If this assessment of the human condition is correct, then it also helps to understand the criticisms that have been raised in Cordeiro-Rodrigues’s reply.

I briefly address two points of criticism that seem to me particularly worthy of consideration: The first criticism says that the God I am proposing is immoral because God apparently accepts gratuitous (animal) suffering.

However, “God as creator is also the father of all existing beings and therefore has stronger duties towards them” [9] than parents have toward their children.

The second criticism says that if God as a transcendent being is not subject to moral rules, then either no objective moral standards exist or they are inscrutable for us.

In either way, our moral order would be permanently undermined because divine morality does not correspond to ours, and, as a consequence, humans would easily get into situations where they would make the wrong decision and thus be responsible for moral evils [9].

The first criticism presupposes that God ought to be thought of as strictly personal and therefore as a moral subject observing those moral rules that are also applicable to us.

Cordeiro-Rodrigues refers to Desmond Tutu’s work for making the point that God cares about right and wrong and, thus, about a moral universe.

In analogy to the obvious moral principle that letting someone suffer is only permissible in the light of a higher good attained through it, God has to respect this principle as well.

This interpretation is undoubtedly widespread in current accounts of theodicy.

Take, for instance, Eleonore Stump’s remarkable reading of the book of Job in her seminal study Wandering in Darkness [10].

She interprets the divine speeches as expression of God’s providential care which is directed toward intimate second-personal closeness to God.

Stump concludes: “Focusing on the second-person account of the divine speeches and the second-person experience of God that Job has while God is speaking to him shows us that there is for Job a second-personal explanation of his suffering [...]” [10].

One has to notice, however, that this line of interpretation faces serious challenges.

In her specific account, Stump has to radically reinterpret the many passages of the divine speeches where a wild and untamable nature is presented, which renews itself through the cycle of eating and being eaten.

Here the experience of a second-personal and caring relationship of God to creation finds hardly any point of connection.

In more general terms, the question arises to what extent higher-good theodicies can convincingly explain that all the suffering in the world is a necessary and indispensable means for achieving these goods.

Stump, for instance, explicitly wants to limit her account to adult and mentally functional humans as she does not know whether it is applicable to the nature of suffering of animals, infants, or cognitively disabled individuals and the possibility of their personal growth of the relationship with God [10].

A positive evaluation might suggest that there are possibilities of adapting the proposed solution.

However, a negative evaluation will interpret this delimitation as a kind of capitulation in front of particularly challenging instances of suffering.

I think we have a strong intuition to assume that if suffering is necessary at all, then less terrible instances of it would do it as well.

Daniel Howard-Snyder expresses this idea as follows: “Suppose God had simply prevented us from ever having genocidal thoughts. Would we then have been unable to perceive the hideousness of living unto ourselves? Would we have lacked the requisite incentive to turn to God? [...] We each need to answer this question for ourselves, but for my own part, on careful reflection I can’t see how [...] God would be justified in permitting so much horrific evil and suffering rather than a lot less” [11].

In other words, the effort to understand God as a moral being can lead to the idea that this conception must be abandoned, and God ought to be disqualified as immoral.

To show that God can have good reasons for allowing terrible suffering does not yet imply that God also has good reasons for permitting any kind of suffering, no matter how horrific.

It is precisely the existence of such evils that makes it so difficult to maintain a comprehensive moral order in which God functions as the source and universal guarantor of it.

This difficulty is also evident in animal theodicies when additional assumptions about possible future developmental scenarios of animals in the eschaton are proposed for avoiding the impression of gratuitous animal suffering.

Thus, the focus on a Tutuist framework for tackling the problem of evil constraints the conceptual resources of the debate considerably because moral standards for human–human relationships are elevated to the general standard for any relationship, including the one between God and humans.

The assumption of such a comprehensive moral order of reality entails a considerable argumentative burden, which is often seen as doomed to failure.

It seems to me that Cordeiro-Rodrigues did not adequately grasp this point or he considers it to be as too easily solvable.

The image of God outlined in the Book of Job (and what I have sympathies for) places God beyond such a moral order.

This does not mean that God has no interest in human beings and their well-being; rather, it says that God wants to liberate human beings from the misleading assumption that the entire cosmos is governed according to a moral order, which guarantees an adequate compensation for all instances of suffering.

Such a moral order, to put it bluntly, is an important and worthwhile ideal of human life but, apparently, not of divine creation.

With such an understanding of the God–world relationship, the unity of a moral order encompassing God and creation is no longer available.

By letting the idea of morality as a leading category for our overall understanding of reality go, the human view is able to open up into a profoundly tragic dimension of our existence.

Thus, Newsom draws the following conclusion of her interpretation of the Book of Job: “Like the ostrich, Job, too, brings his children into a dangerous world, where they may well be crushed and trampled.

Unlike the ostrich, however, which forgets the dangers to its offspring, it is unlikely that Job can be said to forget their vulnerability” [4].

This brings me to the second criticism, which says that if “there is an inscrutable moral code for humans, then [...] this would mean that humans can never be held accountable for moral wrongs” [9].

Even if there were a divine moral code that is beyond human comprehension, this would not imply that we are bereft of any insight into valid moral principles.

Since one can only use what they have got, in such a scenario, we would have to adhere to the moral principles accessible to us thanks to our reason.

Take the moral insight that suffering may only be imposed on others if this is the only way to achieve a higher good.

This insight is not simply given to us, but we can justify it and argue that it is reasonable.

If, therefore, a hidden divine moral code completely different from our moral principles were to exist, then this matter of fact would not further affect us, since any access to this divine order is denied to us.

Note that the view I am proposing is not making any claims in this direction.

Rather, the idea is that there are non-moral values such as continuous creativity, remarkable adaptability, prolific life-circles, amazing bio-diversity, etc., whose axiological weight we are able to grasp.

If God were to appreciate these values, then we were able to grasp at least certain aspects of this holistic divine perspective on the world.

A final point: Is this concept of God proposed still a Christian God? This question shapes the criticisms put forward. I believe this concept of God belongs to the rich biblical tradition which emphasizes that the world as we know it is dangerous.

After all, a single misstep in paradise brought humanity into the world as we know it.

Against this background, the crucial question is: Can it ever be reasonable for participants in terrible sufferings like Job to stop seeing this suffering as an obstacle to trusting that God is interested in our well-being and in a relationship with us? Here is a proposed answer: Those involved in suffering will stop blaming God for it when they accept their lives as they are—even with all the suffering.

This, according to the interpretation I follow, is the lesson that the story of Job wants to teach us.

We come to accept our lives not when we give up all hope but when we reach a point where participation in terrible situations of suffering no longer threatens the integrity of an individual’s personality.

Acceptance does not mean letting go of the conviction that suffering was prima facie ruinous to one’s life, but it does mean letting go of the demand that things should have gone differently.

Acceptance does not mean that the painful, wrong, and prima facie ruinous events count for nothing or that we should no longer care about them.

Rather, these events are no longer capable of destroying our integrity as a human person because we have reached a state where we no longer have to struggle with what has happened and where we no longer try to find a hidden meaning or divine plan where there is none.

The aim is to come to a stable understanding of our place in the cosmos that is able to integrate what has happened into a meaningful context.

From a Christian perspective, one can add that the firm trust that God is our secure fundament finds personal involvement in suffering terrifying (think of Jesus in Gethsemane) but achievable as it involves the hope that the creator of this world can at the same time be the re-creator of a better world.

Such a view of hope for the next life does neither explain suffering away nor dispose of a grand theory of suffering, but it makes it, at best, bearable.


X-linked adrenoleukodystrophy is a peroxisomal disorder caused by mutations in the ABCD1 gene (http://www.x-ald.nl) (Mosser et al., 1993), which codes for the transporter of very long-chain fatty acids (5C22:0) (van Roermund et al., 2008).

ABCD1 defi- ciency impairs peroxisomal very long-chain fatty acid degradation resulting in increased cytosolic very long-chain fatty acid-CoA levels (Kemp et al., 2011), which are further elongated by the very long-chain fatty acid-specific elongase, ELOVL1 (Ofman et al., 2010), thus causing very long-chain fatty acid accumulation (Moser et al., 1981; Kemp and Wanders, 2010).


In males, disease course and symptomatology have been studied extensively (Engelen et al., 2012).

The clinical spectrum ranges from isolated adrenocortical insufficiency, slowly progressive myelopathy and peripheral neuropathy in adulthood (adrenomyeloneuropathy) to a rapidly progressive and fatal cerebral demyelinating disease in boys or adult men (cerebral-adrenoleukodystrophy).

The most frequent phenotype in males is adrenomyeloneuropathy (van Geel et al., 1994; Engelen et al., 2012).


There have been several studies and observations concerning the phenotype of X-linked adrenoleukodystrophy carriers.

O'Neill et al. ( 1984) described 21 obligate carriers and several were shown to have signs and symptoms of myelopathy.

It was esti- mated that 50% develop symptoms at some point in their life (Moser et al., 1991).

In a small study, eight females were found to have myelopathy and in a retrospective study the frequency of symptoms increased with age (van Geel, 2000; Schmidt et al., 2001).

These studies provide no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, as data were acquired in small groups and may be biased towards females with symptoms.


Adrenal insufficiency is rare in X-linked adrenoleukodystrophy car- riers (el-Deiry et al., 1997), and there are only a few reports of X-linked adrenoleukodystrophy carriers that developed cerebral- adrenoleukodystrophy (Pilz and Schiener, 1973; Jung et al., 2007).

Some studies suggested that disease severity could be related to the pattern of X-inactivation, whereas others refuted this observation (Migeon et al., 1981; Watkiss et al., 1993; Maier et al., 2002; Salsano et al., 2012).


The primary goal of our study was to estimate the proportion of X-linked adrenoleukodystrophy carriers that develop symptoms and to characterize these symptoms both clinically and with ancil- lary investigations.

A secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status.


We designed a prospective cross-sectional cohort study.

Female car- riers over the age of 18 years were eligible to participate.

They were recruited from the outpatient clinics of the Academic Medical Centre and the Medical Centre Alkmaar from 2008-10.

To prevent bias for symptomatic women, we tried to examine all female relatives with X-linked adrenoleukodystrophy of the women participating.

