni, or genitourinary (GU) tract infection with Chlamydia trachoma tis. Escherichia coli and Clostridium difficile are also causative enteric agents, although less common (see Table 197.2). Acute rheumatic fever caused by group A streptococcus (see Chapters 229 and 229.1), arthritis associated with infective endocarditis (see Chapter 486), and the tenosynovitis associated with Neisseria gonorrhoeae are similar in some respects to reactive arthritis. Approximately 75 of patients with reactive arthritis are HLA B27 positive. Incomplete elimination of bacteria and bacterial products, such as DNA, has been proposed as a factor in reactive arthritis. A relation ship with clinical characteristics of specific infectious disorders is not present. In postinfectious arthritis, several viruses (rubella, varicella zoster, herpes simplex, cytomegalovirus) have been isolated from the joints of patients. Antigens from other viruses (e.g., hepatitis B, adeno virus) have been identified in immune complexes from joint tissue. Patients with reactive arthritis who are HLA B27 positive have an increased frequency of acute and symptomatic uveitis and other extraarticular features. In addition, HLA B27 is a risk factor for per sistent gastrointestinal (GI) inflammation after enteric infections, even after resolution of the initial infection, and significantly increases the risk that the individual will develop chronic spondyloarthritis. Nev ertheless, reactive arthritis also occurs in HLA B27negative patients, emphasizing the importance of other genes in disease susceptibility. CLINICAL MANIFESTATIONS AND DIFFERENTIAL DIAGNOSIS Symptoms of reactive arthritis begin approximately 3 days to 6 weeks after infection. The classic triad |
6,766 | of arthritis, urethritis, and conjunctivitis is relatively uncommon in children. The arthritis is typically asymmet ric and oligoarticular, with a predilection for the lower extremities. Dactylitis may occur, and enthesitis is common, affecting as many as 90 of patients (Fig. 198.1). Cutaneous manifestations can occur and may include circinate balanitis, ulcerative vulvitis, erythematous oral macules or plaques or erosions, erythema nodosum, paronychia, pain ful erosions or pustules on fingertips, and keratoderma blennorrhag ica, which is similar in appearance to pustular psoriasis (Fig. 198.2). Systemic symptoms may include fever, malaise, and fatigue. Less com mon features may include conjunctivitis, optic neuritis, aortic valve involvement, sterile pyuria, and polyneuropathy. Early in the disease course, markers of inflammationerythrocyte sedimentation rate (ESR), C reactive protein, and plateletsmay be greatly elevated. The clinical manifestations may last for weeks to months. Familiarity with other causes of postinfectious arthritis is vital when a diagnosis of reactive arthritis is being considered. Numerous viruses are associated with postinfectious arthritis and may result in particu lar patterns of joint involvement (Table 198.1). Rubella and hepatitis B virus typically affect the small joints, whereas mumps and varicella often involve large joints, especially the knees. Hepatitis B arthritis dermatitis syndrome is characterized by urticarial rash and a sym metric migratory polyarthritis resembling that of serum sickness. Rubella associated arthropathy may follow natural rubella infection and, infrequently, rubella immunization. It typically occurs in young women, with an increased frequency with advancing age, and is uncommon in preadolescent children and in males. Arthralgia of the knees and hands usually begins within 7 days of onset of the rash or 10 28 days after immunization. Parvovirus B19, which is responsible for erythema infectiosum (fifth disease), can cause arthralgia, symmetric Chapter 198 Reactive and Postinfectious Arthritis Pamela F. Weiss Fig. 198.1 Enthesitisswelling of the posterior aspect of the left heel and lateral aspect of the ankle. (Courtesy Dr. Nora Singer, Case Western Reserve University and Rainbow Babies Hospital.) Fig. 198.2 Keratoderma blennorrhagica. (Courtesy Dr. MF Rein and the Centers for Disease Control and Prevention Public Health Image Library, 1976. Image 6950.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 198 u Reactive and Postinfectious Arthritis 1489 joint swelling, and morning stiffness, particularly in adult women and less frequently in children. Arthritis occurs occasionally during cyto megalovirus infection and may occur during varicella infections but is rare after Epstein Barr virus infection. Varicella may also be com plicated by suppurative arthritis, usually secondary to group A strep tococcus infection. HIV is associated with an arthritis that resembles psoriatic arthritis more than JIA (see Chapter 196). Poststreptococcal arthritis may follow infection with either group A or group G streptococcus. It is typically oligoarticular, affecting lower extremity joints, and mild symptoms can persist for months. Poststreptococcal arthritis differs from rheumatic fever, which typi cally manifests with painful migratory polyarthritis of brief duration. |
6,767 | Because valvular lesions have occasionally been documented by echo cardiography after the acute illness, some clinicians consider post streptococcal arthritis to be an incomplete form of acute rheumatic fever (see Chapter 229.1). Certain HLA DRB1 types may predispose children to development of either poststreptococcal arthritis (HLA DRB101) or acute rheumatic fever (HLA DRB116). Transient synovitis (toxic synovitis), another form of postinfec tious arthritis, typically affects the hip, often after an upper respiratory tract infection (see Chapter 719.2). Males 3 10 years of age are most often affected and have acute onset of severe pain in the hip (groin), with referred pain to the thigh or knee, lasting approximately 1 week. ESR and white blood cell count are usually normal. Radiologic or ultra sound examination may confirm widening of the joint space secondary to an effusion. Aspiration of joint fluid is often necessary to exclude septic arthritis and typically results in dramatic clinical improvement. The trigger is presumed to be viral, although responsible microbes have not been identified. Nonsuppurative arthritis has been reported in children, usually adolescent males, in association with severe truncal acne. Patients often have fever and persistent infection of the pustular lesions. Pyo genic (sterile) arthritis, pyoderma gangrenosum, and acne (cystic) syndrome, an autosomal dominant disorder caused by a pathogenic variant in the PSTPIP1 gene, is a difficult to treat but rare autoin flammatory disorder that has responded to anakinra or antitumor necrosis factor antibody therapy in a few patients (see Chapter 710). Recurrent episodes of erosive arthritis begin in childhood; cystic acne and the painful ulcerating lesions of pyoderma gangrenosum begin during adolescence. Recurrent episodes may also be associated with a sterile myopathy and may last for several months. Infective endocarditis can be associated with arthralgia, arthritis, or signs suggestive of vasculitis, such as Osler nodes, Janeway lesions, and Roth spots. Postinfectious arthritis, perhaps because of immune complexes, also occurs in children with N. gonorrhoeae, Neisseria men ingitidis, Haemophilus influenzae type b, and Mycoplasma pneumoniae infections. DIAGNOSIS A recent GU or GI infection may suggest the diagnosis of reactive arthritis, but there is no diagnostic test. A complete blood count, acute phase reactants, complete metabolic panel, and urinalysis may be helpful to exclude other etiologies. Although stool or urogenital tract cultures can be performed in an attempt to isolate it, the trig gering organism is not typically found at the time arthritis presents. Imaging findings are nonspecific or normal. Documenting previous streptococcal infection with antibody testing (anti streptolysin O and anti DNAse B) may help to diagnose postinfectious arthritis. Serum sickness associated with the antibiotic treatment of preceding infection must be excluded. Because the preceding infection can be remote or mild and often not recalled by the patient, it is also important to rule out other causes of arthritis. Acute and painful arthritis affecting a single joint suggests septic arthritis, mandating joint aspiration. Osteomyelitis may cause pain and an effusion in an adjacent joint but is more often associated with focal bone pain and tenderness at the |
6,768 | site of infection. Arthritis affecting a single joint, particularly the knee, may also be secondary to Lyme disease in endemic areas. The diagnosis of postinfectious arthri tis is often established by exclusion and after the arthritis has resolved. Arthritis associated with GI symptoms or abnormal liver function test results may be triggered by infectious or autoimmune hepatitis. Arthritis or spondyloarthritis may occur in children with IBD, such as Crohn disease or ulcerative colitis (see Chapters 382.1 and 382.2). Parvovirus infection, macrophage activation (hemophagocytic) syn drome, and leukemia should be strongly considered when two or more blood cell lines are low or progressively decrease in a child with arthritis. Persistent arthritis (6 weeks) suggests the possibility of a chronic rheumatic disease, including JIA (see Chapter 196) and SLE (see Chapter 199). TREATMENT Specific treatment is unnecessary for most cases of reactive or postin fectious arthritis. Nonsteroidal antiinflammatory drugs (NSAIDs) are often needed for management of pain and functional limitation. Unless ongoing Chlamydia infection is suspected, attempts to treat the offending organism are not warranted. If swelling or arthralgia recurs, further evaluation may be necessary to exclude active infection or evolving rheumatic disease. Intraarticular corticosteroid injections may be given for refractory or severely involved joints once acute infec tion has been ruled out. Systemic corticosteroids or disease modifying antirheumatic drugs (DMARDs) are rarely indicated but may be con sidered for chronic disease. Participation in physical activity should be encouraged, and physical therapy may be needed to maintain nor mal function and prevent muscle atrophy. For postinfectious arthri tis caused by streptococcal disease, current recommendations include penicillin prophylaxis for at least 1 year. Long term prophylaxis is often recommended, but the duration is controversial and may need to be individualized. COMPLICATIONS AND PROGNOSIS Postinfectious arthritis after viral infections usually resolves without complications unless it is associated with involvement of other organs, such as encephalomyelitis. Children with reactive arthritis after enteric infections occasionally experience IBD months to years after onset. Both uveitis and carditis have been reported in children diag nosed with reactive arthritis. Reactive arthritis, especially after bacte rial enteric infection or GU tract infection with C. trachomatis, has the potential for evolving to chronic arthritis, particularly spondyloarthri tis (see Chapter 197). The presence of HLA B27 or significant systemic features increases the risk of chronic disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 198.1 Viruses Associated with Arthritis TOGAVIRUSES RUBIVIRUS Rubella ALPHAVIRUSES Ross River Chikungunya Onyong nyong Mayaro Sindbis Ockelbo Pogosta ORTHOPOXVIRUSES Variola virus (smallpox) Vaccinia virus Parvoviruses ADENOVIRUSES Adenovirus 7 HERPESVIRUSES Epstein Barr Cytomegalovirus Varicella zoster Herpes simplex PARAMYXOVIRUSES Mumps FLAVIVIRUS Zika virus HEPADNAVIRUS Hepatitis B ENTEROVIRUSES Echovirus Coxsackievirus B CORONAVIRUSES SARS CoV 2 Adapted from Infectious arthritis and osteomyelitis. In: Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. |
6,769 | All rights reserved. 1490 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystem inflammation and the pres ence of circulating autoantibodies directed against self antigens. SLE occurs in both children and adults, disproportionately affect ing females of reproductive age. Although nearly every organ may be affected, most commonly involved are the skin, joints, kidneys, blood forming cells, blood vessels, and the central nervous system. Systemic signs of inflammation such as fever and lymphadenopathy can also be seen. Compared with adults, children and adolescents with SLE have more severe disease and more widespread organ involvement. ETIOLOGY The pathogenesis of SLE remains largely unknown, but several factors likely influence risk and severity of disease, including genetics, hor monal milieu, and environmental exposures. A genetic predisposition to SLE is suggested by the association with specific genetic variants, including congenital deficiencies of C1q, C2, and C4, as well as several polymorphisms (e.g., interferon regulatory factor 5 and protein tyrosine phosphatase N22) and familial clustering of SLE or other autoimmune disease (Table 199.1). In addition, cer tain human leukocyte antigen (HLA) types (including HLA B8, HLA DR2, and HLA DR3) occur with increased frequency in patients with SLE. Although SLE clearly has a genetic component, its occurrence is sporadic in families and its concordance is incomplete (estimated at 25 among dizygotic twins and 2560 among monozygotic twins), suggesting nonmendelian genetics and involvement of epigenetic and environmental factors. Patients with SLE often have family members especially mothers and sisterswith SLE or various other autoimmune diseases. Because SLE preferentially affects females, especially during their reproductive years, it is suspected that hormonal factors are impor tant in pathogenesis. Of individuals with SLE, 90 are female, making female sex the strongest risk factor for SLE. Estrogens are likely to play a role in SLE, and both in vitro and animal model studies suggest that estrogen exposure promotes B cell autoreactivity. Estrogen containing oral contraceptives do not appear to induce flares in quiescent SLE, though the risk of flares may be increased in postmenopausal women receiving hormone replacement. Environmental exposures that may trigger the development of SLE remain largely unknown; certain viral infections (including Epstein Barr virus) may play a role in susceptible individuals, and ultraviolet light exposure is known to trigger SLE disease activity. Environmental influences also may induce epigenetic modifica tions to DNA, increasing the risk of SLE and drug induced lupus; in mouse models, drugs such as procainamide and hydralazine can promote lymphocyte hypomethylation, causing a lupus like syndrome. EPIDEMIOLOGY The reported prevalence of SLE in children and adolescents (1 6100,000) is lower than that in adults (20 70100,000). Prevalence of SLE is highest among patients of African, Asian, Hispanic, Native American, and Pacific Island ancestry for both adult and pediatric populations. SLE predominantly affects females, with a reported 2 5:1 ratio before puberty, 9:1 ratio during reproductive years, and return to near prepubertal ratios in the postmenopausal period. Childhood SLE |
