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Multiple sclerosis and co-morbid autoimmune disease: the final nail in the coffin?

Both genetic and environmental factors influence the risk of developing multiple sclerosis (MS).1,2 How these risk factors lead to the pathology observed in the central nervous system of MS patients is largely unknown but several lines of evidence suggest an abnormal activation of the immune system. The most consistent immunological finding in MS patients is the presence of oligoclonal IgG in their cerebrospinal fluid.3 Furthermore animal models of MS can be adoptively created by the injection of encephalitogenic myelin-specific T cells in mice.4 Finally, it is now widely accepted that genetic variants predisposing to MS exert an immunological function. These include the major histocompatibility complex (MHC) class II HLADRB1*1501 allele (the main MS genetic locus) and tens of non-MHC loci of more modest effect.5,6 The genetic contribution to MS susceptibility is responsible for its evident familial aggregation.7 In addition to MS, other diseases such as type 1 diabetes (T1D), Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by an abnormal activation of the immune system and in combination these immune-mediated diseases (ID) affect approximately 5–10% of the developed world.8 The presence of common pathways and the involvement of similar cell types in their pathogenesis has driven the hypothesis that shared genetic risk factors may influence susceptibility to ID. This hypothesis has been confirmed by studies showing that common genetic pathways underlie risk to both MS and other ID.9,10 However, the extent of this shared genetic risk, its contribution to disease development and the aggregation of ID in MS families has been debated. Dozens of studies have investigated the occurrence of ID other than MS in both MS patients and their first-degree relatives, but the only remarkable conclusion that can be drawn from such studies is their exceptional inconsistency. The frequency of T1D, CD, UC, asthma, Graves’ disease, systemic lupus erythematosus, Addison’s disease, pemphigoid and others have been claimed to be elevated either in MS patients or their relatives over the last decade, but none of them have been confirmed.11-17 For any epidemiological finding, bias, confounding and the simple play of chance all need to be considered to see whether they can explain an observed association before interpreting results as being causally linked. Selection and recall bias are undoubtedly present in some studies, while others are hampered by small sample size. These issues all lead to inconsistent findings. One bias that has been thought to exist but never clearly evidenced is surveillance bias, where MS patients by being in closer contact with healthcare professionals are more likely to be diagnosed with ID than healthy controls who are not accessing healthcare as much. In this issue of the Multiple Sclerosis Journal, Roshanisefat and colleagues investigate the risk of several ID in a large population of Swedish MS patients (n = 20,276) and their parents (n = 23,290) identified using both the National Patient Register and the Swedish Multiple Sclerosis Register. Controls (up to 12 for each case of MS) were carefully matched by age, sex, vital status, region of residence and socioeconomic status. Strikingly, no consistent increased frequency for any ID was found among parents of MS patients. The authors did find an increased frequency of UC, CD, T1D, psoriasis, polyarteritis nodosa and pemphigoid in MS patients but this increase was only present after the diagnosis of MS was made. This is an elegant epidemiological analysis which highlights that surveillance bias was likely entirely behind the associations observed. Such strikingly negative findings, as documented by other large population-based studies,12 strongly suggest a true absence of ID aggregation in MS patients and their families. Do these findings contradict the hypothesis of shared genetic pathways between MS and other ID? Not necessarily. The fact that most of the genetic contribution to MS localizes within the MHC region is relevant since, although this region has been associated with virtually all ID, the risk haplotypes substantially differ from disease to disease.18 Even outside the MHC region sharing genetic pathways does not necessarily implicate sharing risk variants as polymorphisms with opposite effects on susceptibility to different ID (conferring risk for one and protection for another) have been reported.10 The study by Roshanisefat and colleagues unequivocally shows that the frequency of ID other than MS is not increased in either MS patients or in their first-degree relatives suggesting that the potential sharing of risk variants between MS and other ID is not strong enough to create familial aggregation. Further studies investigating this hypothesis appear now to be meaningless.