Through the Dutch X-linked adrenoleukodystrophy patient organization, letters to invite X-linked adrenoleukodystrophy carriers to participate were sent to all members.

The study protocol was approved by the local Institutional Review Board.

After informed consent was obtained, women visited the outpatient clinic for assessment, which included questionnaires, neurological examination, neurophysiological tests, blood samples and skin biopsy.


A careful history with emphasis on neurological complaints and neuro- logical examination was performed.

In particular, symptoms of incon- tinence, gait disorder, maximum walking distance, and sensory disturbance were recorded.

Urinary incontinence was defined as urge incontinence.

Stress incontinence was not considered a symptom of myelopathy.

A gait disorder was considered present if the walking distance was significantly reduced or running was not possible.

Sensory complaints were recorded if there were paraesthesias or numbness in the lower extremities.

Sensory disturbances on examin- ation were considered present if there was reduced sensation to touch, pinprick, vibration or position sense in the lower extremities.

Muscle strength was rated using the Medical Research Council Scale and spasticity was rated using the Ashworth scale (Ashworth, 1964).


An Expanded Disability Status Scale value was scored based on the history and physical examination performed during the visit and recorded in the medical chart (Kurtzke, 1983).


Carriers with peripheral neuropathy or myelopathy were considered symptomatic.

Myelopathy was considered present if: (i) there were symptoms of myelopathy (for instance sphincter disturbance); and (ii) signs of myelopathy on neurological examination (pyramidal tract or dorsal column signs) were present.

If only symptoms were present (for instance faecal incontinence) but no signs on neurological exam- ination, myelopathy was not scored as present.

Peripheral neuropathy was considered present if nerve conduction studies and/or EMG were abnormal (as described below).


All participants completed the Dutch version of the SF-36 (Quality of Life Assessment) (Aaronson et al., 1998), and the AMC Linear Disability Scale (Weisscher et al., 2007).

SF-36 values can be com- pared to reference values for the Dutch population, matched for gender and age.

The AMC Linear Disability Scale values were


Nerve conduction studies and EMG were performed according to a fixed protocol, allowing comparison with reference values and possibly follow-up in the future (Verhamme et al., 2009).

Compound muscle action potential amplitudes, baseline to negative peak, were recorded from the abductor pollicis brevis, abductor hallucis brevis, and extensor digitorum brevis on one side.

A summated compound muscle action potential amplitude was calculated.


Motor nerve conduction velocities were calculated after distal and proximal stimulation of the right median, tibial, and peroneal nerves.

Sensory nerve conduction velocity, calculated based on negative peak markers, and sensory nerve action potentials amplitudes, baseline to negative peak, were investigated for the left median nerve and right sural nerve.

A summated sensory nerve action potential amplitude was calculated.


Electromyography was done of the left anterior tibial, and interosseus I/II muscles.

An axonal peripheral neuropathy was diagnosed if in two separate nerves at least one parameter was outside the 95% confidence interval (CI) and the criteria for demyelinating peripheral neuropathy were not ful- filled (Van Asseldonk et al., 2005).

Somatosensory evoked potentials of left median and the posterior tibial nerves on both sides and brain- stem auditory evoked potentials on both sides were registered, con- forming to local protocols (Aramideh et al., 1992; Aalfs et al., 1993).


Venous blood samples were taken and plasma and lymphocytes stored as described previously (Engelen et al., 2010).


From skin biopsy material primary fibroblast cell lines were generated and cultured as described (Valianpour et al., 2003).

Very long-chain fatty acids (C26:0 and the C26:0/C22:0 ratio) were determined in plasma and fibroblasts as described (Valianpour et al., 2003).


Peroxisomal beta-oxidation activity was measured essentially as described by incubating cells with 30 mM deuterium-labelled C22:0 (D 3 -C22:0) (Kemp et al., 2004).

ABCD1 protein levels were deter- mined by immunofluorescence and quantitative immunoblot (Kemp et al., 1996; Zhang et al., 2011).


Mutation analysis of the ABCD1 gene was performed as described (Boehm et al., 1999).

ABCD1 allele-specific expression (ABCD1 allele-specific expression) of 38 carriers was measured by pyrosequen- cing.

RNA was extracted from primary fibroblasts and complementary DNA synthesized as described (Bieche et al., 2001).

The ratio of normal versus mutant allele expressed was measured by pyrosequen- cing.


Complementary DNA was PCR-amplified using biotin-labelled primers followed by quantitative pyrosequencing using a PyroMark Q96 ID instrument (Qiagen).

Biotin-labelled single-stranded amplicons were isolated following the protocol using the Qiagen PyroMark Q96 Workstation pyrosequenced with a sequencing primer (PCR- and sequencing-primers are provided in Supplementary Table 1).

Each sample was pyrosequenced in the upper direction (with lower biotin- labelled amplicons) and in lower direction (with upper biotin-labelled amplicons).

The ratio of normal versus mutant allele was measured using the PyroMark ID software (Qiagen).


For each carrier, the ABCD1 allele-specific expression value represents the mean of upper and lower reads (determined in two independent experiments).

For included samples, variations between upper and lower reads were 410%.

For validation, we repeated the experiment for a subset of samples (n = 6) using different PCR primers or independent comple- mentary DNA samples.

The ABCD1 allele-specific expression values were similar (variations 44%).


ABCD1 allele-specific expression pattern was defined as 'severely' skewed with an expression of the normal allele 410% and 'moder- ately' skewed with an expression of the normal allele between 11-25%, similar to a previous report (Miozzo et al., 2007).

In the manuscript ABCD1 allele-specific expression will be referred to as X-inactivation.


For five patients the ABCD1 allele-specific expression analysis was not possible because of the complexity of the mutation.

Instead, ABCD1 allele-specific expression values were calculated using ABCD1 protein immunofluorescence and determination of the ratio of ABCD1 protein positive and negative cells.


Data were analysed with IBM SPSS statistics version 19 (IBM Inc.), Microsoft Excel from Office 2010 and Prism version 5 (GraphPad Software).

Depending on the distributional properties, outcome meas- ures were expressed as means AE standard deviation (SD) or as medians with ranges.

Statistical significance was assessed by independent sample Student's t-test for normally distributed continuous data and the Wilcoxon test for non-normally distributed continuous data.

All reported P-values are two-sided and were not adjusted for multiple testing.

The SF-36 scores were converted to z-scores based on the Dutch norm population, using the appropriate age groups.

AMC Linear Disability Scale scores were analysed as described previously (Weisscher et al., 2007).

The relationship between symptomatic status, age and the pattern of X-inactivation in skin fibroblasts were analysed by logistic regression.


Forty-six females from 26 kindreds were enrolled in the study (one kindred with five females, two with four females, two with three, five with two, and 17 with one).

Twelve were recruited through the outpatient clinic, 34 were relatives of these females or responded to the letter sent to members of the Dutch X-linked adrenoleukodystrophy patient organization.

Complete clinical and electrophysiological data were available from 46 females, blood samples were available from 45 females (one refused venepunc- ture) and skin biopsies were obtained from 43 women (two refused skin biopsy, one fibroblast culture failed because of a yeast infection).

The age of the included females ranged from 22 to 76 years (average 48 AE 13 years) (Fig. 1).

Mutation analysis was done in 45 females.

For one obligate carrier no leucocytes were available, the mutation in that subject was considered to be the mutation found in her father and paternal uncle (Table 1).


Symptoms, signs and Expanded Disability Status Scale scores are presented in Table 1 and summarized by age group in Table 2.

Complaints of incontinence (both urinary and faecal), abnormal gait, and sensory symptoms were common.

Myelopathy was found in 29/46 (63%) and peripheral neuropathy in 26/46 (57%).

Two of 46 (4%) had peripheral neuropathy without myel- opathy, and 11/46 (24%) had myelopathy without peripheral neuropathy.

Thirty-one of 46 (67%) were considered symptomatic because of either myelopathy and/or peripheral neuropathy.

The percentage of women with signs and symptoms suggestive of myelopathy increased with age (Table 2).

The percentage of symptomatic females increased from 2/11 (18% in the youngest age group) to 7/8 (88% in the oldest age group).

Logistic regres- sion showed a significant relationship between age and symptom- atic status, with the probability of being symptomatic increasing clearly with age [P = 0.002; odds ratio (OR) 1.2 (1.07-1.34); Fig. 2].


Quality of life, as measured by the SF-36, was not statistically significant different between asymptomatic and symptomatic car- riers.

However, on measures that are related to physical disability (Fig. 3A), there was a trend towards a statistically significant dif- ference.

There were no differences in emotional or mental health between asymptomatic and symptomatic carriers.

The levels of disability were measured by the AMC Linear Disability Scale scores (Fig. 3B) and these were compared to data from the CARPA study, a prospective cohort study in Parkinson's disease (Post et al., 2011).

The AMC Linear Disability Scale scores were lower in the group of symptomatic X-linked adrenoleukodystrophy carriers compared with the asymptomatic carriers.

Symptomatic carriers had AMC Linear Disability Scale scores comparable to patients with Parkinson's disease at baseline and 1 year after diagnosis.


Of the X-linked adrenoleukodystrophy carriers 26/46 (57%) had a peripheral neuropathy.

The abnormalities mostly consisted of a reduction in compound muscle and sensory nerve action potential amplitudes, with a marginal slowing in nerve conduction velocity (Table 3).

This is consistent with a sensorimotor axonal peripheral polyneuropathy, as has been reported to occur in males with X-linked adrenoleukodystrophy (van Geel et al., 1996).


The somatosensory evoked potential from the median (arm) nerve was abnormal in 3/42 (7%) of X-linked adrenoleukodystrophy carriers (four registrations failed because of technical reasons), of the tibial (leg) nerve 14/44 (30%) were abnormal (two registra- tions failed) (Table 4).

The median nerve somatosensory evoked potential was normal in all 15 asymptomatic carriers.

The posterior tibial nerve somatosensory evoked potential was abnormal in one (7%) asymptomatic carrier.

Three of 27 (11%) symptomatic carriers had an abnormal median nerve somatosensory evoked potential and 13/29 (45%) had an abnormal tibial nerve somato- sensory evoked potential.