6,770 | is rare before 5 years of age and is usually diagnosed in adolescence, with a median age at diagnosis of 11 12 years. Up to 20 of all individuals with SLE are diagnosed before age 16 years. Pediatric onset SLE (pSLE) is defined as onset of symptoms before age 16 or 18 years. PATHOLOGY Histologic features most suggestive of SLE include findings in the kidney and skin. Renal manifestations of SLE are classified histo logically according to the criteria of the International Society of Nephrology (see Chapter 560.2). The finding of diffuse prolifera tive glomerulonephritis (class IV) significantly increases the risk for renal morbidity. Renal biopsies are helpful to establish the diag nosis of SLE and to stage disease. Immune complexes are commonly found with full house deposition of immunoglobulin and comple ment. The characteristic discoid rash depicted in Figure 199.1D is characterized on biopsy by hyperkeratosis, follicular plugging, and infiltration of mononuclear cells into the dermal epidermal junc tion. The histopathology of photosensitive rashes can be nonspe cific, but immunofluorescence examination of both affected and nonaffected skin may reveal deposition of immune complexes within the dermal epidermal junction. This finding is called the lupus band test, which is specific for SLE. PATHOGENESIS A hallmark of SLE is the generation of autoantibodies directed against self antigens, particularly nucleic acids. These intracellular antigens are ubiquitously expressed but are usually inaccessible and cloistered within the cell. During cell necrosis or apoptosis, the anti gens are released. SLE skin cells are highly susceptible to damage from ultraviolet light, and the resulting cell death leads to release of cell contents, including nucleic antigens. Individuals with SLE may have impaired apoptosis or impaired ability to clear cell debris, causing prolonged exposure to nucleic antigens in the bloodstream and increased opportunity for recognition by immune cells, lead ing to B cell stimulation and autoantibody production. Circulating autoantibodies form immune complexes and deposit in tissues, lead ing to local complement activation, initiation of a proinflammatory cascade, and, ultimately, tissue damage. Antibodies to double stranded DNA (dsDNA) can form immune complexes, deposit in glomeruli, and initiate inflammation leading to glomerulonephritis. However, many individuals with SLE have circulating antibodies to dsDNA yet do not have nephritis, suggesting that autoantibodies are not the only pathway leading to end organ damage in SLE. Both the innate and adaptive arms of the immune system have been implicated in the dysregulation of the immune system seen in SLE. High levels of interferon production by plasmacytoid dendritic cells promote expression of other proinflammatory cytokines and chemokines, maturation of monocytes into myeloid dendritic cells, promotion of autoreactive B and T cells, and loss of self tolerance. Nearly 85 of patients with SLE exhibit this cytokine profile, known as the type I interferon signature. Other cytokines with increased expression in SLE include interleukin (IL) 1, IL 2, IL 6, IL 10, IL 12, IL 17, and IL 21; antitumor necrosis factor ; interferon ; and B lymphocyte stimulator (BLyS), also known as B cellactivating fac tor |
6,771 | (BAFF). Both B and T cells demonstrate functional impairments in SLE. In active SLE, B cell populations have impaired tolerance and increased autoreactivity, enhancing B cells ability to produce auto antibodies after exposure to self antigen. In addition, cytokines such as BLySBAFF may promote abnormal B cell number and function. T cell abnormalities in SLE include increased numbers of memory T cells and decreased number and function of T regulatory cells. SLE T cells display aberrant signaling and increased autoreactivity. As a result, they are resistant to attrition by normal apoptosis pathways. In addition, a neutrophil signature can be identified in 65 of adult SLE patients and has recently been recognized as a potential biomarker for active lupus nephritis. Chapter 199 Systemic Lupus Erythematosus Rebecca E. Sadun and Stacy P. Ardoin Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 199 u Systemic Lupus Erythematosus 1491 Table 199.1 Reviewed Proteins and Genes Associated with Monogenic Forms of Systemic Lupus Erythematosus and Lupus Like Phenotypes PROTEIN GENE INHERITANCE MECHANISM FEMALE TO MALE PATIENT RATIO ASSOCIATED SYMPTOMS C1q C1QA, C1QB, C1QC Autosomal recessive Complement deficiency 1:1 SLE (cutaneous, renal, CNS, arthritis, ANA), young age onset, recurrent bacterial infections C1rs C1R, C1S Autosomal recessive Complement deficiency 1:1 SLE (fever, cutaneous, arthritis, renal, ANA, ENA), recurrent infections, encapsulated bacteria, Hashimoto thyroiditis C2 C2 Autosomal recessive Complement deficiency 7:1 SLE (cutaneous, arthritis), young age onset, type 1 diabetes C3 C3 Autosomal recessive Complement deficiency 1:1 Recurrent sinopulmonary infections, lupus like syndrome, glomerulonephritis C4 C4A, C4B Autosomal recessive Complement deficiency 1:1 SLE (severe photosensitive rash, renal, ANA, Ro), young age onset TREX1DNASE III TREX1 Autosomal dominant (FCL), autosomal recessive and dominant (AGS) Abnormal DNA clearance leading to IFN activation Likely 1:1 FCL, AGS, SLE MDA5 IFIH1 Autosomal dominant Activation of IFN production Likely 1:1 AGS, SLE, FCL, IgA deficiency SAMHD1 SAMHD1 Autosomal recessive and dominant Abnormal DNA or RNA clearance leading to IFN production Likely 1:1 AGS, SLE, FCL, photosensitivity RNaseH2 RNASH2 Autosomal dominant and recessive Abnormal RNA clearance leading to IFN production Likely 1:1 AGS, SLE ADAR1 ADAR1 Mainly autosomal dominant Abnormal RNA clearance leading to IFN production Likely 1:1 AGS, SLE STING TMEM173 Autosomal dominant Activation of IFN production 1:1 SAVI, FCL, SLE DNase I DNASE1 Autosomal dominant Abnormal DNA clearance break intolerance Likely 1:1 SLE (dsDNA), adolescent onset, Sjgren syndrome DNase 1 like 3 DNASE1L3 Autosomal recessive Abnormal DNA clearance break intolerance 1:2 SLE (hypocomplementemia, dsDNA, cANCA, renal), HUVS DNASE2 DNASE2 Possible autosomal recessive Abnormal DNA clearance 1:1 Neonatal onset cytopenias, hepatosplenomegaly, arthritis, nephritis Protein kinase C delta PRKCD Autosomal recessive; dominant Disrupts B cell proliferation and apoptosis, NK cell activity 1:1 Early onset SLE nephritis, lymphoproliferation autoimmunity RasMAPK Pathway KRAS GoF Somatic mutation Altered cell proliferation, differentiation, apoptosis Likely 1:1 Pancytopenia, autoantibodies, arthritis, hepatosplenomegaly, pericarditis Noonan syndrome NRAS GoF Somatic mutation Altered cell proliferation, differentiation apoptosis |
6,772 | Likely 1:1 Chilblain lupus, pancytopenia, autoantibodies AGS, Aicardi Goutires syndrome; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; CNS, central nervous system; dsDNA, double stranded DNA; ENA, extractable nuclear antigen antibody; FCL, familial chilblain lupus; GOF, gain of function; HUVS, hypocomplementemic urticarial vasculitis syndrome; IFN, interferon; IgA, immunoglobulin A; SAVI, STING associated vasculopathy with onset in infancy; SLE, systemic lupus erythematosus. Modified from Hiraki LT, Silverman ED. Genomics of systemic lupus erythematosus: insights gained by studying monogenic young onset systemic lupus erythematosus. Rheum Dis Clin N Am. 2017;43:415434, Table 1, p. 417. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1492 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) CLINICAL MANIFESTATIONS Any organ system can be involved in SLE, so the potential clinical mani festations are myriad (Table 199.2). The presentation of SLE in childhood or adolescence differs somewhat from that seen in adults. The most com mon presenting complaints of children with SLE include fever, fatigue, hematologic abnormalities, arthralgia, and arthritis. Arthritis is usually present in the first year of diagnosis; arthritis may be painful or painless swelling, often with stiffness in the morning, and is usually a symmetric polyarthritis affecting large and small joints. Tenosynovitis is often pres ent, but joint erosions or other radiographic changes are rare. Renal disease in SLE is often asymptomatic, underscoring the need for careful monitoring of blood pressure and urinalyses; in adolescents, SLE can present with nephrotic syndrome andor renal failure, with the predominant symptoms being edema, fatigue, changes in urine color, and nauseavomiting. Because SLE symptoms and findings may develop seri ally over several years and not all be present simultaneously, the diagnosis may require longitudinal follow up. SLE is often characterized by periods of flare and disease quiescence but may follow a more smoldering disease course. The neuropsychiatric complications of SLE may occur with or without apparently active SLE, posing a particularly difficult diagnostic challenge in adolescents, who are already at high risk for mood disorders (Fig. 199.2). Long term complications of SLE and its therapy, including accelerated atherosclerosis and osteoporosis, become clinically evident in early to middle adulthood. SLE is a disease that evolves over time in each affected individual, and new manifestations arise even many years after diagnosis. A B C D Fig. 199.1 Mucocutaneous manifestations of SLE. A, Malar rash. B, Vasculitic rash on toes. C, Oral mucosal ulcers. D, Discoid rash in malar distribution. Table 199.2 Potential Clinical Manifestations of Systemic Lupus Erythematosus TARGET ORGAN POTENTIAL CLINICAL MANIFESTATIONS Constitutional Fatigue, anorexia, weight loss, fever, lymphadenopathy Musculoskeletal Arthritis, myositis, tendonitis, arthralgias, myalgias, avascular necrosis, osteoporosis Skin Malar rash, discoid (annular) rash, photosensitive rash, cutaneous vasculitis (petechiae, palpable purpura, digit ulcers, gangrene, urticaria), livedo reticularis, periungual capillary abnormalities, Raynaud phenomenon, alopecia, oral and nasal ulcers, panniculitis, chilblains, alopecia Renal Hypertension, proteinuria, hematuria, edema, nephrotic syndrome, renal failure Cardiovascular |
6,773 | Pericarditis, myocarditis, conduction system abnormalities, Libman Sacks endocarditis Neurologic Seizures, psychosis, cerebritis, stroke, transverse myelitis, depression, cognitive impairment, headaches, migraines, pseudotumor, peripheral neuropathy (mononeuritis multiplex), chorea, optic neuritis, cranial nerve palsies, acute confusional states, dural and cerebral venous sinus thrombosis Pulmonary Pleuritis, interstitial lung disease, pulmonary hemorrhage, pulmonary hypertension, pulmonary embolism Hematologic Immune mediated cytopenias (hemolytic anemia, thrombocytopenia or leukopenia), anemia of chronic inflammation, hypercoagulability, thrombocytopenic thrombotic microangiopathy, macrophage activation syndrome Gastroenterology Hepatosplenomegaly, pancreatitis, vasculitis affecting bowel, protein losing enteropathy, peritonitis Ocular Retinal vasculitis, scleritis, episcleritis, papilledema, dry eyes, optic neuritis PSYCHOSIS HEADACHECHOREA COGNITIVE DYSFUNCTION SEIZURES MOOD DISORDER CEREBRO VASCULAR DISEASE Fig. 199.2 Overlapping neuropsychiatric symptoms in pediatric SLE. Patients with pediatric SLE most commonly have more than one neu ropsychiatric symptomin particular for seizures. (From Silverman E, Eddy A. Systemic lupus erythematosus. In Cassidy JT, Petty RE, Laxer RM, et al., eds. Textbook of Pediatric Rheumatology, 6th ed. Philadel phia: Saunders; 2011: Fig. 21 17, p. 329.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 199 u Systemic Lupus Erythematosus 1493 DIAGNOSIS The diagnosis of SLE requires a comprehensive clinical and laboratory assessment revealing characteristic multisystem disease and excluding other etiologies, including infection and malignancy. Classification criteria for SLE were developed to identify appropriate subjects for clinical trials but are often used as guideposts for SLE diagnosis. Over the past several decades, SLE classification criteria have undergone serial updates. Both the American College of Rheumatology (ACR) 1997 Revised Classification Table 199.3 Comparison of 1997 American College of Rheumatology and 2012 Systemic Lupus International Collaborating Clinics (SLICC) Classification Criteria for Systemic Lupus Erythematosus 1997 ACR CRITERIA 2012 SLICC CRITERIA CLINICAL CRITERIA Acute cutaneous lupus Malar rash Malar rash, bullous lupus, toxic epidermal necrolysis variant of SLE, maculopapular lupus rash, photosensitive lupus rash, or subacute cutaneous lupus Chronic cutaneous lupus Discoid rash Classic discoid rash, hypertrophic (verrucous) lupus, lupus panniculitis (profundus), mucosal lupus, lupus erythematous tumidus, chilblains lupus, or discoid lupuslichen planus overlap Mucosal ulcers Oral or nasal ulcers Oral (palate, buccal, tongue) or nasal ulcers Other cutaneous Photosensitivity Nonscarring alopecia Arthritis Nonerosive arthritis in two peripheral joints Synovitis in two peripheral joints Serositis Pleuritis or pericarditis Pleurisy or pericardial pain 1 day, pleural effusion or rub, pericardial effusion or rub, or ECG evidence of pericarditis Renal Persistent proteinuria representing 500 mg24 hr or cellular casts Urine proteincreatinine ratio representing 500 mg protein24 hr or red blood cell casts Neurologic Seizure or psychosis Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, or acute confusional state Hematologic Hemolytic anemia, leukopenia (4,000 mm3, lymphopenia (1,500mm3), or thrombocytopenia (100,000mm3) Hemolytic anemia Leukopenia (4,000mm3) or lymphopenia (1,000mm3) Thrombocytopenia (100,000mm3) IMMUNOLOGIC Positive anti double stranded antibody or positive anti Smith antibody Positive antiphospholipid antibody (false positive rapid plasma reagin test, positive lupus anticoagulant test result, or elevated anticardiolipin antibody level IgG or IgM) Positive ANA Positive anti double |
6,774 | stranded DNA antibody Positive anti Smith antibody Positive antiphospholipid antibody (false positive rapid plasma regain test, positive lupus anticoagulant test, medium to high titer anticardiolipin antibody level IgA, IgG, IgM, or positive anti B2 glycoprotein I antibody IgA, IgG, IgM) Low C3, C4, or Ch50 level Positive direct Coombs test (in the absence of hemolytic anemia) Positive ANA For the 1997 ACR Criteria, the presence of 4 of 11 cumulative criteria establishes the classification of SLE. For the 2012 SLICC criteria, the presence of 4 cumulative criteria also establishes the classification of SLE; however, at least 1 clinical criterion and at least 1 immunologic criterion are required. In addition, the presence of biopsy proven lupus nephritis with positive ANA or antidouble stranded DNA satisfies the 2012 SLICC criteria. For both sets of classification criteria, all items must be attributable to lupus and not an alternate cause (e.g., medication side effect). Each bullet point counts as a single criterion whether 1 or more definitions are satisfied. Adapted from Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus, Arthritis Rheum 1997;40:1725; and from Petri M, et al: Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus, Arthritis Rheum 2012;64:2677 2686. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1494 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Criteria for SLE and the 2012 Systemic Lupus International Collaborat ing Clinics (SLICC) Classification Criteria (Table 199.3) are validated in childhood onset SLE populations, with the SLICC Criteria achieving higher sensitivity and the 1997 ACR Criteria achieving better specificity. In both the 1997 ACR and 2012 SLICC Criteria, a positive antinuclear antibody (ANA) test result is not required for the diagnosis of SLE; however, ANA negative lupus is extremely rare. The ANA test is very sensitive for SLE (9599) but is not very specific (50). The ANA may become positive many years before a diagnosis of SLE is established; however, most asymp tomatic ANApositive patients will never develop SLE. More recently, the 2019 European League Against RheumatismAmerican College of Rheumatology (EULARACR) SLE Classification Criteria (Fig. 199.3) provided a different approach by requiring a positive antinuclear antibody (ANA) test result at a titer 1:80. Allthough the 2019 EULARACR criteria have excellent sensitivity and specificity in the adult SLE population, they are still being validated in pediatric populations. Anti dsDNA and anti Smith antibodies are specific for SLE (98) but not as sensitive (4065) as the ANA. Hypocomplementemia was not included in earlier classification criteria, but has been added to the two most recent classification criteria. The 2012 SLICC Criteria also added as criteria nonscarring alopecia, additional cutaneous and neurologic manifestations, and a positive direct Coombs test in the absence of hemolytic anemia. If absent, do not classify as SLE If |
6,775 | present, apply additive criteria Entry criterion Antinuclear antibodies (ANA) at a titer of 1:80 on HEp2 cells or an equivalent positive test (ever) .Do not count a criterion if there is a more likely explanation than SLE..Occurrence of a criterion on at least one occasion is sufficient..SLE classification requires at least one clinical criterion and 10 points..Criteria need not occur simultaneously..Within each domain, only the highest weighted criterion is counted toward the total score. Additive criteria Total score: Classify as systemic lupus erythematosus with a score of 10 or more if entry criterion fulfilled. Clinical domains and criteria Constitutional Fever Antiphospholipid antibodies Anticardiolipin antibodies OR Anti2GP1 antibodies OR Lupus anticoagulant Complement proteins Low C3 OR low C4 Low C3 AND low C4 SLEspecific antibodies AntidsDNA antibody OR AntiSmith antibody Hematologic Leukopenia Thrombocytopenia Autoimmune hemolysis Neuropsychiatric Delirium Psychosis Seizure Mucocutaneous Nonscarring alopecia Oral ulcers Subacute cutaneous OR discoid lupus Acute cutaneous lupus Serosal Pleural or pericardial effusion Acute pericarditis Musculoskeletal Joint involvement Renal Proteinuria 0.5 g24hr Renal biopsy class II or V lupus nephritis Renal biopsy class Ill or IV lupus nephritis 2 2 6 5 6 4 8 10 6 2 2 4 6 3 4 4 3 4 2 3 5 Weight Immunology domains and criteria Weight Fig. 199.3 Classification criteria for systemic lupus erythematosus (SLE). Additional criteria items within the same domain will not be counted. In an assay with 90 specificity against relevant disease controls. (From Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against RheumatismAmerican College of Rheumatology classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2019;719:14001412.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 199 u Systemic Lupus Erythematosus 1495 DIFFERENTIAL DIAGNOSIS Multiorgan disease is the hallmark of SLE, and given its wide array of potential clinical manifestations, SLE is in the differential diagnosis of many clinical scenarios, including unexplained fevers, joint pain or arthritis, rash, cytopenias, nephritis, nephrotic syndrome, pleural or pericardial effusions or other cardiopulmonary abnormalities, and new onset psychosis or seizures. For patients ultimately diagnosed with pediatric SLE, the initial differential diagnosis often includes infections (sepsis, Epstein Barr virus, parvovirus B19, endocarditis), malignan cies (leukemia and lymphoma), poststreptococcal glomerulonephritis, other rheumatologic conditions (juvenile idiopathic arthritis, vasculi tides), and drug induced lupus (Table 199.4). Drug induced lupus refers to the presence of SLE manifestations triggered by exposure to specific medications, including hydrala zine, minocycline, many anticonvulsants, sulfonamides, antiar rhythmic agents, and other drugs (Table 199.5). In individuals prone to SLE, these agents may act as a trigger for true SLE, but more commonly these agents provoke a reversible lupus like syndrome. Unlike SLE, drug induced lupus affects males and females equally. A genetic predisposition toward slow drug acetylation may increase the risk of drug induced lupus. Circulating antihistone antibodies are often present in drug induced SLE; these antibodies are only detected in up |
6,776 | to 20 of individuals with SLE. Hepatitis, which is rare in SLE, is more common in drug induced lupus. Individuals with drug induced lupus are less likely to demonstrate antibodies to dsDNA, hypocomplementemia, and significant renal or neuro logic disease. In contrast to SLE, manifestations of drug induced lupus typically resolve after withdrawal of the offending medica tion; however, complete recovery may take several months to years, requiring treatment, often with hydroxychloroquine, NSAIDs, and or corticosteroids. LABORATORY FINDINGS A positive ANA test is present in 9599 of individuals with SLE. The ANA has poor specificity for SLE, as up to 20 of healthy indi viduals also have a positive ANA test result, making the ANA a poor screen for SLE when used in isolation. After diagnosis, ANA titers are not reflective of disease activity; therefore repeat ANA testing in SLE patients is not helpful. Antibodies to dsDNA are specific for SLE, and in many individuals, anti dsDNA levels correlate with disease activity, particularly in those with significant nephritis. Anti Smith antibody, although found specifically in patients with SLE, does not correlate with disease activity. Serum levels of total hemolytic com plement (CH50), C3, and C4 are typically decreased in active disease and often improve with treatment. Table 199.6 lists autoantibodies Table 199.4 Main Differential Diagnoses of SLE (SLE Mimickers) OTHER CONNECTIVE TISSUE DISEASES Sjgren (SSA), dermatomyositis (rash), mixed connective tissue disease INFECTIOUS DISEASES Endocarditis; hepatitis A, B, C, E; parvovirus B19; HIV; EBV; CMV; Lyme; disseminated gonococcal arthritis; toxoplasmosis; histoplasmosis; mycobacterial diseases; tinea faciei; visceral leishmaniasis; Whipple disease HEMATOLOGIC MALIGNANCIES Hodgkin lymphoma, myelodysplastic syndromes, angioimmunoblastic T cell lymphoma SOLID TUMORS AND PARANEOPLASTIC SYNDROMES Thymoma, carcinoma of the lung, breast, and ovary with paraneoplastic syndromes OTHER DISEASES Meigs and Pseudo Meigs syndrome Multiple sclerosis Castleman disease Interferonopathies (monogenic SLE) Still disease (and other autoinflammatory diseases) Evans syndrome (with primary immune deficiency) Complement deficiency Hypocomplementemic urticarial vasculitis Schizophrenia and other psychoses Kikuchi disease IgG4 related disease Chilblains (cold induced) Ackerman syndrome and erythema elevatum diutinum with polyarthritis Drug induced lupus and drug induced polyarthritis Graft versus host disease Systemic manifestations of atrial myxoma Prolidase deficiency From Chasset F, Richez C, Martin T, et al. Rare diseases that mimic systemic lupus erythematosus (lupus mimickers). Joint Bone Spine. 2019;86:165171, Table 1, p. 166 Copyright Elsevier Masson SAS. Table 199.5 Medications Associated with Drug Induced Lupus DEFINITE ASSOCIATION Minocycline, procainamide, hydralazine, isoniazid, penicillamine, diltiazem, interferon , methyldopa, chlorpromazine, etanercept, infliximab, adalimumab PROBABLE ASSOCIATION Phenytoin, ethosuximide, carbamazepine, sulfasalazine, amiodarone, quinidine, rifampin, nitrofurantoin, blockers, lithium, captopril, interferon , hydrochlorothiazide, glyburide, docetaxel, penicillin, tetracycline, statins, gold, valproate, griseofulvin, gemfibrozil, propylthiouracil Table 199.6 Autoantibodies Commonly Associated with Systemic Lupus Erythematosus (SLE) ANTIBODY CLINICAL ASSOCIATION Antidouble stranded DNA (anti dsDNA) Correlates with disease activity, especially nephritis, in some with SLE Anti Smith antibody (anti Sm) Specific for the diagnosis of SLE Anti ribonucleoprotein antibody (anti RNP) Increased risk for Raynaud phenomenon, interstitial lung disease, and pulmonary hypertension Anti Ro antibody (anti SSA) Anti La antibody (anti SSB) Associated with sicca |
6,777 | syndrome May suggest diagnosis of Sjgren syndrome Increased risk of neonatal lupus in offspring (congenital heart block) May be associated with cutaneous and pulmonary manifestations of SLE May be associated with isolated discoid lupus Antiphospholipid antibodies (including lupus anticoagulant and anti cardiolipin or anti beta 2 glycoprotein antibodies) Increased risk for venous and arterial thrombotic events Antihistone antibodies Present in a majority of patients with drug induced lupus May be present in SLE Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1496 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) found in SLE along with their clinical associations. Hypergamma globulinemia is a common but nonspecific finding. Inflammatory markers, particularly the erythrocyte sedimentation rate, are often elevated in active disease. C reactive protein (CRP) correlates less well with disease activity; significantly elevated CRP values often reflect infection, whereas chronic mild elevation of CRP may indicate increased cardiovascular risk. Antiphospholipid antibodies, which increase clotting risk, can be found in up to 66 of children and adolescents with SLE. The primary antiphospholipid antibodies are lupus anticoagulant, anticardiolipin, and antibeta 2 glycoprotein antibodies. When an arterial or venous clotting event occurs in the presence of an antiphospholipid antibody, antiphospholipid antibody syndrome is diagnosed. Antiphospho lipid antibody syndrome can occur in the context of SLE (secondary) or independent of SLE (primary) (see Chapter 528). Rarely, antiphos pholipid antibodies can result in catastrophic antiphospholipid syn drome, a condition in which clots affect three or more organstissues simultaneously; this condition has a very high mortality rate. TREATMENT Treatment of SLE is tailored to the individual and is based on specific disease manifestations and medication tolerability. For all patients, sunscreen and avoidance of prolonged direct sun exposure and other ultraviolet light may help control disease and should be reinforced at every visit with the patient. Hydroxychloroquine is recommended for all individuals with SLE when tolerated. In addition to treating mild SLE manifestations such as rash and mild arthritis, hydroxychloroquine prevents SLE flares, improves lipid profiles, and may have a beneficial impact on mortality and renal outcomes. Potential toxicities include retinal pigmentation that leads to vision impairment; therefore annual ophthalmology exams are recommended for patients taking hydroxychlo roquine, including automated visual field testing and spectral domain optical coherence tomography (SD OCT). Given that risk factors for ocular toxicity include duration of use and dose, hydroxychloroquine in SLE should not be prescribed at doses greater than 5 mgkg to a maximum of 400 mg daily. Corticosteroids are a treatment mainstay for significant manifes tations of SLE and work quickly to improve acute deterioration; side effects often limit patient adherence, especially in adolescence, and potential toxicities are worrisome. It is important to limit the dose and length of exposure to corticosteroids whenever possible. Potential consequences of corticosteroid therapy include growth disturbance, weight gain, striae, acne, hyperglycemia, hypertension, cataracts, avas cular |