The average latency of the cortical peak increased with age for median nerve and tibial nerve somatosen- sory evoked potential.

The percentage of abnormal somatosensory evoked potentials increased with age (Table 4).


Brainstem auditory evoked potential measurement failed for tech- nical reasons in one participant (Table 4).

For the entire group, 26/45 (58%) had an abnormal brainstem auditory evoked poten- tial, mostly consisting of an increased I-V and I-III interval.

In the asymptomatic group, 3/13 (23%) had a normal brainstem audi- tory evoked potential.

In the symptomatic group this proportion was 23/32 (72%) had an abnormal brainstem auditory evoked potential.

There were no significant left-right differences.


Plasma C26:0 were increased (2.26 AE 0.69 mmol/l; reference values 1.05 AE 0.078 mmol/l; Table 5).

Thirty-one of 45 (69%) had abnormal plasma very long-chain fatty acids levels.

There were no significant differences in plasma C26:0 levels between asymptomatic and symptomatic carriers (P = 0.16).

In contrast to what we reported before, C26:0 levels did not increase with age (Stradomska and Tylki-Szymanska, 2001).


Fibroblast C26:0 levels were increased in 37/43 (86%), and the C26:0/C22:0 ratio in 36/43 (84%) (Table 5).

The D 3 -C16:0/D 3 - C22:0 flux-ratio was decreased in 26/43 (60%), indicating reduced peroxisomal very long-chain fatty acids beta-oxidation capacity.

Two of 43 (5%) carriers had normal C26:0 levels in plasma and fibroblasts, and 1/45 (2%) had normal C26:0 levels and normal peroxisomal beta-oxidation.

There was a clear correl- ation between the ABCD1 protein levels in fibroblasts and the residual peroxisomal beta-oxidation capacity, C26:0 synthesis and very long-chain fatty acids levels (Fig. 4).


The distribution of ABCD1 allele-specific expression (which will be referred to as the pattern of X-inactivation) is shown in Fig. 5A.

There was no evidence for skewing to either the mutated or normal ABCD1 allele.

The pattern appeared random and the median value was exactly 0.5.

The pattern of X-inactivation was similar between age groups (Fig. 5B).

This contrasts with previous reports that documented a highly skewed pattern of X-inactivation in X-linked adrenoleukodystrophy carriers (Migeon et al., 1981).


We subsequently correlated the pattern of X-inactivation with biochemical parameters in fibroblasts, i.e. ABCD1 protein levels, residual beta-oxidation activity and very long-chain fatty acids levels (Fig. 6).

A clear correlation was found between the pattern of X-inactivation and the biochemical parameters in the fibro- blasts.

Indeed, if there was preferential expression of the normal allele, the level of ABCD1 protein was higher, residual rates of beta-oxidation were higher, very long-chain fatty acids synthesis was lower, and very long-chain fatty acids levels were lower, and vice versa.


To determine if the pattern of X-inactivation correlates with symptomatic status it is important to consider age as there is a strong correlation between age and symptomatic status (Fig. 2).

Logistic regression showed no correlation between symptomatic status and the ABCD1 allele-specific expression pattern, also after adjustment for age [P = 0.74; OR 1.00 (0.97-1.02)].

In Fig. 5C and D the distribution of X-inactivation in asymptomatic and symptomatic carriers is plotted.


X-linked adrenoleukodystrophy carriers develop neurological symptoms.

In fact, one of the earliest descriptions of an adreno- myeloneuropathy-like phenotype in X-linked adrenoleukodystro- phy was a female patient (Penman, 1960).

This is not common knowledge among physicians (Jangouk et al., 2012).

Several X-linked adrenoleukodystrophy carriers were reported to undergo cervical laminectomy for suspected cervical spondylogenic myelop- athy (van Geel et al., 1997).


In this largest prospective cross-sectional cohort of female carriers to date, we found that neurological abnormalities are common and that the frequency increases steeply with age.

The main symptoms were consistent with myelopathy, as in males with adrenomyeloneuropathy.

It is striking how often faecal incontin- ence is reported as an early symptom.

One should bear in mind, however, that it is often not voluntarily reported because it is felt to be embarrassing.

To our knowledge, this is not reported often in males with adrenomyeloneuropathy or in other degenerative myelopathies, for instance, hereditary spastic paraplegia, albeit that this feature may not have been specifically asked for (Salinas et al., 2008).


In our cohort sphincter disturbance is a frequent (13/46) and early symptom, and even occurs in a few (2/17) symptomatic carriers without other signs of myelopathy.

Interestingly, most females with X-linked adrenoleukodystrophy were actually relieved to find out that their symptoms were related to X-linked adrenoleukodystrophy, as often they had been told that an X-linked disease does not cause symptoms in 'carriers'.

Signs of peripheral neuropathy were mostly absent or minor clinically, and did not seem to contribute much to the overall dis- ability.

It is possible that signs and symptoms were masked by the more prominent signs of myelopathy.

Notwithstanding, on elec- trophysiological testing about 57% of the females in this cohort fulfilled the criteria for an axonal sensorimotor neuropathy.


There was no statistically significant difference in SF-36 scores between asymptomatic and symptomatic carriers (Fig. 3A).

Although any symptom may affect quality of life, it seems that the majority of symptomatic carriers have symptoms that do not impact the SF-36 enough to be visible at group level.

The z-scores are usually below zero for the symptomatic carriers on the meas- ures related to physical symptoms (Fig. 3A), but the standard de- viation is large, supporting the previous assumption.

However, symptomatic females show a trend towards reduced quality of life in domains related to physical symptoms (Fig. 3A), correspond- ing to the signs of myelopathy frequently present in our cohort.


Analysis of the AMC Linear Disability Scale revealed that mani- festing X-linked adrenoleukodystrophy carriers had similar disabil- ity as patients with Parkinson's disease 1 year after the diagnosis.

However, compared to our cohort, the Parkinson's disease cohort was significantly older (average age 67 versus 48 years), suggest- ing that the burden of disease in X-linked adrenoleukodystrophy carriers is considerable.


Somatosensory evoked potential was reported to be very sensi- tive in detecting abnormalities in X-linked adrenoleukodystrophy carriers in a presymptomatic stage (Restuccia et al., 1997).

In our cohort, however, somatosensory evoked potentials of the median nerve (arm) were normal in all asymptomatic, and abnormal in only 11% of the symptomatic females.

This is not surprising, as in none of the symptomatic females the arms were affected clin- ically.

Somatosensory evoked potentials of the posterior tibial nerve (legs) were only abnormal in 7% of the asymptomatic and 45% of the symptomatic females.

Therefore, we conclude that somatosensory evoked potential is not superior to clinical examination in detecting myelopathy in our cohort.


In agreement with an earlier report, brainstem auditory evoked potential was abnormal in 58% (Restuccia et al., 1997).

A larger proportion of the symptomatic carriers had an abnormal brainstem auditory evoked potential compared with the asymptomatic car- riers (72% versus 23%).

The findings were non-specific, mostly consisting of an increased I-V or III-V interval.

This indicates a slowing of conduction in the brainstem.

For clinical practice brain- stem auditory evoked potential has no value as a diagnostic tool.


As has been known for several decades, 15-20% of X-linked adrenoleukodystrophy carriers have normal plasma C26:0 (Moser et al., 1999).

We found that a slightly higher proportion (31%) had normal plasma C26:0.

Furthermore, even in cultured fibro- blasts the C26:0 can be normal (Moser et al., 1983), as was the case in 6/43 (14%).


Combining C26:0 levels in plasma and fibro- blasts marks 41/43 (95%) of the females in our cohort as biochemically abnormal.

This corresponds to an earlier observation that by combining very long-chain fatty acids measurements in plasma and fibroblasts 93% of carriers can be identified (Moser et al., 1983).


Peroxisomal very long-chain fatty acids beta-oxidation activity in cultured fibroblasts varied from com- pletely normal to values found in males with X-linked adrenoleu- kodystrophy.

By combining very long-chain fatty acids measurements and beta-oxidation activity, 44/45 X-linked adre- noleukodystrophy carriers (98%) could be identified.


However, this still does not reliably identify all X-linked adrenoleukodystro- phy carriers.

Therefore, in females, only ABCD1 mutation analysis identifies all carriers.


We showed that the biochemical abnormalities in fibroblasts correlated with the X-inactivation pattern, i.e. the more skewed to the mutant allele, the more abnormal the fibroblasts were bio- chemically.

Our study showed that in fibroblasts, ABCD1 allele- specific expression (ABCD1 allele-specific expression) predicts the biochemical phenotype.


X-inactivation was considered to be skewed preferentially to the mutant allele (Migeon et al., 1981).

That finding cannot be repro- duced in our data set (Fig. 5).

In fact, the median skewing was 49:51, suggesting a random ABCD1 allele-specific expression pattern.

For over two decades there has been controversy over whether X-inactivation predicts the symptomatic status of X-linked adrenoleukodystrophy carriers.

Watkiss et al. ( 1993) reported that symptomatic status and X-inactivation in fibroblasts do not correl- ate in a small sample of 12 females.

A more recent report sug- gested that skewed X-inactivation patterns in leukocytes did correlate with symptoms in X-linked adrenoleukodystrophy carriers (Maier et al., 2002).

However, the assay used in that study (HUMARA) has limitations because of the genetic distance be- tween the human androgen receptor (Xq12) and ABCD1 gene A limitation of our study is that not all X-linked adrenoleukody- strophy carriers in The Netherlands were examined.

Even though we tried to minimize selection bias by including not only females from the outpatient clinic, and $75% of the participants were recruited through the X-linked adrenoleukodystrophy patient organization (with 52 female members) and relatives, it is still possible that the participants are not a totally random sample of X-linked adrenoleukodystrophy carriers.

Based on the frequency in our cohort it can be estimated there are at least 200 X-linked adrenoleukodystrophy carriers in the Netherlands.

Our cohort therefore probably contains no more than 25-30% of all X-linked adrenoleukodystrophy carriers in The Netherlands.

It cannot be excluded that those without symptoms were less likely to participate.

Although there was no age-matched control cohort, it is unlikely that the symptoms described are attributable to normal ageing.