6,778 | necrosis, and osteoporosis. The optimal dosing of corticosteroids in children and adolescents with SLE remains unknown; severe dis ease is often treated with high doses of intravenous methylpredniso lone (e.g., 30 mgkgday to a maximum of 1,000 mg for each of 3 days, sometimes followed by a period of weekly pulses) andor high doses of oral prednisone (often starting at 1 mgkgday). As disease manifestations improve, corticosteroid dosages are gradually tapered over months. For most patients it is necessary to introduce a steroid sparing immunosuppressive medication in order to limit cumulative steroid exposure. Steroid sparing immunosuppressive agents for the treatment of pediatric SLE include methotrexate, leflunomide, azathioprine, myco phenolate mofetil, tacrolimus, cyclophosphamide, rituximab, and beli mumab. Methotrexate, leflunomide, and azathioprine are often used to treat persistent moderate disease, including arthritis, significant cuta neous or hematologic involvement, and pleural disease. Cyclophos phamide, mycophenolate mofetil, and azathioprine are appropriate for the treatment of lupus nephritis, whereas mycophenolate mofetil and rituximab are often used for the treatment of significant hematologic manifestations, including severe leukopenia, hemolytic anemia, or thrombocytopenia. Cyclophosphamide, usually administered intravenously, is reserved for the most severe, potentially life threatening SLE manifestations, such as renal, neurologic, and cardiopulmonary disease. Although cyclophosphamide is highly effective in controlling disease, the poten tial toxicities are significant, including cytopenias, infection, hemor rhagic cystitis, premature gonadal failure, and increased risk of future malignancy. Attention to adequate hydration can attenuate the risk of hemorrhagic cystitis. Fortunately, young females are at much lower risk of gonadal failure than older women, and the use of gonadotropin releasing hormone agonists, such as leuprolide acetate, may help pre vent gonadal failure. The Childhood Arthritis Rheumatology Research Alliance (CARRA) has developed a consensus treatment plan for induction therapy of newly diagnosed proliferative lupus nephritis (class III and IV) that is specific to the pSLE population; the treatment plan is considered necessary for class III and IV lupus nephritis but also appropriate for certain patients with other classes of lupus nephritis. The CARRA treatment plan advises 6 months of induction therapy with either cyclophosphamide (given per the National Institutes of Health NIH protocol as 500 1,000 mgm2 IV monthly) or myco phenolate mofetil (dosed as 600 mgm2 bid up to 1,500 mg bid), used in combination with one of three standardized glucocorticoid regi mens. For patients who fail to achieve a partial response in 6 months, it is appropriate to switch agents. For adult weight adolescents, the cyclophosphamide dosing regimen used in the Euro Lupus Nephritis Trial can be considered in lieu of the previous 6 month therapy in an effort to reduce toxicity from cyclophosphamide exposure. Per this protocol, a fixed dose of 500 mg is given every 2 weeks for 3 months; in adults, this regimen is althought to reduce adverse effects while maintaining comparable efficacy for lupus nephritis, though this reg imen has not been studied specifically in pediatric lupus. It should be noted that oral medication adherence is very poor in pSLE, and this must be taken into consideration when |
6,779 | weighing the benefits of an IV infusion versus a twice daily oral medication such as mycophenolate mofetil. After the 6 month induction therapy, maintenance therapy for lupus nephritis consists of quarterly IV cyclophosphamide (dosed 500 1,000 mgm2 once every 3 months), mycophenolate, or azathio prine, with mycophenolate generally being the preferred agent. Main tenance therapy is typically continued for a minimum of 30 months after the completion of induction therapy, but in many circumstances, it is continued longer. Calcineurin inhibitors such as tacrolimus are often adjunct therapy in the treatment of refractory lupus nephritis. Voclosporin, Food and Drug Administration (FDA)approved for adults with lupus nephri tis, awaits pediatric study. Clinical trial data on the use of rituximab in SLE with treatment resistant glomerulonephritis has been largely disappointing, but post hoc analysis from the LUNAR study suggests there may be benefit for subpopulations of SLE patients. The FDA has approved the use of belimumab, a monoclonal antibody against BLyS BAFF, for the treatment of lupus in adults and children; when added to standard SLE therapy, belimumab improves markers of disease activity in renal and nonrenal lupus. Belimumab has been shown to improve renal outcomes in adults, and while it is not used as monotherapy to treat lupus nephritis, it can be used in addition to standard therapy to help achieve renal remission without substantial increase in risk of infectious complications. Anifrolumab (a monoclonal antibody to the interferon receptor), achieved 2021 FDA approval for treatment of adult nonrenal SLE, and studies in lupus nephritis and pediatric lupus are forthcoming. Several novel therapies are in the pipeline for the treatment of SLE and lupus nephritis, including Janus kinase inhibitors. Given the lifelong nature of SLE, optimal care of children and adoles cents with this disease also involves preventive practices. Owing to the enhanced risk of atherosclerosis in SLE, attention to cholesterol levels, smoking status, body mass index, blood pressure, and other traditional cardiovascular risk factors is warranted. Even though the Atheroscle rosis Prevention in Pediatric Lupus Erythematosus (APPLE) study failed to support placing all children with SLE on a statin, post hoc analyses suggest that statins can be considered for primary prevention of atherosclerotic disease in certain clinical circumstances, particularly pubertal patients with an elevated CRP. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 199 u Systemic Lupus Erythematosus 1497 SLE patients with antiphospholipid antibody syndrome (antiphos pholipid antibodies and a history of arterial or venous clot or preg nancy morbidity) are treated with long term anticoagulation to prevent thrombotic events; for SLE patients who are antiphospholipid antibody positive without a history of clots, many pediatric rheumatologists pre scribe aspirin 81 mg daily. For all SLE patients, adequate intake of calcium and vitamin D is nec essary to prevent future osteoporosis, particularly as vitamin D levels are lower in pSLE patients compared with age matched healthy |
6,780 | controls. It is worth noting recent studies suggest a link between hypovitaminosis D and SLE susceptibility and also offer an emerging role for vitamin D in immunomodulation. Infections, particularly pneumococcal disease, commonly com plicate SLE, so routine immunization is recommended, including the annual influenza vaccination, SARS CoV 2 vaccination, and vaccination against human papilloma virus (HPV). In addition, pSLE patients age 6 or older should receive a dose of PPSV23 at least 8 weeks after completing all recommended pneumococcal vac cine series with PCV13 or PCV15. Many of the immunosuppressant medications used in SLE contraindicate administration of live vac cines. Prompt attention to febrile episodes should include an evalu ation for serious infections. Because pSLE patients are at high risk for developing anxiety and depression, screening for depression is important. Peer support and cognitive behavioral therapy interven tions reduce pain and enhance resilience in pSLE. Pregnancy can worsen SLE, and obstetric complications are com mon. In addition, many medications used to treat SLE are terato genic. As a consequence, it is important to counsel adolescent girls about these risks and facilitate access to appropriate contraceptive options. Hydroxychloroquine is recommended throughout preg nancy for all SLE patients, whereas other medications may need to be adjusted. COMPLICATIONS Within the first several years of diagnosis, the most common causes of death in individuals with SLE include infection and complications of glomerulonephritis and neuropsychiatric disease (Table 199.7). Over the long term, the most common causes of mortality are atherosclerosis and malignancy. The increased risk of premature atherosclerosis in SLE is not explained by traditional risk factors and is partly a result of the chronic immune dysregula tion and inflammation associated with SLE. Increased malignancy rates may be caused by immune dysregulation and exposure to medications with carcinogenic potential. Potential lupus emergen cies are noted in Table 199.8. PROGNOSIS SLE disease severity is higher in childhood onset SLE compared with adult onset SLE. Fortunately, advances in the diagnosis and treat ment of SLE have led to dramatically improved survival over the past 50 years. The 5 year and 10 year survival rates for pSLE are 99 and 97, respectively, in high income countries, although these survival rates are 85 and 79, respectively, in low and middle income coun tries. Infection contributes significantly to mortality in pediatric lupus. In addition, early in the disease course, lupus nephritis, lupus cereb ritis, and complications such as macrophage activation syndrome are primary causes of mortality, whereas later in the disease course, ath erosclerosis and malignancy become larger contributors to mortality. Given their long burden of disease, children and adolescents with SLE face high risks of future morbidity and mortality from the disease and its complications, as well as medication side effects. Because pSLE is a complex, chronic disease with a high risk for morbidity and mortality, optimal care for children and adolescents with SLE includes treatment by pediatric rheumatologists in a multidisciplinary clinic with access to a full complement of pediatric subspecialists. Furthermore, because SLE is a lifelong disease, |
6,781 | it is critically important to ensure an appropri ate transition to an adult model of care, which helps avoid interrup tions in rheumatology care. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 199.7 Morbidity in Childhood Lupus Renal Hypertension, dialysis, transplantation Central nervous system Organic brain syndrome, seizures, psychosis, neurocognitive dysfunction Cardiovascular Atherosclerosis, myocardial infarction, cardiomyopathy, valvular disease Immune Recurrent or severe infection, functional asplenia, malignancy Musculoskeletal Osteopenia, compression fractures, avascular necrosis Ocular Cataracts, glaucoma, retinal detachment, blindness Endocrine Diabetes, obesity, growth failure, infertility, fetal wastage From Cassidy JT, Petty RE, Laxer RM, et al., eds. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia: Saunders; 2011. Table 199.8 A Summary of Signs and Symptoms Indicative of Lupus Emergencies SIGNSSYMPTOMS DIFFERENTIAL CONSIDERATIONS Fever Evaluate for infection Consider disease flare Consider macrophage activation syndrome Thrombosishemoptysis May be arterial or venous Evaluate for antiphospholipid syndrome Chest pain Pleurisy, pericarditis, pulmonary infarctionembolus Dyspnea Pneumonitis, alveolar hemorrhage, pleural effusions, congestive heart failure Headache Vascular headaches, meningitis, thrombus, cerebrovascular accident, hypertensive crisis Altered mental status Cerebritis, hypertensive crisis, macro phage activation syndrome, stroke, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome Rash Vasculitis lesions, palpable purpura, infarction Icterus Autoimmune hemolysis Autoimmune hepatitis Petechiae Thrombotic thrombocytopenia purpura Seizure Cerebritis, infection, metabolic causes, hypertensive crisis From Harry O, Yasin S, Brunner H. Childhood onset systemic lupus erythematosus: a review and update. J Pediatr. 2018;196:2230, Table IV. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1498 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) 199.1 Neonatal Lupus Deborah M. Friedman, Jill P. Buyon, Rebecca E. Sadun, and Stacy P. Ardoin Neonatal lupus erythematosus (NLE), an entity distinct from SLE, is one of the few rheumatic disorders manifesting in the neonate. NLE is not an autoimmune disease of the fetus, but instead results from passively acquired autoimmunity, when maternal immunoglobulin G autoanti bodies cross the placenta and enter the fetal circulation. In contrast to SLE, neonatal lupus is not characterized by ongoing immune dysregula tion, although infants with neonatal lupus may be at some increased risk for development of future autoimmune disease. The vast majority of NLE cases are associated with maternal anti Ro (also known as SSA), anti La antibodies (also known as SSB), or anti RNP autoantibodies. Despite the clear association with maternal autoantibodies, their presence alone is not sufficient to cause disease, as only 2 of offspring born to mothers with anti Ro and anti La antibodies develop neona tal lupus. Increasing evidence supports the observation that generally high maternal anti Ro titers are necessary for fetal clinical disease. In the prospective evaluation of fetuses with autoimmune associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) study, the median anti Ro titer for pregnancies resulting in heart block was 5 times as high as the median anti Ro titer in unaffected pregnancies. Another |
6,782 | group identified heart block in 8 of cases with very high anti Ro antibody titers, with no cases among women with low or moderate titers. Siblings of infants with NLE have a 1520 chance of develop ing NLE. Neonatal lupus seems to be independent of the maternal health because many mothers are asymptomatic and only identified to have anti Roanti La antibodies subsequent to the diagnosis of NLE. Roughly half of the infants with NLE are born to the mothers with a defined rheumatic disease such as Sjogren syndrome or SLE. Clinical manifestations of neonatal lupus include a characteristic annular or macular rash typically affecting the face (especially the periorbital area), trunk, and scalp (Fig. 199.4). The rash can be pres ent at birth but more often appears within the first 6 8 weeks of life, after exposure to ultraviolet light, and typically lasts 3 4 months. Infants may also have cytopenias and hepatitis, each occurring in 25 of cases, but the most concerning complication is congenital heart block. Conduction system abnormalities range from prolongation of the PR interval to complete heart block, with development of progressive cardiomyopathy in the most severe cases. The noncardiac manifesta tions of neonatal lupus are usually reversible, whereas third degree congenital heart block is permanent. Conduction system abnormalities can be detected in utero by fetal echocardiogram beginning at 16 weeks of gestational age. Neonatal lupus cardiac disease has a mortality rate of 20. Cardiac NLE can manifest as heart block, cardiomyopathy, valvular dysfunction, and endocardial fibroelastosis. Fetal bradycardia from heart block can lead to hydrops fetalis. In vitro studies suggest that during cardiac development via apop tosis, Ro and La antigens may be exposed on the surface of cardiac cells in the proximity of the atrioventricular node, making the antigens accessible to maternal autoantibodies. Binding incites a local immune response, resulting in fibrosis within the conduction system and more extensive disease in fatal cases. In the skin, exposure to ultraviolet light results in cell damage and the subsequent exposure of Ro and La anti gens, inducing a similar local inflammatory response that produces the characteristic rash. Although the scant clinical trial data have been mixed, fluori nated corticosteroids (dexamethasone or betamethasone), intra venous immunoglobulin (IVIG) at 1 2 gkg maternal weight, plasmapheresis, hydroxychloroquine, and terbutaline (combined with steroids) have been used in pregnant women with anti Ro or anti La antibodies to prevent occurrence or progression of fetal car diac abnormalities. Most encouraging are retrospective cohort studies suggesting mater nal treatment with hydroxychloroquine may reduce the frequency and recurrence of congenital heart block. In a multicenter, single arm, open label clinical trial assessing the efficacy of hydroxychloroquine to prevent recurrent autoantibody associated congenital heart block, hydroxychloroquine treatment reduced the risk of recurrent heart block compared to historical controls by over 50, from 17.5 to less than 8 of pregnancies. Significant conduction system abnormalities after birth are treated with cardiac pacing and occasionally IVIG and steroids, whereas severe cardiomyopathy may require cardiac transplantation. If the |