Myelopathy and peripheral neuropathy cannot be considered a part of healthy ageing.

Co-morbidity, like dia- betes, was rare in the cohort.


In summary, X-linked adrenoleukodystrophy carriers are highly likely to develop symptoms.

The most important predictor is age, with most carriers having some clinical manifestation beyond age 60.

Clinical manifestations are mostly related to myelopathy.

Especially striking is the high incidence of faecal incontinence.

Peripheral neuropathy is not prominent clinically, although based on nerve conduction studies 57% have a sensorimotor axonal peripheral neuropathy.


Biochemical abnormalities are common, but cannot exclude X-linked adrenoleukodystrophy with certainty in females.

The biochemical abnormalities in fibroblasts are clearly related to the X-inactivation pattern.

We were not able to show a link between X-inactivation and symptomatic status, but this may be related to the limitations stated above.


X-linked


Sir, In an interesting study recently published in Brain, Engelen et al. ( 2014) describe a cohort of 46 Dutch heterozygotes with X-linked adrenoleukodystrophy, representing 26 kindreds.

They found that signs and symptoms of neurological involvement increased with age among the females included [1].

However, the authors express concern that selection bias may have skewed their results towards preferential inclusion of symptomatic subjects.

We reported the same phenomenon of age-dependent penetrance among females in our own study (Horn et al., 2013), published in Pediatric Neurology (March, 2013), but not referred to in the present article [3].


This was the first prevalence study that looked at males and females with X-linked adrenoleukodystrophy using modern diagnostic methods, including 26 adult females belonging to 13 separate kindreds.

This study had no selection bias, as all known cases of X-linked adrenoleukodystrophy in Norway (population 5 million) were included.

All symptomatic females were older than 50 years, the asymptomatic ones were younger than 50 years.

Asymptomatic females with neurological signs of long involvement constituted a middle group age-wise.

Four tract females, reportedly healthy, were unavailable for clinical examination.

Naturally, asymptomatic females with no symptomatic family members could not be included except by screening measures, not yet established in Norway.


The findings by Engelen and coworkers lend support to our own results.

Subsequently, further support was found in our recent study (Horn et al., 2014) of small nerve fibre involvement in subjects with a disease-causing mutation in the ABCD1 gene (males and females with or without symptoms of X-linked adrenoleukodystrophy): 10 of 11 subjects showed evidence of small nerve fibre involvement [2].

This was found even among young, asymptomatic heterozygotes with no clinical signs of emerging myelopathy, and increased with age and severity of symptoms.

This indicates that the central and peripheral nervous system is affected in most or all heterozygotes with a mutation in the ABCD1 gene, hence these subjects are not simply carriers of a gene mutation.


Sir, We thank Horn et al. ( 2014) for their comments.

The paper they refer to was published after the first version of the manuscript of our paper (Engelen et al., 2014) was completed, otherwise it would have been included as a reference.


Their findings are indeed completely in line with our study.


We read with interest the recent report from Horn et al. on small nerve fibre dysfunction in X-linked adrenoleukodystrophy and will certainly look at that in our patient population in the future.


It follows that the response of services to missed appointments should be in keeping with the seriousness of the consequences, yet current evidence for telephone prompts and other interventions to encourage attendance is equivocal at best and only relates to studies in newly referred patients (Macharia et al, 1992; Reda & Makhoul, 2001).

Mitchell & Selmes (2007, this issue) state that 'Many [patients] who miss appointments because of slips and lapses later rearrange without adverse consequences'.

If this were true, there would be no indication for these authors' recommendation that further clinic appointments be sent after a non-attendance without first awaiting contact from the patient.

However, the study on which this statement is based (Sparr et al, 1993) was carried out in a military clinic for combat veterans in the USA and had several methodological limitations such that the results have to be interpreted with caution: the non-attendance rate was particularly low (9%); data were collected retrospectively from the treating clinician without corroboration from the case notes; and no definition of what was meant by an 'adverse outcome' was given.

Sparr et al reported that over 70% of patients who missed their appointment spontaneously contacted the clinic to reschedule and they concluded that there was no need for the clinic to actively re-engage non-attenders.

However, in our prospective study of non-attenders at a psychiatric out-patient clinic in London, we found that both new and follow-up patients who missed a single appointment were very


In this issue of APT Mitchell & Selmes present an article detailing why patients miss appointments and how clinicians should respond.

Many of the papers quoted relate to the psychiatric out-patient clinic.

In this commentary, as well as picking up on some of the themes that emerge from their article, I explore the attachment that psychiatrists seem to have to this particular model of patient contact.

unlikely to re-engage with the clinic (Killaspy et al, 2000), and one study from outside the UK found that only half those who missed an appointment re-engaged (Pang et al, 1996).


These 'slips and lapses' are a combination of cleri- cal error on the part of the clinic and, with regard to follow-up patients, social disorganisation secondary to the executive dysfunction and negative symptoms of the mental illness.

Clerical error accounts for a lower proportion of missed appointments in psy- chiatric clinics (5-12%: Sparr et al, 1993; Killaspy et al, 2000) than in other medical specialties (28-33%: Verbov, 1992; Potamitis et al, 1994) but this is a po- tentially preventable cause of non-attendance.

Al- though simple systems to remind patients about their appointments may appear to have face validity, they can only be effective for people who are con- tactable, such as those who actually have a work- ing telephone (Burgoyne et al, 1983).

The associated resources involved also have to be considered and there are currently no published examples of well- conducted cost-effectiveness analyses of telephone or other prompts to reduce non-attendance at mental health appointments in the UK.

Written information leaflets and orientation statements, which are help- ful in reducing anxiety about the appointment for newly referred patients, may be more effective at improving attendance rates than prompts (Kluger & Karras, 1983; Swenson & Pekarik, 1988).


Last year I was invited to write a review article for APT on the origins and future of the out-patient clinic in contemporary mental health services (Killaspy, 2006).

This article detailed the history of how the model developed some 300 years ago from a vehicle to triage new admissions to asylums and later became a replica of the approach used in other medical specialties for patient assessment and review.

Given the consistently high non- attendance rates and evidence of poor outcomes for non-attenders with severe and enduring mental health problems, I suggested that it might be time to review the usefulness of the clinic model for this client group.

I explored an alternative approach that could be integrated within our existing and highly developed community mental health services to facilitate assessment and brief interventions for newly referred patients with common mental disorders and that would provide appropriate triage for patients requiring longer-term care from secondary mental health services.


New Roles for Psychiatrists (National Working Group on New Roles for Psychiatrists, 2004) and the Mental Health Policy Implementation Guide: Community Mental Health Teams (Department of Health, 2002) have far reaching implications and contain detailed guidance on the delivery of assess- ment services for patients newly referred to mental health services and on ongoing treatment for patients with severe and enduring mental health problems.

Both documents describe a secondary mental health service that appears to have no out-patient clinics.

So why, despite the relevant policy to support a new direction, are psychiatrists still inclined to use the clinic model? Is it because we see ourselves as hospital doctors whose activity is measured in the familiar approach of the out-patient clinic? Is it that we enjoy the only part of the job where we get to form a one-to-one therapeutic alliance with our patients, providing a welcome relief from our usual role of multidisciplinary team work? Are we under- confident in our non-medical colleagues' skills in assessment and one-to-one interventions? Are there some more-challenging patients that we feel only we have the experience to contain?


None of these possible explanations has been researched, but in exploring the issue of the thera- peutic alliance, Mitchell & Selmes suggest that the patient's perception of the therapeutic alliance with the clinician and of the latter's helpfulness is important in preventing disengagement from the clinic ('Attendance at follow-up appointments is more a reflection of the patient's satisfaction with care than of the perceived need for further help').

However, the two large studies that have investigated satisfaction with psychiatric out-patient services have not found a statistically significant relationship between dissatisfaction with care and drop-out (Killaspy et al, 1998; Rossi et al, 2002), although considerable patient dissatisfaction has been expressed about being seen by the junior doctor rather than the consultant (Killaspy et al, 1998; McIvor et al, 2004).

In fact, the content of the interaction between patients with psychosis and their psychiatrists appears to be rather unsatisfactory at out-patient appointments (McCabe et al, 2002).

The report on proposed new roles for consultant psychiatrists highlighted the problems of the out- patient clinic model:


'There was almost universal dissatisfaction with out-patient clinics.

The doctor is isolated from the team and patients frequently do not attend.

Patients may present very differently in the artificial environment leading to differences with staff who see the patient at home.

Patients are brought back routinely so as not to lose touch with them rather than out of necessity' (National Working Group on New Roles for Psychiatrists, 2004: p. 12).


Since out-patient non-attendance is no longer a Healthcare Commission performance indicator, it is likely that managerial attention on the out-patient clinic will fade.

The evidence currently suggests that the out-patient model is best targeted at people who are most able and likely to keep appointments and that alternative approaches are indicated for those with more complex mental health problems, including assertive outreach for particularly 'difficult- to-engage' clients.

A more radical review of the model could allow the integration of assessment and brief interventions for newly referred patients, and multidisciplinary triage of those requiring longer- term care under the care programme approach within the full range of community mental health services.

Alternatively, we could continue to organise our services so that the most expensive member of the team sees the patients with the least complex problems and accept the resultant waste of resources when 1 in 3 do not attend.


None.


Patients miss about 20% of scheduled appointments for mental health treatment, almost twice the rate in other medical specialties.

Up to 50% of patients who miss appointments drop out of scheduled care.

Many who miss appointments because of slips and lapses later rearrange their appointments without adverse consequences.

Those that do not are at risk of further deterioration, relapse and hospital readmission.

Predictors of non-attendance are complex and linked with the predictors of missed medication.

Service barriers and administrative errors are common but are often overlooked in the absence of feedback from patients.

Of prime importance are the therapeutic alliance and degree of ‘helpfulness’ of the clinician but again these are rarely measured routinely.

Useful markers of engagement include patient-rated trust, satisfaction and degree of perceived participation in treatment decisions.

Much can be done to improve attendance in most services.

Simple measures such as offering prompt, convenient appointments, offering reminders and augmenting with telephone contact have a reasonable evidence base.