6,783 | conduction defect is not addressed, affected children are at risk for exercise intoler ance, arrhythmias, and death. With cardiac pacing, however, children with conduction system disease in the absence of cardiomyopathy have an excellent prognosis. In a long term follow up study of 239 subjects enrolled in the Research Registry for Neonatal Lupus, 22 of subjects had cardiac dysfunction in the first year of life. Cardiac dysfunction often regressed; nevertheless, some dysfunction did appear later in childhood. Risk factors for cardiac dysfunction were being male or of low socioeconomic status and having low fetal heart rates, a longer period of pacing, or extranodal cardiac disease. In a Swedish cohort of 119 children with congenital heart block, 16.8 developed cardiomy opathy congestive heart failure. Congenital heart block increased the risk of cerebral infarctions and infections. Pacemaker treatment was associated with decreased risk of developing cerebral infarction but increased risk of infection and cardiomyopathy. Noncardiac manifestations are typically transient and are con servatively managed, often with supportive care alone. Topical ste roids can be used to treat moderate to severe NLE rash. Cytopenias may improve over time but severe cases occasionally require IVIG. Supportive care is usually appropriate for hepatic and neurologic manifestation. When the neonate clears maternal autoantibodies over the first 6 months of life, these inflammatory manifestations gradually resolve. Fig. 199.4 Neonatal lupus syndrome. Typical rash, often photosensi tive with a malar distribution, appearing as annular plaques with ery thema and scaling. (From Pain C, Beresford MW. Neonatal lupus syn drome. Paediatr Child Health. 2007;17:223227.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 199 u Systemic Lupus Erythematosus 1499 Fig. 199.5 Suggested algorithm for the management of anti Ro anti La pregnancy. All such preg nancies should include counseling and serial fetal echocardiograms. One Approach to the Management of AntiRo AntiLa Pregnancy Counseling by rheumatologist and cardiologist for hightiter antibodies; consider maternal hydroxychloroquine (especially if prior AV block) Home fetal Doppler monitor fetal echocardiography weeklybiweekly from pregnancy week 17 week 26 Postnatal EKG and echocardiogram: 1st month of life (all) and 1 year of age (optional) Normal fetal echocardiograms PR interval 140 msec (2SD), andor moderate tricuspid regurgitation 2 or alternating 23 AV block 3 (complete) AV block, no hydrops fetalis 3 (complete) AV block, severe hydrops fetalis PR interval 150 msec (3SD) In 2448 hr, repeat fetal echocardiogram Dexamethasone 48 mg daily plus IVIG Consider dexamethasone 48 mg daily for 1 week Dexamethasone 48 mg daily plus IVIG; ? apheresis; consider termination AV block with signs of EFE, myocarditis, CHF, andor hydrops Because maternal autoantibodies begin to gain access to the fetus through the placenta via FcRn at about 12 weeks gestation, all preg nant women with circulating anti Ro andor anti La antibodies, or those with a history of offspring with neonatal lupus or congenital heart block, are generally advised to |
6,784 | be monitored by a pediatric car diologist, with screening fetal echocardiography performed weekly or biweekly from 17 26 weeks of gestation. The period of greatest vulnerability is usually 18 24 weeks. If fetal bradycardia is found dur ing routine in utero monitoring in a mother never evaluated for the putative antibodies and if fetal echocardiography confirms a conduc tion defect, screening for maternal anti Ro and anti La antibodies is warranted. In pregnancies at risk for congenital heart block, maternal home monitoring of fetal heart rate using a handheld fetal heart rate monitor 2 3 times daily allows for accurate and early detection of heart rate abnormalities. A proposed management algorithm is presented in Figure 199.5. A multicenter retrospective study concluded that maternal treat ment with dexamethasone andor intravenous gamma globulin should be initiated in all cases of antiSSARo antibody cardiac manifestations, including significant firstdegree or any higher atrioventricular block, isolated endocardial fibroelastosis, or sinus bradycardia. However, other studies suggest that treatment should be individualized to fetuses at high risk and not universally instituted for isolated complete third degree block, which is generally considered immutable. The negative predictive value of antibody titers to identify pregnan cies at low risk of fetal atrioventricular block has also been studied. Excluding women with previously affected children, leveraging sam ples obtained from antiSSARo exposed pregnancies with and without fetal atrioventricular block, no case of heart block developed among subjects with antiRo52 and antiRo60 titers of 110 arbitrary units per milliliter using the multiplex bead assay of the Associated Regional and University Pathologists Laboratories (n141). Applying these 100 negative predictive value thresholds, approximately 50 of the antiRoSSA antibody pregnancies that ultimately had no fetal atrio ventricular block could be excluded from surveillance. Emerging data suggest that not all mothers with antiSSARo anti bodies require surveillance. Based on review of the literature, the Society for MaternalFetal Medicine published guidelines that rec ommended that serial fetal echocardiograms for assessment of the PR interval not be routinely performed in patients with antiSSASSB antibodies outside of a clinical trial setting but rather that, Doppler assessment of fetal heart rate during routine prenatal visits can be used to screen for fetal complete heart block. Once complete heart block develops, management is expectant, with weekly ultrasound examina tions recommended to assess for hydrops. Guidelines in this domain continue to evolve as new data advances our approach to risk stratification Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1500 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Juvenile dermatomyositis (JDM) is the most common of the juvenile idiopathic inflammatory myopathies (JIIMs), representing up to 85 of all patients with these rare vasculopathic diseases. It is characterized by proximal muscle weakness and distinctive rashes of the face and extensor joint surfaces. EPIDEMIOLOGY The incidence of |
6,785 | JDM is approximately 3 cases1 million childrenyr, with an incidence similar in White and Black non Hispanics and an apparent lower incidence in Hispanics. The peak age of onset is 7 years with a second peak of onset in late adulthood (45 64 years); however, adult onset dermatomyositis appears to be a distinctly separate entity, both in prognosis and etiology. In the United States the ratio of females to males with JDM is 2:1. Multiple cases of myositis in a single family are rare, but familial autoimmune disease may be increased in families with children who have JDM when compared to families of children without autoimmune disease. Reports of seasonal association have not been confirmed, although clusters of cases may occur. ETIOLOGY A precise understanding of the etiology and pathogenesis of JDM remains elusive; many factors that affect elements of innate and adap tive immunity have been identified as contributing to onset and per petuation of disease. Evidence suggests that the etiology of JDM is multifaceted, with a genetic predisposition influenced by an environ mental factor triggering events leading to disease pathogenesis. Genetic factors that are associated with increased susceptibility to JDM include human leukocyte antigen (HLA) alleles DRB10301, DQA10501, and DQA10301. Additionally, HLA DQA10501 is found on maternal cells present in blood and tissue samples of chil dren with JDM, an example of maternal microchimerism, which has been proposed to play an etiologic role in JDM by creating an immune response comparable to graft versus host disease (GVHD). Other polymorphisms implicated in JDM include those affecting cytokine genes such as the tumor necrosis factor (TNF) promoter and the variable number tandem repeats of the interleukin (IL) 1 receptor antagonist A1 gene. An increase in TNF may be associated with persistent immune activation leading to a longer disease course. The IL 1 receptor antagonist A1 allele is associated with the development of JIIM in White but not in Black persons, in whom the A3 allele, instead, is a possible risk factor. Environmental factors may also play a contributing role, with geographic and seasonal clustering reported. Short term increases in ultraviolet (UV) index before the onset of disease have been reported; however, no clear theory of etiology has emerged. A history of infection in the 3 months before disease onset is usually reported; multiple studies have failed to produce a causative organism. Constitutional signs and upper respiratory symptoms pre dominate, but one third of patients report preceding gastrointestinal (GI) symptoms. Group A streptococcus, upper respiratory infections, GI infections, coxsackievirus B, toxoplasma, enteroviruses, parvovirus B19, and multiple other organisms have been postulated as possible pathogens in the etiology of JDM. Despite these concerns, results of serum antibody testing and polymerase chain reaction amplification of the blood and muscle tissue for multiple infectious diseases have not been revealing. PATHOGENESIS JDM and related immune myositis syndromes are believed to be an autoimmune vasculopathic inflammatory disease affecting capillaries of multiple organs, but most notably, the skin, muscles, and GI tract (Table 200.1). Pathogenic mechanisms are |
6,786 | both immune and nonim mune with cellular and soluble constituents of the innate and adap tive immune systems and pathways of cellular injury involved. Type I interferons (IFNs), principally and , are cytokines of the innate immune system that play a significant role in the pathogenesis of JDM by modulating several immune mechanisms, including upregu lation of major histocompatibility complex (MHC) class I molecules on muscle cells; induction of proinflammatory cytokine, chemokine, and adhesion molecule production; and supporting cytotoxic effects of innate and adaptive immune cells. Plasmacytoid dendritic cells (pDCs) play an important role in JDM and are principal producers of type I IFN upon activation of Toll like receptor (TLR) 9 on their surface by viruses. Cells involved in the inflammatory cascade include mono cytesmacrophages (CD14), T cell subsets (CD4, CD8, Th17), natural killer (NK) cells (CD56), and dendritic cells (DCs). MHC class I upreg ulation induces endoplasmic reticulum (ER) stress, which results in the degradation of contractile proteins; additional downstream effects of type I IFN include autoantibody production and B cell proliferation. Galectin 9 and CXCL10 (IP 10) are two IFN related proteins that have been validated as sensitive and specific peripheral biomarkers of dis ease activity in JDM. CLINICAL MANIFESTATIONS Children with JDM present with either rash, insidious onset of weak ness, or both. Fevers, dysphagia or dysphonia, arthritis, muscle ten derness, and fatigue are also commonly reported at diagnosis (Tables 200.2 and 200.3). Certain myositis specific antibodies are associated with different phenotypic patterns of disease (Fig. 200.1). Rash develops as the first symptom in 50 of patients and appears concomitant with weakness only 25 of the time. Children often exhibit extreme photosensitivity to UV light exposure with general ized erythema in sun exposed areas. If seen over the chest and neck, this erythema is known as the shawl sign. Erythema is also commonly seen over the knees and elbows. The characteristic heliotrope rash is a blue violet discoloration of the eyelids that may be associated with periorbital edema (Fig. 200.2). Facial erythema crossing the nasolabial folds is also common, in contrast to the malar rash without nasolabial involvement typical of systemic lupus erythematosus (SLE). Classic Gottron papules are bright pink or pale, shiny, thickened, or atrophic plaques over the metacarpal phalangeal joints, proximal interphalan geal joints, and distal interphalangeal joints and occasionally on the knees, elbows, small joints of the toes, and ankle malleoli (Fig. 200.3). The rash of JDM is sometimes mistaken for eczema or psoriasis. Rarely, a thickened erythematous and scaly rash develops in children over the palms (known as mechanics hands) and soles along the flexor ten dons, which is associated with antiJo 1 antibodies. Evidence of small vessel inflammation is often visible in the nail folds and gums as individual capillaries display changes including loops, thickening, tortuosity, or loss (Fig. 200.4C). Telangiectasias may be visible to the naked eye but are more easily visualized under cap illaroscopy or with another magnifier (e.g., ophthalmoscope). Severe vascular inflammation causes cutaneous ulcers on toes, fingers, |