Scales to assess therapeutic alliance are now available.

Complex interventions need to be evaluated carefully in order that the overall benefits outweigh costs.

We suggest that clinicians consider accessibility, discharge policies and patient feedback when examining local rates of non-attendance.


This is the second of two articles by Mitchell & Selmes in APT on patient engagement and retention in treatment.

The first, which addressed non-adherence to medication, appears in the previous issue of the journal [1].

The financial cost of missed appointments in the National Health Service (NHS) has been estimated at £360 million per year [2], most of this accounted for by non-attendance in primary care and hospital out-patient clinics.

The purpose of this article is to review the extent and predictors of non-attendance in people with mental disorders presenting in primary and secondary care.

Although one approach may be to fundamentally question the merits of out-patient clinics [3], our approach is to examine essential predictors and solutions within current models of care.


In considering the classification of missed appointments it is important to distinguish between those who do not attend their first appointment and those who do not attend follow-up appointments.

Unfortunately, in reviewing the literature few studies uphold this distinction.

It is also useful to separate individuals who occasionally miss appointments (partial non-attendance) and those who disengage from any follow-up (often called treatment drop-outs).

To put non-attendance in context, patients may experience difficulty following medical advice at each stage of their patient journey (Fig. 1).


The extent of non-attendance in psychiatry (and perhaps its impact on the patient) may be significantly greater than in other medical specialties.

In 2002–2003, 19.1% of psychiatry out-patient appointments were missed in England, compared with an NHS-wide figure of 11.7% [4].

Of note, the Commission for Healthcare Improvement (now the Healthcare Commission) showed that non-attendance rates varied more than fivefold across 83 mental health trusts in England [5].

These national figures have been replicated in numerous small studies based in psychiatry outpatient clinics, which have reported non-attendance rates of 15.6–28% when examined as a proportion of all offered appointments [6][7][8][9].

Rates of initial non-attendance are usually higher than follow-up non-attendance, although this pattern may not hold for certain specialties [1].

The frequency of partial non-attendance is higher than the rate of full discontinuation (drop-out), echoing the findings of studies of missed medication [1].

Regarding partial non-attendance, Akerblad et al [10] in Sweden found that among 1031 patients with depression treated in primary care over a 6 month period only 54.6% of all scheduled appointments were kept.

In the largest study of full disengagement, Young et al [11] found that 31% of community psychiatric patients were lost to follow-up over the course of 1 year.

Over the course of 2 years the documented attrition rate for unscheduled drop-out may be as high as 50% [12].


In this issue of APT Mitchell & Selmes present an article detailing why patients miss appointments and how clinicians should respond.

Many of the papers quoted relate to the psychiatric out-patient clinic.

In this commentary, as well as picking up on some of the themes that emerge from their article, I explore the attachment that psychiatrists seem to have to this particular model of patient contact.


The evidence that non-attendance of patients at psychiatric out-patient clinics is a major problem that is highly wasteful of resources is unequivocal, but evidence-based guidance regarding what to do about missed appointments is much less clear.

Up to 50% of people with any form of mental health problem miss an appointment either in primary or secondary care at some point during a treatment episode, around 30% of all psychiatric out-patient appointments are missed and somewhere between a quarter and a half of people who miss an appointment completely disengage from mental health services [1][2].

However, the consequences of missing an appointment are more serious for people with severe and enduring mental health problems such as schizophrenia, schizo-affective disorder and bipolar affective disorder, who are much more likely to require a subsequent admission than those with common mental disorders [3][4][5].

Most people being seen as follow-up patients have a diagnosis of a severe and enduring mental health problem, whereas newly referred patients generally have common mental disorders [6][7][5].


Response to missed appointments


It follows that the response of services to missed appointments should be in keeping with the seriousness of the consequences, yet current evidence for telephone prompts and other interventions to encourage attendance is equivocal at best and only relates to studies in newly referred patients [8][9].

Mitchell & Selmes [2] state that ‘Many [patients] who miss appointments because of slips and lapses later rearrange without adverse consequences’.

If this were true, there would be no indication for these authors’ recommendation that further clinic appointments be sent after a non-attendance without first awaiting contact from the patient.

However, the study on which this statement is based [10] was carried out in a military clinic for combat veterans in the USA and had several methodological limitations such that the results have to be interpreted with caution: the non-attendance rate was particularly low (9%); data were collected retrospectively from the treating clinician without corroboration from the case notes; and no definition of what was meant by an ‘adverse outcome’ was given.

Sparr et al reported that over 70% of patients who missed their appointment spontaneously contacted the clinic to reschedule and they concluded that there was no need for the clinic to actively re-engage non-attenders.

However, in our prospective study of non-attenders at a psychiatric out-patient clinic in London, we found that both new and follow-up patients who missed a single appointment were very unlikely to re-engage with the clinic [5], and one study from outside the UK found that only half those who missed an appointment re-engaged [4].


These ‘slips and lapses’ are a combination of clerical error on the part of the clinic and, with regard to follow-up patients, social disorganisation secondary to the executive dysfunction and negative symptoms of the mental illness.

Clerical error accounts for a lower proportion of missed appointments in psychiatric clinics (5–12%: [10][5]) than in other medical specialties (28–33%: [11][12]) but this is a potentially preventable cause of non-attendance.

Although simple systems to remind patients about their appointments may appear to have face validity, they can only be effective for people who are contactable, such as those who actually have a working telephone [13].

The associated resources involved also have to be considered and there are currently no published examples of well-conducted cost-effectiveness analyses of telephone or other prompts to reduce non-attendance at mental health appointments in the UK.

Written information leaflets and orientation statements, which are helpful in reducing anxiety about the appointment for newly referred patients, may be more effective at improving attendance rates than prompts [14][15].


Relevance of the out-patient model in contemporary mental health services


Last year I was invited to write a review article for APT on the origins and future of the out-patient clinic in contemporary mental health services [1].

This article detailed the history of how the model developed some 300 years ago from a vehicle to triage new admissions to asylums and later became a replica of the approach used in other medical specialties for patient assessment and review.

Given the consistently high non-attendance rates and evidence of poor outcomes for non-attenders with severe and enduring mental health problems, I suggested that it might be time to review the usefulness of the clinic model for this client group.

I explored an alternative approach that could be integrated within our existing and highly developed community mental health services to facilitate assessment and brief interventions for newly referred patients with common mental disorders and that would provide appropriate triage for patients requiring longer-term care from secondary mental health services.


New Roles for Psychiatrists [16] and the Mental Health Policy Implementation Guide: Community Mental Health Teams [17] have far reaching implications and contain detailed guidance on the delivery of assessment services for patients newly referred to mental health services and on ongoing treatment for patients with severe and enduring mental health problems.

Both documents describe a secondary mental health service that appears to have no out-patient clinics.

So why, despite the relevant policy to support a new direction, are psychiatrists still inclined to use the clinic model? Is it because we see ourselves as hospital doctors whose activity is measured in the familiar approach of the out-patient clinic? Is it that we enjoy the only part of the job where we get to form a one-to-one therapeutic alliance with our patients, providing a welcome relief from our usual role of multidisciplinary team work? Are we under-confident in our non-medical colleagues’ skills in assessment and one-to-one interventions? Are there some more-challenging patients that we feel only we have the experience to contain?


None of these possible explanations has been researched, but in exploring the issue of the therapeutic alliance, Mitchell & Selmes suggest that the patient’s perception of the therapeutic alliance with the clinician and of the latter’s helpfulness is important in preventing disengagement from the clinic (‘Attendance at follow-up appointments is more a reflection of the patient’s satisfaction with care than of the perceived need for further help’).

However, the two large studies that have investigated satisfaction with psychiatric out-patient services have not found a statistically significant relationship between dissatisfaction with care and drop-out [18][19], although considerable patient dissatisfaction has been expressed about being seen by the junior doctor rather than the consultant [18][20].

In fact, the content of the interaction between patients with psychosis and their psychiatrists appears to be rather unsatisfactory at out-patient appointments [21].


The report on proposed new roles for consultant psychiatrists highlighted the problems of the out-patient clinic model:


‘There was almost universal dissatisfaction with out-patient clinics.

The doctor is isolated from the team and patients frequently do not attend.

Patients may present very differently in the artificial environment leading to differences with staff who see the patient at home.

Patients are brought back routinely so as not to lose touch with them rather than out of necessity’ [16].


Since out-patient non-attendance is no longer a Healthcare Commission performance indicator, it is likely that managerial attention on the out-patient clinic will fade.

The evidence currently suggests that the out-patient model is best targeted at people who are most able and likely to keep appointments and that alternative approaches are indicated for those with more complex mental health problems, including assertive outreach for particularly ‘difficult-to-engage’ clients.

A more radical review of the model could allow the integration of assessment and brief interventions for newly referred patients, and multidisciplinary triage of those requiring longer-term care under the care programme approach within the full range of community mental health services.

Alternatively, we could continue to organise our services so that the most expensive member of the team sees the patients with the least complex problems and accept the resultant waste of resources when 1 in 3 do not attend.


Chronic opioid use for non-cancer-related illness has been increas- ingly scrutinised in recent years.

While the total number of opioid prescriptions is decreasing in the United States, the average number of prescriptions per year remains at 51.4 per 100 citizens.

1 This im- plies that a large number of prescriptions continue to be provided for non-cancer-related conditions.

This problem is not limited to the United States, as emerging literature over the past few years from Europe reports increased rates of opioid prescriptions for non-can- cer-related pain.

2,3 Data suggest that chronic opioid use impairs clinical care with worse disease outcomes and increases all-cause mortality.


Inflammatory bowel disease (IBD) is a chronic illness with a re- lapsing and remitting course.

Disease flares are accompanied by symptoms such as abdominal pain, nausea/vomiting and diarrhoea.

These symptoms are often severe enough to prompt emergency room visits, during which patients are likely to receive opioids as our group has shown previously.

5 This phenomenon has also been docu- mented outside the US, as prior studies reported Canadian patients with chronic opioid use and IBD had more emergency department visits and decreased quality of life as compared to patients without chronic opioid use.

6,7 Furthermore, previous studies have found chronic opioid use in IBD is associated with worse surgical outcomes, longer hospital stays and increased mortality.