6,787 | axillae, or epicanthal folds. Early in disease, weakness associated with JDM is often insidious and difficult to differentiate from fatigue. It is typically symmetric, affecting proximal muscles such as the neck flexors, shoulder girdle, and hip flexors. Parents may report difficulty climbing stairs, combing hair, and getting out of bed. Examination reveals inability to perform a sit up, head lag in a child after infancy, and Gower sign (use of hands climbing on thighs to help stand from a sitting position). Patients with JDM may roll to the side rather than sit straight up from lying to com pensate for truncal weakness. Approximately half of children exhibit muscle tenderness because of muscle inflammation. Esophageal and respiratory muscles are also affected, resulting in aspiration or respiratory failure. It is essential to assess for dysphonia or nasal speech, palatal elevation with gag, dysphagia, and gastroesopha geal reflux by means of history and physical examination. If any of these are abnormal, a swallow study should be pursued. Respiratory muscle weakness can be a medical emergency and lead to respiratory failure. Chapter 200 Juvenile Dermatomyositis Jeffrey A. Dvergsten and Ann M. Reed Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 200 u Juvenile Dermatomyositis 1501 Table 200.1 Clinical Associations: Myositis Specific Antibodies (MSA) and Myositis Associated Antibodies (MAA) in Juvenile Onset Myositis (JOM) AUTOANTIBODY TARGET AUTOANTIGEN PREVALENCE () IN PATIENTS WITH JOM CLINICAL ASSOCIATIONS Common myositis specific autoantibodies are found in 4555 of patients with juvenile onset myositis Anti Mi2 Nucleosome remodeling deacetylase complex (NuRD) 34 Classic dermatomyositis Responds well to standard therapies Favorable prognosis Anti TIF1g (p155140, TRIM33) Transcriptional intermediary factor 1 gamma (TIF1 ) 1835 Severe cutaneous disease Rashes in photoexposed pattern Chronic disease course Lipodystrophy Anti NXP2 (p140, MJ) Nuclear matrix protein 2 (NXP2) 1522 Calcinosis More severe muscle disease Gastrointestinal bleeding, ulcers, and dysphagia Worse disease outcome and functional status Anti MDA5 (CADM 140) Melanoma differentiation associated gene 5 (MDA5) 6 More common in East Asia, where associated with clinically amyopathic myositis, rapidly progressive interstitial lung disease, and a high mortality rate In White populations associated with mild muscle disease, interstitial lung disease, arthritis, and ulceration Rare but clinically important myositis specific autoantibodies are found in 58 of patients with juvenile onset myositis antisynthetases (Jo 1, PL12, PL7, OJ, EJ, KS, Zo, and Ha) ANTISYNTHETASES Antisynthetase syndrome: myositis, interstitial lung disease, fever, mechanics hands, Raynaud phenomenon, and arthritis Occurs in older children Increased mortality Jo 1 Histidyl 23 PL12 Alanyl 23 PL7 Threonyl 23 OJ Isoleucyl 23 EJ Glycyl 23 KS Asparaginyl 23 Zo Phenylalanyl 23 Ha Tyrosyl 23 Anti SRP Signal recognition particle (SRP) 2 Necrotizing autoimmune myositis Severe weakness, muscle necrosis, high CK Cardiac involvement Occurs in older children No rash May be refractory to standard treatment Anti HMGCR HMGCR 1 Necrotizing autoimmune myositis, muscle necrosis, high CK, dysphagia, no statin |
6,788 | exposure Anti SAE Small ubiquitin like modifier activating enzyme (SAE) 1 Initially amyopathic disease with muscle involvement occurring later Myositis associated autoantibodies are found in 1620 of patients with juvenile onset myositis. Some may occur in conjunction with a myositis specific autoantibody. Anti PmScl Exosome associated PM Scl 75; PM Scl 100; C1D 5 Overlap syndromes Anti U1RNP U1RNP 2 Overlap syndromes Anti Ro52 Ro52 5 Overlap syndromes May be found in conjunction with other MSA, particularly antisynthetases Common MSAs are present in 4555 of the U.S. pediatric population with juvenile onset myositis. Rare MSAs are present in 58. Myositis associated autoantibodies (MAAs) are found in 1620 of juvenile onset myositis, with or without an accompanying MSA. CK, Creatine kinase; HMGCR, 3 hydroxy 3 methylglutaryl coenzyme reductase; MDA, melanoma differentiation associated; NuRD, nucleosome remodeling deacetylase; SAE, small ubiquitin like modifieractivating enzyme; SRP, signal recognition particle; TIF, transcriptional intermediary factor. Modified from Pachman LM, Khojah AM. Advances in juvenile dermatomyositis: myositis specific antibodies aid in understanding disease heterogeneity. J Pediatr. 2018;195:1627. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1502 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Children with respiratory muscle weakness do not manifest typical symptoms of impending respiratory failure with increased work of breathing, instead demonstrating hypercarbia rather than hypoxemia. Evaluation of respiratory muscle function by negative inspiratory force (NIF) measurement can be performed in the clinic or at the bedside. DIAGNOSIS Diagnosis of dermatomyositis requires the presence of a characteris tic rash and at least three signs of muscle inflammation and weakness (see Table 200.2). Diagnostic criteria developed in 1975 predate the use of MRI and have not been validated in children. Diagnosis is often delayed because of the insidious nature of disease onset. Electromyography (EMG) shows signs of myopathy (increased insertional activity, fibrillations, sharp waves) and muscle fiber necro sis (decreased action potential amplitude and duration). Nerve con duction studies are typically normal unless severe muscle necrosis and atrophy are present. It is important that EMG be performed in a cen ter with experience in pediatric EMG and its interpretation. Muscle biopsy is typically indicated when the diagnosis is in doubt or for grad ing disease severity (see Fig. 200.4A). Biopsy of involved muscle reveals focal necrosis and phagocytosis of muscle fibers, fiber regeneration, endomysial proliferation, inflammatory cell infiltrates and vasculitis, and tubuloreticular inclusion bodies within endothelial cells. Findings of lymphoid structures and vasculopathy may portend more severe disease. Some children present with classic rash but no apparent muscle weakness or inflammation; this variation is called amyopathic JDM or dermatomyositis sine myositis. It is unclear whether these children have isolated skin disease or mild undetected muscle inflammation, risking progression to more severe muscle involvement with long term sequelae such as calcinosis and lipodystrophy if untreated. DIFFERENTIAL DIAGNOSIS The differential diagnosis depends on the presenting symptoms. |
6,789 | If the presenting complaint is solely weakness without rash or atypi cal disease, other causes of myositis or myopathy should be consid ered, including polymyositis, infection related myositis (influenza A and B, coxsackievirus B, and other viral illnesses), muscular dys trophies (e.g., Duchenne, Becker), myasthenia gravis, Guillain Barr syndrome, endocrinopathies (hyperthyroidism, hypothyroidism, Cushing syndrome, Addison disease, parathyroid disorders), mito chondrial myopathies, TNF receptorassociated periodic syndrome (TRAPS), and metabolic disorders (glycogen and lipid storage dis eases). Infections associated with prominent muscular symptoms include trichinosis, Bartonella infection, toxoplasmosis, staphylococ cal pyomyositis, and SARS CoV 2. Blunt trauma and crush injuries may lead to transient rhabdomyolysis with myoglobinuria. Myositis in children may also be associated with vaccinations, drugs, growth hormone, and GVHD. The rash of JDM may be confused with dys hidrotic eczema, psoriasis, erythema nodosa, malar rash from SLE, capillary telangiectasias from Raynaud phenomenon, and other rheu matic diseases. Muscle inflammation is also seen in children with SLE, juvenile idiopathic arthritis, mixed connective tissue disease, inflammatory bowel disease, and antineutrophil cytoplasmic anti bodypositive vasculitides. Necrotizing immune mediated myopa thies are characterized by muscle necrosis without lymphocytic infiltration. Antibodies to signal recognition particle (SRP) or 3 hydr oxy 3 methylglutaryl coenzyme A (HMG CoA) distinguish the two types from each other and from JDM. Table 200.4 compares other juvenile idiopathic inflammatory myositis disorders: JDM, juvenile polymyositis, and juvenile connective tissue myositis. LABORATORY FINDINGS Elevated serum levels of muscle derived enzymes (creatine kinase CK, aldolase, aspartate transaminase, alanine transaminase ALT, lactate dehydrogenase) reflect muscle inflammation. Not all enzyme levels rise with inflammation in a specific individual; ALT is usually elevated on initial presentation, whereas CK level may be normal. Table 200.2 Diagnostic Criteria for Juvenile Dermatomyositis Classic rash Heliotrope rash of the eyelids Gottron papules Plus three of the following: Weakness Symmetric Proximal Muscle enzyme elevation (1) Creatine kinase Aspartate transaminase Lactate dehydrogenase Aldolase Electromyographic changes Short, small polyphasic motor unit potentials Fibrillations Positive sharp waves Insertional irritability Bizarre, high frequency repetitive discharges Muscle biopsy Necrosis Inflammation Data from Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292:403407. Table 200.3 Clinical Features of Juvenile Dermatomyositis During Disease Course FEATURE Muscle weakness 90 100 Dysphagia or dysphonia 13 40 Muscle atrophy 10 Muscle pain and tenderness 30 75 Skin lesions 85 100 Heliotrope rash of eyelids 66 95 Gottron papules 57 95 Erythematous rash of malarfacial area 42 100 Periungual (nail fold) capillary changes 80 90 Photosensitive rash 5 42 Ulcerations 22 30 Calcinosis 12 30 Lipodystrophy 11 14 Raynaud phenomenon 2 15 Arthritis and arthralgia 22 58 Joint contractures 26 27 Fever 16 65 Gastrointestinal signs and symptoms 8 37 Restrictive pulmonary disease 4 32 Interstitial lung disease 1 7 Cardiac involvement 0 3 From Rider LG, Lindsley CB, Cassidy JT. Juvenile dermatomyositis. In: Cassidy JT, Petty RE, Laxer RM, et al., eds. Textbook of Pediatric Rheumatology, 6th ed. Philadelphia: Saunders; 2011: Table 24.20, p. 410. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from |
6,790 | ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 200 u Juvenile Dermatomyositis 1503 The erythrocyte sedimentation rate (ESR) is often normal, and the rheumatoid factor (RF) test result is typically negative. There may be anemia consistent with chronic disease. Antinuclear antibody (ANA) is present in 80 of children with JDM. Serologic testing results are divided into two groups: myositis associated antibodies (MAAs) and myositis specific antibodies (MSAs) (see Table 200.1). MAAs are associated with JDM but are not specific and can be seen in both overlap conditions and other rheumatic diseases. The pres ence of MAAs such as SSA, SSB, Sm, ribonucleoprotein (RNP), and double stranded (ds) DNA may increase the likelihood of overlap disease or connective tissue myositis. Antibodies to PmScl identify a small, distinct subgroup of myopathies with a protracted disease course, often complicated by pulmonary interstitial fibrosis and car diac involvement. MSAs are specific for myositis and are identified in photo sensitive rash ulceration A B C ulceration generalized lipodystrophy proximal myopathy rash Antip155140 AntiMJ(NXP2) AntiMDA5 calcinosis rash interstitial lung disease myopathy arthritis GI bleed, ulcers, dysphagia severe cutaneous involvement Fig. 200.1 Phenotypes associated with the three most common myositis specific antibodies in children with myositis: anti p155140, anti MJ, and antiMDA 5. A, Anti p155140, present in 1830 of idiopathic juvenile inflammatory myopathies, displays an extensive photosensitive rash that ulcerates, a chronic disease course, and generalized lipodystrophy. B, Fifteen to twenty three percent of children positive for anti MJ (nuclear matrix protein 2 in the United Kingdom) may have disease onset at a younger age and have dysphonia, muscle cramps, atrophy, and contractures, with increased weakness, and they are more likely to develop calcifications and gastrointestinal symptoms; their rash often spares the truncal area. C, AntiMDA 5 is increased in the Japanese population (33) vs the United Kingdom (6) and is associated with inflammatory lung disease, oral and cutaneous ulcers, arthritis, and a milder form of muscle involvement. GI, gastrointestinal. (Modified from Rider LG, Nistala K. The juvenile idiopathic inflammatory myopathies: Pathogenesis, clinical and autoantibody phenotypes, and outcomes. J Intern Med. 2016;280:2438, Fig 3.) Fig. 200.2 The facial rash of juvenile dermatomyositis. There is ery thema over the bridge of the nose and malar areas with violaceous (heliotropic) discolorations of the upper eyelids. Fig. 200.3 The rash of juvenile dermatomyositis. The skin over the metacarpal and proximal interphalangeal joints may be hypertrophic and pale red (Gottron papules). Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1504 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) approximately 4060 of children with JIM. These antibodies sug gest a diagnosis of myositis, and their presence may define distinct clinical subsets and may predict prognosis. Anti TIF 1 antibod ies are reported in 2330 |
6,791 | of children with JDM and are associated with photosensitive rashes, ulceration, and lipodystrophy. Unlike in adults, this antibody is not associated with malignancy in children with JDM. Anti NXP2 antibodies are reported in 1223 of children with JDM and are associated with cramps, muscle atrophy, contrac tures, and dysphonia. Anti MDA5 antibodies are found in approxi mately 7 of children with JDM and may predict the development of interstitial lung disease (ILD). Because certain MSAs have defined clinical phenotypes in JDM and IFN related biomarkers that may correlate with disease activity, there is interest in assessing IFN sig nature by MSA type. Radiographic studies aid both diagnosis and medical management. MRI using T2 weighted images and fat suppression (see Fig. 200.4B) identifies active sites of disease, reducing sampling error and increas ing the sensitivity of muscle biopsy and EMG, results of which are nondiagnostic in 20 of cases if the procedures are not directed by MRI. Extensive rash and abnormal MRI findings may be found despite normal serum levels of muscle derived enzymes. Muscle biopsy often demonstrates evidence of disease activity and chronicity that is not sus pected from the levels of the serum enzymes alone. A contrast swallow study may document palatal dysfunction and risk of aspiration. Pulmonary function testing detects a restrictive defect consistent with respiratory weakness and reduced diffusion capacity of carbon monoxide from alveolar fibrosis associated with other con nective tissue diseases. Serial measurement of vital capacity or negative inspiratory force can document changes in respiratory weakness, espe cially in an inpatient setting. Calcinosis is seen easily on radiographs, along the fascial planes, and within muscles (see Figs. 200.4D and E and Fig. 200.5). TREATMENT The aid of an experienced pediatric rheumatologist is invaluable in outlining an appropriate course of treatment for a child with JDM. Before the advent of corticosteroids, one third of patients spontane ously improved; a third had a chronic, lingering course; and a third died from the disease. Corticosteroids have altered the course of the disease, lowering morbidity and mortality. Methotrexate decreases the length of treatment with corticosteroids, thereby reducing morbidity from steroid toxicity. Intravenous (IV) gamma globulin is frequently used as an adjunct for the treatment of severe disease and can be given at 2 gkg (maximum 70 g) every 2 weeks for three doses, then every 4 weeks as needed. The efficacy and safety have been reported in open label studies. In the 2010 Childhood Arthritis and Rheumatology Research Alliance (CARRA) treatment utilization report, IVIG was used most frequently for initial treatment of severe disease and treat ment of refractory disease. It is also a steroid sparing agent. Consensus treatment plans for guiding treatment of children with JDM are avail able from CARRA online through PubMed and Figure 200.6. Corticosteroids remain the mainstay of treatment. In a clinically stable child without debilitating weakness, oral prednisone at 2 mg kgday (maximum 60 mg daily) is recommended. Children with GI involvement may have decreased absorption of oral corticosteroids and require IV administration. |
6,792 | In more severe cases with respiratory or oropharyngeal weakness, high dose pulse methylprednisolone is used (30 mgkgday for 3 days, maximum dose 1 gday) with ongoing weekly or monthly IV dosing along with daily oral corticosteroids as needed. Corticosteroid dosage is slowly tapered over 12 months, after indicators of inflammation (muscle enzymes) normalize and strength improves. Weekly oral, IV, or subcutaneous methotrexate (the lesser of 1 mgkg or 15 mgm2) is often used as a steroid sparing agent in JDM. The con comitant use of methotrexate halves the cumulative dosage of steroids needed for disease control. Risks of methotrexate include immunosup pression, blood count dyscrasias, chemical hepatitis, pulmonary tox icity, nauseavomiting, and teratogenicity. Folic acid is typically given with methotrexate starting at a dose of 1 mg daily to reduce toxicity and side effects of folate inhibition (oral ulcers, nausea, anemia). Children who are taking immunosuppressive medications such as methotrex ate should avoid live virus vaccination, although inactivated influenza vaccination is recommended yearly. An international trial found the combination of methotrexate plus corticosteroids to perform better than corticosteroids alone and with fewer side effects than corticoste roids plus cyclosporine A. Hydroxychloroquine has little toxicity risk and is used as a second ary disease modifying agent to reduce rash and maintain remission. A B C D E F Fig. 200.4 Features of juvenile dermatomyositis. A, Perivascular and perifascicular inflammatory infiltrates with necrotic fibers, perifascicular atro phy, and regeneration in a muscle biopsy. B, MRI is a sensitive indicator of myositis. Inflamed areas appear bright on short tau inversion recovery weighted images (arrows). C, Capillaries are most often abnormal when viewed at the nail fold. Typical changes of dilation with adjacent dropout (arrow) are seen. D, About 30 of juvenile dermatomyositis (JDM) patients have dystrophic calcinosis. E, Cutaneous ulceration with central necrosis, crust, and surrounding erythema at the elbow of 10 year old boy with severe JDM. F, Lipoatrophy of the forearm (arrow) in a boy with JDM. (From Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008;371:22012212, Fig. 3, p. 2205.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 200 u Juvenile Dermatomyositis 1505 Typically, it is administered at doses of 4 6 mgkgday orally in either tablet or liquid form. Ophthalmologic follow up one time per year to monitor for rare retinal toxicity is recommended. Other side effects include hemolysis in patients with glucose 6 phosphate deficiency, GI intolerance, and skinhair discoloration. The use of rituximab in a trial of steroid dependent patients with resistant inflammatory myopathies, including JDM, did not meet the primary study end point showing a difference in time to improvement between individuals given rituximab at baseline or at 8 weeks, but over all, 83 of all patients met the definition of improvement in the trial. Additionally, rituximab was noted |
6,793 | to have a significant steroid sparing effect. Other medications used to treat severe refractory disease include mycophenolate mofetil, cyclosporine, and cyclophosphamide. Given the strong type I IFN signal in JDM and that these cytokines activate intracellular signaling through the Janus kinase (JAK)signal transduc ers and activators of transcription (STAT) pathway, consideration of JAK inhibitors, including tofacitinib, baricitinib, and ruxolitinib, as potential therapeutic candidates has been bolstered by case reports and case series that report generally promising results with these drugs in off label treatment of JDM. Children with pharyngeal weakness may need nasogastric or gas trostomy feedings to avoid aspiration, whereas those with GI vasculitis require full bowel rest. Rarely, children with severe respiratory weak ness require ventilator therapy and even tracheostomy until the respi ratory weakness improves. Physical therapy and occupational therapy are integral parts of the treatment program, initially for passive stretching early in the disease course and then for direct reconditioning of muscles to regain strength and range of motion. Therapy may improve muscle strength measures and cardiovascular fitness. Bed rest is not indicated, because weight bearing improves bone density and prevents contractures. Social work and psychology services may facilitate adjustment to the frustration of physical impairment in a previously active child and aid with sleep disturbances associated with rheumatic disease. All children with JDM should avoid sun exposure and apply high sun protection factor (SPF) sunscreen daily, even in winter and on cloudy days. Vitamin D and calcium supplements are indicated for all Table 200.4 Frequency of Manifestations of Juvenile Dermatomyositis (JDM), Juvenile Polymyositis (JPM), and Overlap Myositis MANIFESTATION FREQUENCY AT ONSET () JDM JPM OVERLAP MYOSITIS Progressive proximal muscle weakness 82 100 100 100 Easy fatigue 80 100 85 84 Gottron papules 57 91 0 74 80 Heliotrope rash 66 87 0 40 59 Erythematous rash of malarfacial area 42 100 0 6 20 51 Periungual nailfold capillary changes 35 91 33 67 80 Muscle pain or tenderness 25 83 61 66 55 Weight loss 33 36 52 53 Falling episodes 40 59 29 Arthritis 10 65 0 45 69 80 Fever 16 65 0 41 0 49 Lymphadenopathy 8 75 0 12 20 22 Dysphagia or dysphonia 15 44 39 40 Joint contractures 9 55 17 42 57 60 V or shawl sign rashes 19 29 3 6 8 14 Dyspnea on exertion 5 43 17 42 40 Gastrointestinal symptoms 5 37 9 33 6 53 Photosensitive rashes 5 51 0 6 22 40 Raynaud phenomenon 9 28 0 24 41 60 Edema 11 34 15 20 Gingivitis 6 30 9 0 37 Cutaneous ulceration 5 30 3 20 22 Calcinosis 3 34 6 24 Cardiac involvement 2 13 36 19 Interstitial lung disease 5 15 26 Lipodystrophy 4 14 3 0 6 Gastrointestinal bleeding or ulceration 3 4 3 4 10 From Rider LG, Lindsley CB, Miller FW. Juvenile Dermatomyositis. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn L, eds. Textbook of Pediatric Rheumatology, 7th ed. Philadelphia: Elsevier; 2016: Table 26.4. Downloaded for |
6,794 | mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1506 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) children undergoing long term corticosteroid therapy to reduce drug induced osteopenia and osteoporosis. COMPLICATIONS Most complications from JDM are related to prolonged and severe weakness from muscle atrophy to cutaneous calcifications and scarring or atrophy to lipodystrophy. Secondary complications from medical treatments are also common. Children with acute and severe weak ness are at risk for aspiration pneumonia and respiratory failure and occasionally require nasogastric feeding and mechanical ventilation until weakness improves. Rarely, vasculitis of the GI tract develops in children with severe JDM. Crampy abdominal pain and occult GI bleeding may indicate bowel wall vasculitis and lead to ischemia, GI bleeding, and perforation if not treated with complete bowel rest and aggressive treatment for the underlying inflammation. Surgery should be avoided, if possible, because the GI vasculitis is diffuse and not easily amenable to surgical intervention. Contrast enhanced CT may show dilation or thickening of the bowel wall, intraluminal air, or evidence of bowel necrosis. Involvement of the cardiac muscle with pericarditis, myocarditis, and conduction defects with arrhythmias has been reported, as has reduced diastolic and systolic function related to ongoing disease activity. Lipodystrophy and calcinosis are thought to be associated with long standing or undertreated disease (see Fig. 200.4D F). Dystrophic deposition of calcium phosphate, hydroxyapatite, or fluoroapatite crys tals occurs in subcutaneous plaques or nodules, resulting in painful ulceration of the skin with extrusion of crystals or calcific liquid. Cal cification is found in up to 40 of large cohorts of children with JDM. Pathologic calcifications may be related to severity of disease and pro longed delay to treatment and potentially to genetic polymorphisms of TNF 308. Calcium deposits tend to form in subcutaneous tissue and along muscle. Some ulcerate through the skin and drain a soft calcific liquid, and others manifest as hard nodules along extensor surfaces or embedded along muscle. Draining lesions serve as a nidus for celluli tis or osteomyelitis. Nodules cause skin inflammation that may mimic cellulitis. Spontaneous regression of calcium deposits may occur, but there is no evidence based recommendation for treatment of calcino sis. Some experts recommend aggressive treatment of underlying myo sitis. Others have recommended bisphosphonates, TNF inhibitors, and sodium thiosulfate, but no evidence based trials have been conducted for this condition. Lipodystrophy manifests in 1040 of patients with JDM and can be difficult to recognize. Lipodystrophy results in progressive loss of subcutaneous and visceral fat, typically over the face and upper body, and may be associated with a metabolic syndrome similar to polycys tic ovarian syndrome with insulin resistance, hirsutism, acanthosis, hypertriglyceridemia, and abnormal glucose tolerance. Lipodystrophy may be generalized or localized. Children receiving prolonged corticosteroid therapy are prone to complications such as cessation of linear growth, weight gain, hirsut ism, adrenal suppression, |
6,795 | immunosuppression, striae, cushingoid fat deposition, mood changes, osteoporosis, cataracts, avascular necrosis, and steroid myopathy. Families should be counseled on the effects of corticosteroids and advised to use medical alert identification and to consult a nutritionist regarding a low salt, low fat diet with adequate vitamin D and calcium supplementation. An association with malignancy at disease onset is observed in adults with dermatomyositis but very rarely in children. PROGNOSIS The mortality rate in JDM has decreased since the advent of corti costeroids, from 33 to currently approximately 1; little is known about the long term consequences of persistent vascular inflamma tion. The period of active symptoms has decreased from about 3.5 years to 1.5 years with more aggressive immunosuppressive ther apy; the vascular, skin, and muscle symptoms of children with JDM generally respond well to therapy. At 7 years of follow up, 75 of patients have little to no residual disability, but 25 continue to have chronic weakness and 40 have chronic rash. Up to one third may need long term medications to control their disease. Children with JDM appear able to repair inflammatory damage to vasculature and muscle, but there is some emerging concern about long term effects on cardiovascular risk. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. A B Fig. 200.5 Calcifications in dermatomyositis. A, Skin effects of calcifi cation. B, Radiographic evidence of calcification. MODERATE JDM Plan 2 Plan 1 AND IV methylprednisolone 30 mgkg for 3 d, then weeklyc Plan 3 Plan 2 AND IVIG 2 gkgd q2wk 3 doses then monthIy Plan 1 Methotrexatea 15 mgm2 or 1 mgkg weekly AND Prednisoneb 2 mgkgd for 4 wk then decrease by 20 SKIN PREDOMINANT JDM Plan 2 Plan 1 AND Methotrexatea 15 mgm2 or 1 mgkg weekly Plan 3 Plan 2 AND Prednisoneb 2 mgkgd for 4 wk then decrease by 20 Plan 1 Hydroxychloroquine 5 mgkgde SKIN RESISTANT JDM Plan 2 Plan 1 AND Mycophenolate mofetilf BID 10 mgkgdose OR 600 mgm2 Plan 3 Cyclosporine 3 mgkgg Plan 1 IVIG 2 gkgd q2wks 3 doses then monthly Fig. 200.6 Recommended consensus treatment plans from CARRA for JDM patients with moderate, skin predominant, and skin resistant disease. IV, intravenous; IG, immunoglobulin. aLesser of 15 mgm2 or 1 mgkg (max 40 mg), bmax 60 mg, coptional, dmax 70 g, emax 400 mg, fmax 1,500 mg bid, ghigher doses based on toxicity, efficacy. (From Kim H, Huber AM, Kim S. Updates on juvenile dermatomyositis from the last decade: classification to outcomes. Rheum Dis Clin N Am. 2021;47:669690, Fig. 1, p. 679.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 201 u Scleroderma and Raynaud Phenomenon 1507 Juvenile scleroderma encompasses a range of conditions unified by the presence of fibrosis of the skin. Juvenile scleroderma is divided into two major categories, juvenile localized scleroderma (JLS, also known as morphea), which is largely limited |
6,796 | to the skin, and juvenile systemic sclerosis (JSSc), with multisystem organ involve ment. Localized disease is the predominant type seen in pediatric populations (95), but systemic sclerosis is associated with mor tality and severe multiorgan morbidity. ETIOLOGY AND PATHOGENESIS The etiology of scleroderma is unknown, but the mechanism of dis ease appears to be a combination of a vasculopathy, autoimmunity, immune activation, and fibrosis. Triggers, including trauma, infec tion, and, possibly, subclinical graft versus host reaction from per sistent maternal cells (microchimerism), injure vascular endothelial cells, resulting in increased expression of adhesion molecules. These molecules entrap platelets and inflammatory cells, resulting in vascu lar changes with manifestations such as Raynaud phenomenon and pulmonary hypertension. Inflammatory cells infiltrate the area of ini tial vascular damage, causing further vascular damage and resulting in thickened artery walls and reduction in capillary numbers. Mac rophages and other inflammatory cells then migrate into affected tis sues and secrete cytokines that induce fibroblasts to reproduce and synthesize excessive amounts of collagen, resulting in fibrosis and subsequent lipoatrophy and dermal fibrosis, with loss of sweat glands and hair follicles. In late stages the entire dermis may be replaced by compact collagen fibers. Autoimmunity is believed to be a key process in the pathogenesis of both localized and systemic scleroderma, given the high percentage of affected children with autoantibodies (Table 201.1). Children with local ized disease often have a positive antinuclear antibody (ANA) test result (42), and 47 of this subgroup have antihistone antibodies. Children with JSSc have higher rates of ANA positivity (80.7) and may have anti Scl 70 antibody (34, antitopoisomerase I). The relationship between specific autoantibodies and the various forms of scleroderma is not well understood, and all antibody test results may be negative, especially in JLS. CLASSIFICATION Localized scleroderma is distinct from systemic scleroderma and rarely progresses to systemic disease. The category of JLS includes several subtypes differentiated by both the distribution of the lesions and the depth of involvement (Tables 201.2 and 201.3). Up to 15 of children have a combination of two or more subtypes. EPIDEMIOLOGY Juvenile scleroderma is rare, with an estimated prevalence of 1 in 100,000 children. Localized scleroderma (LS) is much more common than sys temic sclerosis (SSc) in children, by a 10:1 ratio, with linear scleroderma being the most common subtype. LS is predominantly a pediatric con dition, with 65 of patients diagnosed before age 18 years. After age 8 years the femalemale ratio for both LS and SSc is approximately 3:1, whereas in patients younger than 8 years, the prevalence is equal. CLINICAL MANIFESTATIONS Localized Scleroderma The onset of scleroderma is generally insidious, and manifestations vary according to disease subtype. The initial skin manifestations of localized disease usually include erythema or a bluish hue seen around an area of waxy induration; subtle erythema may be the only presenting Chapter 201 Scleroderma and Raynaud Phenomenon Heather A. Van Mater and C. Egla Rabinovich Table 201.1 Clinical Subtypes of Systemic Sclerosis: Associated Organ Manifestations and Autoantibody Association SUBTYPE ORGAN |