8,9 Many predictors of chronic opioid use are associated with poorer outcomes in IBD such as smoking, depression and therapeutic non-compliance.

5,10 We sus- pect that chronic opioid use may further interfere with productive therapy by enhancing patient behaviours that compromise effective clinical management.


In recent years, IBD therapeutic management has placed in- creasing emphasis on rapid escalation of therapy in response to disease biomarkers to improve outcomes.

11 Thus, clinicians are often hypervigilant in modifying therapeutic regimens in response to perceived disease flares.

While 'tight control' improves disease management in the vast majority of IBD patients, we suspect that it potentiates an unintended negative impact in patients who regularly receive opioids.


IBD patients receiving chronic opioids are susceptible to both IBD flares and the clinical manifestations of opioid withdrawal.

12 There is similarity between symptoms of opioid withdrawal and IBD flares including abdominal pain, nausea, diarrhoea and malaise, which falsely mimics disease re- currence and complicates disease management.


In the interest of maintaining 'tight control' of IBD, we suspect that providers abandon biologic therapies and label patients with chronic opioid use as 'primary non-responders'. 13 Currently, there are no studies investigating the impact of the recent shift in IBD management to obtain 'tight control' on patients with chronic opioid use.


We hypothesise that this group may have rapid therapeutic cycling, which quickly leaves patients without treatment options.

This study is designed to determine if chronic opioid use is associated with early discontinuation of biologic therapies independent of disease severity.


This study followed a retrospective cohort design.

The study population included individuals diagnosed with IBD who received their first biologic prescription during the years 2011-2016.

Individuals with IBD were identified utilising the ICD-9 (555.X, 556.X) or ICD-10 (K50.X, K51.X) diagnosis codes for Crohn's dis- ease and ulcerative colitis.

The study index date was identified as the earliest date associated with either inpatient administration or outpatient prescription claims of a biologic agent of interest, in- cluding adalimumab, infliximab, certolizumab, golimumab, vedoli- zumab and ustekinumab.

Inpatient administrations were identified by Healthcare Common Procedure Coding System J-codes, and outpatient prescription claims were identified by Generic Product Identifier codes.


At the index date, individuals were included if they were ≤65 years of age and fully enrolled with prescription drug bene- fits for at least 6 months prior to the index date and 2 years after the index date.

Patients >65 were excluded from analysis due to incomplete data in the Truven MarketScan Commercial Database, which does not include Medicare claims data.

Relevant covariates and outcomes of interest for each individual were extracted begin- ning 6 months prior to the index date and ending either at a gap in full enrolment or the study termination date (31 December 2016).


Individuals were then separated into cohorts based upon ob- served chronic opioid use throughout the entire study period.

Outpatient opioid prescription claims were identified utilising GPI codes beginning with '65'.

Chronic opioid use was defined as hav- ing at least a 90-day supply of outpatient opioid prescriptions in a 6-month period without any 30-day gaps in opioid coverage, a defi- nition that has been utilised in previous studies.

5,14-18 Chronic opi- oid use was observed both in the 6-month pre-index period and the post-index study period.


Insurance claims data utilised in this study were procured from the Truven MarketScan Commercial Claims and Encounters da- tabase.

The Truven MarketScan Research Databases (www.truve nheal th.com) are administrative claims-based databases represent- ing more than 255 million covered individuals and are considered representative of the privately insured population in the US.

More than 2100 peer-reviewed articles have been published utilising MarketScan data.


The primary outcome of interest was persistence to biologic ther- apy.

Persistence days were defined as the period from the index 13652036, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.16269 by Stanford University, Wiley Online Library on [03/10/2025].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License date to the first 8-week gap in supply of any biologic of interest.


An 8-week gap was chosen as it would be equivalent to missing a full dosing interval of the any of the biologics of interest.

Individuals were deemed non-persistent if they had an 8-week gap in supply prior to the end of the study window or their eligible period of en- rolment.

Secondary outcomes of interest included the number of unique biologics utilised by individuals, and the days persistence to each biologic in chronological sequence.

All persistence calculations were carried out in SAS software version 9.4 20 utilising previously validated methods.


Demographic covariates of interest were collected, including sex, age, geographic region and enrolment dates.

Diagnosis of relevant comorbid conditions and Charlson comorbidity index were evalu- ated and reported.

23 All diagnoses were identified utilising Clinical Classifications Software for ICD-9 and ICD-10 from the Healthcare Cost and Utilization Project (HCUP), as well as previous litera- ture.

24,25 Diagnoses were coded as binary variables for individuals with at least one diagnosis code during the 6-month pre-index pe- riod or the post-index study period.


Patterns of healthcare utilisation were also examined, includ- ing hospital admissions, emergency department visits, abdominal surgeries, endoscopies, the utilisation of inpatient and outpatient steroids and receipt of opioid agonist therapy.

Abdominal surger- ies and endoscopies were identified utilising Procedure Classes Software from HCUP.

26 Inpatient medication utilisation was determined by Healthcare Common Procedure Coding System J-codes, and outpatient medication claims were identified by Generic Product Identifier codes.

Variations in assessed outcomes and covariates in IBD patients with or without chronic opioid use were initially examined and assessed for statistical significance (P < 0.05) utilising Chi-square and t test methods in SAS software, version 9.4.


A survival analysis was conducted with chronic opioid use as the in- dependent variable of interest and days of biologic persistence con- sidered as the endpoint.

Patients who were persistent to biologic therapy at the end of their observation period were treated as right- censored.

Univariable survival curves were estimated for categorical variables, and the functional form of continuous variables was as- sessed.

Univariable hazard ratios were reported for categorical vari- ables and for those continuous variables that showed evidence of being linear in the log-hazard.


A Cox proportional hazards regression model was developed to assess the relationship between chronic opioid use and the risk of discontinuing therapy, while adjusting for potential confounding in- fluences.

A purposeful variable selection strategy was followed in developing the multivariate model.

27 Model discrimination and cali- bration were quantified by Harrell's c statistic and the May-Hosmer goodness-of-fit test 28 with G = 10 risk score groups respectively.

R Core Team 29 was used for the survival data analysis, with the survival package 30 for statistical modelling, and the survminer package 31 for plotting survival curves.

Significance level for null hypothesis testing was set at 5%.


The final study cohort comprised of 16 624 individuals with IBD who were initiated on biologic therapy during the study period.

In this co- hort, we identified 9013 (54.2%) individuals who received an opioid prescription, with 1768 (10.6%) meeting criteria for chronic opioid use.

Substance use disorder was diagnosed in 26.9% of the chronic opioid use cohort, and 15.2% received opioid agonist therapy.

Subjects with chronic opioid use were observed to have greater periods of continu- ous insurance coverage than others in the study population, which allowed for longer follow-up during this study period.

Individuals with chronic opioid use had a median follow-up time of 1443 days compared to 1270 days in those without a diagnosis of chronic opioid use (P < 0.0001; Table 1).

A significantly greater proportion of IBD patients with chronic opioid use had Crohn's disease as compared to those without (87% vs 84.2%, P = 0.002), whereas no significant dif- ference between the cohorts was observed in the incidence of ulcera- tive colitis and indeterminate colitis.

For this reason, disease subtype was included in the multivariable model.

However, other results were not classified by disease subtype in order to simplify reporting.


Significant differences in patient demographics were noted among those with chronic opioid use, including sex, age and geographic re- gion.

Patients with chronic opioid use were predominantly female (57.4% vs 50.8%) and older (mean age of 45 vs 37).

The majority of patients with chronic opioid use were in the age range of 45-65 years old (55.1%), while just 35.7% of IBD patients without chronic opioid use fell into this same range (P < 0.0001).

Patients with chronic opi- oid use were more likely to reside in the 'Southern' region than those without chronic opioid use (P < 0.0001), whereas patients without chronic opioid use were more likely to reside in the 'Northeast.'


IBD patients in the chronic opioid use cohort were significantly more likely to utilise more than one biologic agent during the study pe- riod (P < 0.0001; Table 2).

Subjects with chronic opioid use utilised a mean 1.5 different biologics, as compared to 1.37 biologics in the reference IBD cohort (P < 0.0001).

Individuals with chronic opioid use were significantly more likely to utilise adalimumab (P < 0.0001), golimumab (P = 0.0003), certolizumab (P < 0.0001) and ustekinumab (P = 0.029) than those in the reference IBD cohort.

Furthermore, 13652036, 2021, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/apt.16269 by Stanford University, Wiley Online Library on [03/10/2025].

See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License individuals with chronic opioid use were less likely to receive inf- liximab (P = 0.0002).

There was no significant difference in vedoli- zumab use between groups.


In addition to a higher number of unique biologic agents used over the study period, we found that IBD patients with chronic opi- oid use had decreased duration of persistence to biologic therapy Table 3).

A sig- nificantly greater proportion of patients with chronic opioid use had decreased persistence to biologic therapy when compared to the IBD reference group (P < 0.0001), as evidenced by the low percentage of biologic therapy persistence observed in the chronic opioid use group (16.2%) compared to the IBD reference group (33.5%) at the end of the study period (P <0.0001) (Figure 1).

Treatment duration on the first and second biologic agents prescribed for IBD was significantly shorter in patients with chronic opioid use compared to those with- out (P < 0.0001).

However, no significant difference was observed between groups by the third, fourth or fifth lines of therapy.


Healthcare utilization, including emergency department visits, hos- pital admissions, abdominal surgeries, mean number of endosco- pies and steroid usage, was observed to be significantly higher in the chronic opioid use cohort (P < 0.0001) (Table S1).

The rates of common comorbidities and conditions, including fistula, malnutri- tion, mental disorder, cancer, chronic pain and arthritis diagnoses, were all significantly higher in the chronic opioid use cohort com- pared to the reference IBD patients.

The average Charlson comor- bidity index was significantly higher in chronic opioid use patients compared to the reference IBD patients (1.17 vs 0.69; P < 0.0001).

The chronic opioid use cohort experienced more comorbid condi- tions and disease complications, while also utilising healthcare re- sources to a greater extent than the reference cohort.


Univariable survival curves by chronic opioid use status were sig- nificantly different (P < 0.0001).

Subjects with chronic opioid use were 56% more likely to be non-persistent (hazard ratio 1.56, 95% CI [1.48-1.65]).

Among other categorical variables, only Crohn's disease failed to show a significant univariable association with risk of non- persistence (hazard ratio 0.98, 95% CI [0.93-1.03]) (Table S2).

Among After variable selection and assessment of the proportional haz- ard assumption, the main effects model included chronic opioid use, dichotomous age (<50 vs ≥50), gender, arthritis, mental disorder, ab- dominal surgery, inflammatory bowel disease type, number of inpa- tient admissions and inpatient steroid exposure (Table 4).

Subjects with chronic opioid use were 23% more likely to be non-persistent to biologic therapy, after adjusting for the other variables included in the final multivariable model (hazard ratio 1.23, 95% CI [1.16- 1.31]).

Diagnostics indicated that the final model was stable and well-calibrated (P-values in all 10 risk score groups were well above 0.05).

Concordance was c = 0.60, indicating moderate predictive accuracy.


This study addresses the hypothesis that chronic opioid use among IBD patients portends shorter periods of persistence on biologic therapies independent of disease severity.

In this analysis, we found that IBD patients with chronic opioid use trialled a greater mean number of biologic therapies and had shorter mean durations of therapy on the first and second agents trialled.

These results are strengthened by a large, nationwide sample that allows for greater generalisability of the findings.

An additional strength is the use of predictive modelling, which confirmed a significant difference in the risk of early discontinuation of biologic therapy when controlling for factors such as healthcare utilisation, abdominal surgeries, age, sex, steroid use and other medical comorbidities.


Based upon our univariable analysis, the time to discontinuation decreases with increased comorbid conditions, emergency depart- ment visits, inpatient admissions and steroid therapies.

IBD patients with chronic opioid use in our study population were observed to have higher rates of comorbidities and healthcare utilisation as com- pared to the reference cohort.

Using these variables as surrogate markers for disease acuity, we acknowledge the possibility that chronic opioid users have more severe IBD, which contributes to higher rates of biologic failure and therefore decreased persistence to biologic therapy.

We also considered the possibility that the chronic opioid use cohort was simply sicker overall, given this group had a higher Charlson comorbidity index compared to the reference group.

However, the chronic opioid use cohort was still 23% more likely to discontinue biologic therapy early even when controlling for the most relevant surrogate factors of disease severity using a mul- tivariable predictive model.

This suggests that the difference cannot be solely attributed to greater disease severity or concomitant co- morbidities in the chronic opioid use cohort, which lends strength to the study's conclusions.


Results presented show that the risk of biologic discontinuation increased linearly as the number of emergency department visits and outpatient steroid usage increased.

IBD patients with chronic opioid use were observed to visit the emergency department more frequently and receive higher doses of steroid therapy for presumed IBD flares.

More frequent emergent healthcare utilisation in pa- tients as well as a greater reliance on rescue steroid therapy may lead to earlier determination of biologic therapy failure and subse- quently decreased persistence.


However, given that IBD patients with chronic opioid use are more likely to have early discontinuation of biologic therapy even when controlling for surrogate markers of disease severity, including measures of healthcare utilisation, we suspect that other factors associated with chronic opioid use de- crease the likelihood of persistence to biologic therapies.

Symptoms of opioid withdrawal that occur with chronic opioid use resemble IBD flares, and may lead providers to inappropriately switch bio- logic therapies under a false assumption of poor disease control.

Additionally, gaps in biologic therapy due to shorter periods of per- sistence may diminish treatment effect and increase the risk for the development of antibodies to biologics, necessitating discontinua- tion or therapeutic switch.

32 It is interesting to note that patients with chronic opioid use were significantly more likely to receive self-injectable biologic therapies than those without chronic opioid use.

This could be an additional reason for decreased persistence to therapy in this patient popula- tion, as it places increased onus on patients to obtain and self-admin- ister therapy without further provider contact.

Lack of persistence to therapy may be detected in a timelier manner in those receiving infusion therapies and allow for more rapid intervention to ensure patients remain on track with therapy.


This study relies on commercial insurance claims data, which may not be representative of the non-insured and Medicaid/Medicare populations.

The retrospective design of this study may introduce increased risk of confounding factors.

Due to the large scale of data collection, we were unable to track direct indicators of disease se- verity, including abdominal CT scan findings, endoscopy findings, faecal calprotectin, C-reactive protein, etc.

Therefore, we were un- able to directly control for disease severity and were forced to use surrogates of disease severity including abdominal surgeries, fistula and inpatient admissions.

We acknowledge that direct indicators of disease severity are a major factor in clinical decision-making with regard to therapeutic alteration.


We found that chronic opioid use is independently associated with a shorter period of persistence to biologic therapy.

The number of biologic therapeutic options for IBD remains relatively limited, and recognition of this phenomenon is of paramount importance for pre- serving therapeutic options for IBD patients.

Prior to abandoning a biologic therapy, we implore clinicians to remain hypervigilant for withdrawal symptoms, and ensure that patients with chronic opioid use demonstrate definitive biomarkers of ongoing disease activity such as elevated faecal calprotectin and/or endoscopic appearance.

Furthermore, we suggest that clinicians involved in the care of IBD pa- tients remain vigilant in identifying patients at risk for chronic opioid use and work with patients to find alternative methods for symptom and pain control.

Future study investigating the benefit of partner- ships with addiction medicine to improve outcomes in IBD is merited.


Patients with IBD frequently endure chronic pain.

Despite the drawbacks of opioids in IBD, a significant proportion of IBD patients rely on them.

In line with the global opioid epidemic, the use of opioids has increased in IBD [1].

Up to 30% of IBD outpatients and up to 70%-90% of hospitalised patients receive opioids [2].

In this journal, Rhudy et al report a retrospective study assessing the association between chronic opioid use and biologic agent persistence [3].

The authors hypothesise that IBD patients with chronic opioid use frequently experience symptoms of opioid withdrawal.

These symptoms may mimic disease recurrence, resulting in a rapid cycling of biologics.

Using the Truven MarketScan Database, 1768 out of 16,624 patients were identified as chronic opioid users.

The primary outcome ‘persistence’ was defined as the period from the index date to the first 8-week gap in supply of any biologic of interest.

The IBD patients with chronic opioid use utilised more different biologics (1.5 vs 1.37 in the reference group) and had a lower persistence on biologics (16.2% vs 33.5%).

When controlling for various confounders, patients with chronic opioid use are 1.23 more likely to be non-persistent to biologic therapy.


This does not necessarily mean that biologics are discontinued inappropriately in IBD patients with chronic opioid use.

First, reasons for discontinuation were not recorded.

Second, although the association between chronic opioid use and persistence was independent of surrogate markers of disease activity (steroids, healthcare utilisation), objective markers were missing.

Third, conclusions about causal relationships between chronic opioid use and persistence could not be drawn from the present study.

Chronic opioid users may have a more complex IBD, which is characterised by a higher turnover of different biologics.

In contrast, chronic opioid users may develop difficult to control symptoms which are interpreted as disease recurrence, leading to treatment cycling.

Despite the inherent limitations of the retrospective design, the results are strengthened by the large patient population and sound statistical methods.

More importantly, this study touches upon a relevant topic in clinical practice.

Chronic opioid use is associated with numerous side effects, increased infections, and mortality [2, 4, 5].

Even more worrisome, data supporting a benefit of opioids for pain control and quality of life are lacking [6, 7]. What to do with this information?

First, opioid use should be discussed with patients before discharge or during outpatient visits.

Second, the stepwise pain management should be critically reviewed, focusing on non-opioid pharmacological alternatives (COX-2 inhibitors, tricyclic antidepressants) and psychological and behavioural support [8].

A recent study shows that a multimodal intervention, including an IV acetaminophen protocol, a gastroenterology consult note ‘smartphrase’, an IBD pain management pathway, and automated text message alerts, substantially reduced intravenous opioid use and hospital length of stay, with similar pain scores [9].

Implementation of a multidisciplinary team and a holistic approach in order to reduce chronic opioid use and prevent further harm is of vital importance.


We thank Dr van der Have and Dr Maljaars for their commentary on our work [1], [2].

This study was inspired by observations in our IBD clinic, a large tertiary referral centre in a state plagued by the opioid epidemic.

While the limitations of using large databases such as Truven are well highlighted, we agree with the statement, 'chronic opioid users may develop difficult to control symptoms interpreted as disease recurrence, leading to treatment cycling.' This phenomenon further underscores the importance of relying on objective evidence of disease recurrence, be it elevated biomarkers (eg CRP or fecal calprotectin), weight loss, imaging, or endoscopic visualization, prior to abandoning therapy.


Drs van der Have and Maljaars provide many wonderful examples of strategies and interventions which can be pursued for identifying and treating IBD patients at risk for chronic opioid use.

We agree a multidisciplinary approach is essential for the management of IBD patients at risk for opioid dependence, and believe future studies quantifying their benefit will further incentivize widespread implementation.


The authors' declarations of personal and financial interests are unchanged from those in the original article [2].


Mitral regurgitation is a public health problem, as the most frequent valvular disease 1 leading to frequent referrals, hospitalizations, and cardiac surgery, 2 and its burden is expected to increase with ageing of the population.

1 Degenerative mitral regurgitation (DMR) with mi- tral valve prolapse is the most frequent organic mitral regurgitation and the most repairable, but it is often undertreated in routine clinical practice.

3 This prevalent under treatment in both Europe and North America has multiple causes, 4 but is favoured by sub-optimal risk as- sessment.

2 In DMR, individual risk factors have been identified 5-11 and endorsed by clinical guidelines.

12,13 However, while guidelines strongly recommend a combination of those risk factors in an inte- grated process, 12,13 there has so far been no attempt at deriving and validating a risk score satisfying such unmet need.

The lack of an inte- grated risk score usable at diagnosis contrasts with the availability of surgical risk scores, 14 which are nevertheless instrumental mainly in surgical decisions.

Current unavailability of a mortality score in DMR should not be surprising, since very large cohorts of patients with uni- form diagnosis and comprehensive clinical data are required, war- ranting multi-centre collaboration to obtain separate cohorts for the derivation and validation process (the two mandatory steps to obtain a score and to make it applicable to daily practice).