6,797 | SYSTEM ORGAN SYSTEM FEATURES ANTIBODY ASSOCIATION Diffuse cutaneous (dc) Skin Thickness proximal to elbows and knees Rapid progressive thickening Topoisomerase (Scl 70) RNA Polymerase III U3RNP (fibrillarin) Cardiac Congestive heart failure Conduction abnormalities Renal Scleroderma renal crisis Pulmonary Interstitial lung disease Limited cutaneous (lc) Skin Thickness limited to distal extremities (and face) Restricted and nonprogressive thickening Centromere ThTo Gastrointestinal Esophageal dysmotility GI strictures Malabsorption Pulmonary Pulmonary arterial hypertension Overlap syndrome Skin Either dcSSc or lcSSc pattern Skin manifestations of other CTD, such as Gottron papules (DM) and malar rash (SLE) PM Scl U1 RNP Ku Musculoskeletal Arthritis Myositis Cardiac Can have any of the dcSSc or lcSSc manifestations Additional organ involvement in association with other CTD feature, such as lupus nephritisRenal Pulmonary Gastrointestinal CTD, Connective tissue disease; DM, dermatomyositis; PM Scl, polymyositis scleroderma antibody; SLE, systemic lupus erythematosus; U1 RNP, U1 ribonucleoprotein antibody. From Petty RE, Laxer RM, Lindsley CB, et al., eds. Textbook of Pediatric Rheumatology, 8th ed. Philadelphia: Elsevier; 2021: Table 27.3, p. 382. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1508 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) sign (Fig. 201.1). Edema and erythema are followed by indurated, hypopigmented or hyperpigmented atrophic lesions (Fig. 201.2). LS varies in size from a few centimeters to the entire length of the extrem ity, with varying depth. Patients may present with arthralgias, syno vitis, or flexion contractures (Fig. 201.3). Children also experience limb length discrepancies as a result of growth impairment caused by involvement of muscle and bone. Children with en coup de sabre may have symptoms unique to central nervous system (CNS) involvement, such as seizures, hemifacial atrophy, ipsilateral uveitis, and learning behavioral changes (Fig. 201.4). Up to 25 of children with LS have extracutaneous manifestations, most frequently arthritis (47) in lin ear disease and neurologic symptoms (17) associated with en coup de sabre. Systemic Scleroderma SSc is a severe disease in children, starting with an insidious onset fol lowed by a prolonged course characterized by periods of remission and exacerbation, commonly resulting in chronic disability and death, with a 5 year mortality rate of 7.5. The skin manifestations of SSc include an early phase of edema that spreads proximally from the dorsum of the hands and fingers and includes the face. An eventual decrease in edema is followed by indura tion and fibrosis of skin, ultimately resulting in loss of subcutaneous fat, sweat glands, and hair follicles. Later, atrophic skin becomes shiny and waxy in appearance. As lesions spread proximally, flexion contractures develop at the elbows, hips, and knees associated with secondary mus cle weakness and atrophy. In the face, this process results in a small oral stoma with decreased mouth aperture. Skin ulceration over pressure points, such as the elbows, may be associated with subcutaneous calci fications. Severe Raynaud phenomenon (RP; Fig. 201.5) causes |
6,798 | ulcer ation of the fingertips with subsequent loss of tissue pulp and tapered fingers (sclerodactyly) (Fig. 201.6). Resorption of the distal tufts of the distal phalanges may occur (acroosteolysis). Hyperpigmented postin flammatory changes surrounded by atrophic depigmentation give a salt and pepper appearance to skin. Over years, remodeling of lesions sometimes results in focal improvement in skin thickening. Pulmonary disease is the most common visceral manifestation of SSc and includes both arterial and interstitial involvement (alveolitis). Symp toms range from asymptomatic disease to exercise intolerance, dyspnea at Table 201.2 Classification of Pediatric Scleroderma (Morphea) LOCALIZED SCLERODERMA Plaque morphea Confined to dermis, occasionally superficial panniculus Well circumscribed circular area of induration, often a central waxy, ivory colored area surrounded by a violaceous halo; unilateral Generalized morphea Involves dermis primarily, occasionally panniculus Defined as confluence of individual morphea plaques or lesions in three or more anatomic sites; more likely to be bilateral Bullous morphea Bullous lesions that can occur with any of the subtypes of morphea Linear scleroderma Linear lesions can extend through the dermis, subcutaneous tissue, and muscle to underlying bone; more likely unilateral Limbstrunk: One or more linear streaks of the extremities or trunk Flexion contracture occurs when lesion extends over a joint; limb length discrepancies En coup de sabre: Involves the scalp andor face; lesions can extend into the central nervous system, resulting in neurologic sequelae, most commonly seizures and headaches Parry Romberg syndrome: Hemifacial atrophy without a clearly definable en coup de sabre lesion; can also have neurologic involvement Deep Morphea Involves deeper layers, including panniculus, fascia, and muscle; more likely to be bilateral Subcutaneous morphea: Primarily involves the panniculus or subcutaneous tissue Plaques are hyperpigmented and symmetric Eosinophilic fasciitis: Fasciitis with marked blood eosinophilia Fascia is the primary site of involvement; typically involves extremities Classic description is peau dorange, or orange peel texture, but early disease manifests as edema (see Fig. 201.2) Morphea profunda: Deep lesion extending to fascia and sometimes muscle, but may be limited to a single plaque, often on the trunk Disabling pansclerotic morphea of childhood: Generalized full thickness involvement of skin on the trunk, face, and extremities, sparing fingertips and toes SYSTEMIC SCLEROSIS Diffuse Most common type in childhood Symmetric thickening and hardening of the skin (sclerosis) with fibrous and degenerative changes of viscera Limited Rare in childhood Previously known as CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome Table 201.3 Provisional Criteria for Classification of Juvenile Systemic Sclerosis (JSSc) MAJOR CRITERION (REQUIRED) Proximal skin sclerosisinduration of the skin proximal to metacarpophalangeal or metatarsophalangeal joints MINOR CRITERIA (AT LEAST TWO REQUIRED) Cutaneous: Sclerodactyly Peripheral vascular: Raynaud phenomenon, nail fold capillary abnormalities (telangiectasias), digital tip ulcers Gastrointestinal: Dysphagia, gastroesophageal reflux Cardiac: Arrhythmias, heart failure Renal: Renal crisis, new onset arterial hypertension Respiratory: Pulmonary fibrosis (high resolution CTradiography), decreased diffusing capacity for carbon monoxide, pulmonary arterial hypertension Neurologic: Neuropathy, carpal tunnel syndrome Musculoskeletal: Tendon friction rubs, arthritis, myositis Serologic: Antinuclear antibodiesSSc selective autoantibodies (anticentromere, antitopoisomerase I Scl 70, antifibrillarin, anti PMScl, antifibrillin, |
6,799 | or anti RNA polymerase I or III) Diagnosis requires at least one major and at least two minor criteria. From Zulian F, Woo P, Athreya BH, et al. The Pediatric Rheumatology European Society American College of RheumatologyEuropean League against Rheumatism provisional classification criteria for juvenile systemic sclerosis. Arthritis Rheum. 2007;57:203212. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 201 u Scleroderma and Raynaud Phenomenon 1509 rest, and right sided heart failure. Pulmonary arterial hypertension is a poor prognostic sign, developing because of lung disease or independently as part of the vasculopathy. Clinical manifestations of pulmonary arterial hypertension in children appear late in the course, are subtle, and include cough and dyspnea on exertion. Pulmonary evaluation should include pulmonary function tests (PFTs) such as diffusion capacity of carbon mon oxide (DLco), bronchoalveolar lavage (BAL), and high resolution chest computed tomography (HRCT). PFTs reveal decreased vital capacity and decreased DLco, whereas neutrophilia or eosinophilia on BAL suggests active alveolitis. Chest CT is much more sensitive than chest radiographs, which are often normal, showing typical basilar ground glass abnormali ties, reticular linear opacities, nodules, honeycombing, and mediastinal adenopathy. Gastrointestinal tract disease is seen in 25 of children with SSc. Common manifestations include esophageal and intestinal dysmotility resulting in dysphagia, reflux, dyspepsia, gastroparesis, bacterial over growth, dilated bowel loops and pseudoobstruction, and dental caries, as well as malabsorption and failure to thrive. Renal arterial disease can cause chronic or severe episodic hypertension; unlike adult disease, renal crisis is rare. Cardiac fibrosis is associated with arrhythmias, ventricular hypertrophy, and decreased cardiac function. Mortality from JSSc is usu ally a result of cardiopulmonary disease. A scoring system helps identify the severity of the multiorgan involvement (Table 201.4). Fig. 201.2 Inactive linear scleroderma demonstrating hyperpigment ed lesion with areas of normal skin (skip lesions). Fig. 201.3 Child with untreated linear scleroderma resulting in knee contracture, immobility of ankle, chronic skin breakdown of scar on the lateral knee, and areas of hypopigmentation and hyperpigmentation. The affected leg is 1 cm shorter. Fig. 201.4 Child with en coup de sabre lesion on scalp extending down to forehead. Before treatment, the skin on the scalp was bound down with chronic skin breakdown. Note the area of hypopigmentation extending down the forehead (arrows). Fig. 201.5 Active Raynaud phenomenon with well demarcated pallor at the fingertips in a patient with scleroderma. (From Firestein GS, Budd RC, Gabriels SE, et al., eds. Firestein Kelleys Textbook of Rheumatol ogy, 11th ed. Philadelphia: Elsevier; 2021: Fig. 89.2, p. 1507.) Fig. 201.6 Sclerodactyly and finger ulcerations in a patient with sys temic sclerosis who is poorly compliant with treatment. Fig. 201.1 Child with generalized morphea. Note the active circular lesion (arrowheads) with a surrounding rim of erythema. The largest le sion has areas of postinflammatory hyperpigmentation and depression with an area of erythema on the right. The small lesion |
6,800 | (arrow) demon strates depression caused by lipoatrophy. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1510 Part XIV u Rheumatic Diseases of Childhood (Connective Tissue Disease, Collagen Vascular Diseases) Table 201.4 Medsger Systemic Sclerosis Severity Scale ORGAN SYSTEM 0 (NORMAL) 1 (MILD) 2 (MODERATE) 3 (SEVERE) 4 (END STAGE) General Wt loss 5 Wt loss 510 Wt loss 1015 Wt loss 1520 Wt loss 20 Hct 37 Hct 3337 Hct 2933 Hct 2529 Hct 25 Hb 12.3 gdL Hb 11.0 12.2 gdL Hb 9.7 10.9 gdL Hb 8.3 9.6 gdL Hb 8.3 gdL Peripheral vascular No RP; RP not requiring vasodilators RP requiring vasodilators Digital pitting scars Digital tip ulcerations Digital gangrene Skin TSS 0 TSS 1 14 TSS 15 29 TSS 30 39 TSS 40 Jointtendon FTP 0 0.9 cm FTP 1.0 1.9 cm FTP 2.0 3.9 cm FTP 4.0 4.9 cm FTP 5.0 cm Muscle Normal proximal muscle strength Proximal weakness, mild Proximal weakness, moderate Proximal weakness, severe Ambulation aids required Gastrointestinal tract Normal esophagogram; normal small bowel series Distal esophageal hypoperistalsis; small bowel series abnormal Antibiotics required for bacterial overgrowth Malabsorption syndrome; episodes of pseudoobstruction Hyperalimentation required Lung DLco 80 FVC 80 No fibrosis on radiograph sPAP 35 mm Hg DLco 7079 FVC 7079 Basilar rales; fibrosis on radiograph sPAP 35 49 mm Hg DLco 5069 FVC 5069 sPAP 50 64 mm Hg DLco 50 FVC 50 sPAP 65 mm Hg Oxygen required Heart ECG normal ECG conduction defect ECG arrhythmia ECG arrhythmia requiring therapy CHF LVEF 50 LVEF 4549 LVEF 4044 LVEF 3040 LVEF 30 Kidney No history of SRC with serum creatinine 1.3 mgdL History of SRC with serum creatinine 1.5 mgdL History of SRC with serum creatinine 1.5 2.4 mgdL History of SRC with serum creatinine 2.5 5.0 mgdL History of SRC with serum creatinine 5.0 mgdL or dialysis required If two items are included for a severity grade, only one is required for the patient to be scored as having disease of that severity level. CHF, Congestive heart failure; DLco, diffusing capacity for carbon monoxide, predicted; ECG, electrocardiogram; FTP, fingertip to palm distance in flexion; FVC, forced vital capacity, predicted; Hb, hemoglobin; Hct, hematocrit; LVEF, left ventricular ejection fraction; RP, Raynaud phenomenon; sPAP, estimated pulmonary artery pressure by Doppler echo; SRC, scleroderma renal crisis; TSS, total skin score; Wt, weight. Modified from Medsger TA Jr, Bombardieri S, Czirjak L, et al. Assessment of disease severity and prognosis, Clin Exp Rheumatol. 2003;21(3 Suppl 29):S51, Table 1, p. S 43. Raynaud Phenomenon Raynaud phenomenon is the most frequent initial symptom in pediatric SSc, present in 70 of affected children months to years before other manifestations and seen in nearly all over the course of the disease. RP refers to the classic triphasic sequence of blanching, cyanosis, and ery thema of the digits induced by cold exposure andor emotional stress |
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