The international MIDA registries 15,16 provide the unique opportunity to analyse a comprehensive set of risk markers (prospectively and homoge- neously collected) in an integrated manner, allowing derivation and subsequent external validation of a MIDA Score specifically applicable to DMR.


Accordingly, we aimed at developing a risk score easily derivable from routinely collected clinical/echocardiographic parameters endorsed by guidelines and at validating this score externally.

We also wanted to verify the hypothesis that a user-friendly MIDA mor- tality score is independently and incrementally predictive of short- and long-term survival after diagnosis of DMR.

In summary, we aimed at providing for the first time a tool able to position a given patient within a continuous spectrum of mortality risk whether assigned to surgical treatment or to continuing medical therapy.


A fully detailed 'Methods' section is available as Supplementary material online, whereas a more concise version is reported below.


The Mitral Regurgitation International DAtabase (MIDA) registries were created by systematically merging a series of prospectively assembled electronic institutional echocardiographic databases, each originally generated to optimize echocardiographic reporting (see Appendix).

All patients provided prior informed consent for anonymous publication of their clinical data; the study was conducted in accordance with institu- tional guidelines, national legal requirements, and the revised Helsinki declaration.

The present reporting complies with the TRIPOD statement and dedicated tutorials.

17 18


All MIDA registries share analogous general eligibility criteria: (i) inclusion of consecutive patients with primary DMR by transthoracic echocardiog- raphy; (ii) availability of a comprehensive clinical/instrumental evaluation at index echocardiography; (iii) exclusion of secondary (functional) mitral regurgitation of any aetiology, ischaemic regurgitation, significant con- comitant aortic disease, mitral stenosis, active endocarditis, congenital diseases, prior valve surgery.


Patients analysed in the Derivation Cohort were those included in the MIDA-Flail Registry encompassing 1/1/1980 to 12/31/2005.

15 Patients en- rolled in the MIDA-Flail Registry fulfilled the general inclusion/exclusion criteria of the MIDA registries, but, as an additional requirement, they all received a diagnosis of DMR and flail leaflets.


The Validation Cohort consists of consecutive patients enrolled in the MIDA-BNP Registry, encompassing 1/1/2000 to 31/12/2013.

16 The MIDA-BNP Registry fulfils the general inclusion/exclusion criteria of the MIDA registries, but it additionally requires -as a specific inclusion criter- ion- a blood sample collection.

The diagnosis of flail leaflets is not manda- tory for the MIDA-BNP Registry, and both DMR and mitral valve prolapse or DMR and flail leaflets can be included.

By study design, pa- tients could be part of only one of the two cohorts.


Echocardiographic data were analysed as collected at the time of echo- cardiography 19 without subsequent modification.

The severity of DMR was based on the final diagnosis reported in the original echocardio- graphic report, which was performed by integrating all recorded echocar- diographic parameters.


Prognostic markers analysed to create the MIDA Score were selected on the basis of their known link to outcome in DMR and their guideline- based mention as a potential trigger for surgery (i.e. age > _65 years, left atrial diameter > _55 mm, ejection fraction < _60%, left ventricular end- systolic diameter > _40 mm, heart failure symptoms, atrial fibrillation, and right ventricular systolic pressure >50 mmHg).


The primary end point was long-term survival.

The secondary end point was 1-year survival.

Outcome was ascertained by investigators blinded to baseline predictors of outcome.

The follow-up was completed up to death, end of the study or at least 5 years in 3322 (91%) patients.


Since surgery is a competing risk event when analysing survival under medical management, we took advantage of competing risk analysis.

This approach makes it possible to estimate hazard rates separately for each transition, diagnosis to surgery, or diagnosis to death, stratified by centre.

A Markov proportional hazards model was used to estimate the hazard ratios (HR) for predictors at transitions from diagnosis to surgery, or diagnosis to death.

Proportional hazard assumptions were evaluated with scaled Schoenfeld residuals.


Hazard ratios of univariate competing risk models were estimated in the Derivation Cohort for the components of the Score.

Weights for these risk factors were calculated by redoing the univariate, transition-specific HR.

In order to capture the risk attached to the consequences of volume overload (rather than the nonspecific risk of death related to aging), 11 the weight for age > _ 65 years in keeping with the results of competing risk analysis was set at a value of 3 (see Supplementary material online for more explanation).

For each pa- tient the MIDA Score was calculated as the sum of these weights (Table 2).


The predictive ability of the MIDA Score for survival under med- ical management was described using a Harrell's C-statistic for the survival models.

21 The C-statistic ranges from 0.5 to 1.0, with values of 0.5 indicating no predictive ability, and a value of 1.0 indicating per- fect predictive ability.

The C-statistic was estimated by fitting a com- peting risk model to the derivation data and the validation data separately.


Since some variables may not have been detectable (e.g. systolic pulmon- ary pressure in the absence of tricuspid regurgitation), the main analysis was based on the clinical principle that absent or missing variables are counted as negative.

As an additional analysis, multiple imputation was used to generate 10 data sets and then to average the results.


Association of the MIDA Score with 1-year mortality was analysed with a logistic regression model in the Derivation Cohort and validated for the Validation Cohort.

The C-statistic (Somer's D) was used to examine the predictive power of the score in the Validation Cohort.


Baseline characteristics of 2472 patients included in the Derivation Cohort are summarized in Table 1 (left column).

Flail leaflet was idio- pathic in 2301 (93%) patients, caused by healed endocarditis in 171 (7%).

Involvement was confined to the posterior leaflet in 1956 (79%) patients and to the anterior leaflet in 346 (14%), while both leaflets were involved in 170 (7%) patients.


During follow-up (9.2 ± 5.4 years), 960 deaths occurred (390 under medical management).

Overall survival at 10 years was 68 ± 1% (56 ± 2% in patients symptomatic at diagnosis).


At univariate analysis, symptom presence, ejection fraction < _60%, left-ventricular end-systolic diameter > _40 mm, atrial fibrillation pres- ence, right ventricular systolic pressure > _50 mmHg, left atrial diam- eter > _55 mm, and age > _65 years were all associated with survival Table 2.


In the Derivation Cohort, the median MIDA Score was 4 (25th- 75th percentile: 2-6) (Table 3).

The MIDA Score adjusted for age was independently associated with an increased risk of death under med- ical follow-up (adjusted HR [95% CI] per unit 1.20 [1.15-1.25] P < 0.001).

The independent prognostic significance of the MIDA- Score was also confirmed by competing risk model and multiple im- putation (adjusted HR [95% CI] per unit 1.18 [1.13-1.23] P < 0.001).

The concordance for the model with the MIDA Score adjusted for age in the Derivation Cohort was satisfactory [c = 0.78; standard de- viation (SD) 0.02].


Mitral valve surgery was eventually performed in 1934 (78%) pa- tients (89% repair).

The median time (25th-75th percentile) from the baseline echocardiogram to the operation was 0.2 (0.1-1.9) years.

During a post-surgical follow-up of 9.2 ± 4.8 years (median [25-75th percentile], 8.7 [6.3-12.1] years), 570 patients died.

The MIDA Score regardless of age was associated with an increased risk of post- surgical death (adjusted HR [95% CI] per unit 1.15 [1.11-1.19] P < 0.0001).

Data on recurrence of regurgitation after repair were available for 1480/1713 patients; 20 years' freedom from > _3þ mitral regurgitation was 88% (95% CI, 86-90).


Baseline characteristics of the Validation Cohort (n = 1194) and MIDA Score distribution are depicted in Tables 1 and 3, respectively.

When compared to the Derivation Cohort, patients included in the Validation Cohort were more often symptomatic, although showing less severe consequences of DMR.

These findings can be explained by the limited reproducibility of symptom assessments, the higher prevalence of female patients in the Validation Cohort, and the higher use of beta-blockers rather than digoxin in this group.

22 During a follow-up of 4.8 ± 2.4 years, 191 deaths occurred (131 under medical management).

Overall survival at 10 years was 68 ± 5% (59 ± 7% in patients symptomatic at diagnosis).

Surgery was eventually per- formed in 725 patients (93% repair).


Competing risk analysis confirmed the MIDA Score to be re- gardless of age associated with long-term risk of death under medical management (adjusted HR [95% CI] per unit 1.13 [1.01-1.22]; P < 0.001) (c = 0.81; SD 0.03).

The MIDA Score re- gardless of age also predicted long term post-surgical outcome (adjusted HR [95% CI] per unit 1.35 [1.19-1.54]; P < 0.001).

Association of the MIDA Score with 1-year mortality was analysed with a logistic regression model in the Derivation Cohort and validated in the Validation Cohort and found to be satisfactory (Derivation Cohort: c = 0.7540; Validation Cohort: c = 0.7537) (Figure 1).


Since remarkably similar 5- and 10-year survival rates were recorded and an analogous prognostic ability of the MIDA Score had been con- firmed, we combined Derivation and Validation Cohorts to further increase the sample size in order to facilitate long-term follow-up and sub-group analyses.

Baseline characteristics of the Combined Cohort are reported in Tables 1 and 3, respectively.

During a follow-up of 7.8 ± 5.0 years, 1151 patients died.

Overall survival at 5 and 10 years was 84 ± 1 and 69 ± 1% years, respectively.

During a medical follow-up of 2.1 ± 3.5 years, 521 patients died.

Figure 2 reports the independent association of the MIDA Score with mortality under medical management in selected sub-groups.

Long- term survival according to the categories of MIDA Score is depicted in Figure 3A and (using multiple imputation) in Figure 4A (see Supplementary material online).


Surgery was eventually performed in 2659 patients (90% repair).

During a post-surgical follow-up of 7.8 ± 4.8 years, 630 patients died.

Perioperative mortality occurred in 40 patients (1.5%).

The mean EuroSCORE II was: 1.72% (median [25-75th percentile] 1.17 [0.75- 1.98]) in the entire population; 3.04% in patients who died during the perioperative period (vs. 1.71% in those who survived, P = 0.004); 1.99% in those who were treated exclusively medically (vs. 1.62% in those who were operated on, P < 0.001).