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Multiple Sclerosis


Table 3: Single Case Studies of Autoimmune Conditions Associated with Disease-modifying Agents used in MS Condition


Description Autoimmune hepatitis Systemic lupus erythematosus Rheumatoid arthritis Urticarial vasculitis


One case has been reported of GA-induced acute exacerbation of autoimmune hepatitis in an MS patient


One case has been reported of a patient with RRMS who developed lupus syndrome after 32 months of IFNβ therapy


One case has been reported of new-onset rheumatoid arthritis in an MS patient during IFNβ therapy


One case has been reported of urticarial vasculitis induced by GA treatment in an MS patient


GA = glatiramer acetate; IFNβ = interferon beta; MS = multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis.


pulmonary disease was excluded from the study—presumably to select specifically for atopic asthma. However, a retrospective study in Wales established an inverse relationship between asthma and MS (odds ratio 0.33; 95 % confidence interval 0.15–0.77).29


• Can we identify biomarkers to help us predict the outcomes of these treatments?


This was supported by a


study of general practitioner prescribing data from Wales, which found that MS patients were prescribed fewer anti-asthma drugs (e.g., bronchodilators and inhaled corticosteroids) compared with controls (but the authors noted that treatments given to MS patients could improve asthma symptoms, thus potentially reducing the need for anti-asthma medication).30


Conversely, an Australian study of 136 MS


cases and 272 matched controls reported that MS patients were more likely (p=0.02) than controls to have asthma that started before the onset of MS symptoms.31


Some researchers believe that there may be


a link between asthma and autoimmune conditions including MS; the detection of certain autoantibodies (e.g., antibodies to the β-2 adrenergic receptor) in asthmatics may support this.32


This link,


however, is controversial, and much more data are needed to clarify putative associations and possible common mechanisms.


In summary, the data published to date show a marked association between MS and certain autoimmune comorbidities. Table 1 gives an overview of some of the more frequent autoimmune conditions and their degree of association with MS. Future studies should look at comorbidities as well as taking into account the modifying effects of socioeconomic status, ethnic origin, and cultural factors in MS.33


Autoimmune Comorbidities in Multiple Sclerosis—Genetic and Environmental Factors Autoimmune conditions have been shown to be more common in families at high risk of multiple sclerosis than in the general population, suggesting that these diseases might arise on a genetic background of generalized susceptibility to autoimmunity.23


On the other hand, a


population-based study found that, when data were adjusted for sex, no excess of common autoimmune diseases could be identified in MS patients or their families.19


Such conflicting results lead to four questions:


• Are MS patients indeed more likely to have other autoimmune diseases?


• •


Is there anything special (clinically, radiologically, immunologically, genetically) in patients with MS and autoimmune comorbidities that can help us better understand MS?


Are MS treatments beneficial or harmful to other autoimmune conditions?


136


Studies investigating genetic susceptibility to MS have identified a number of genomic regions and specific genes of interest, most of which are associated with immune response, in particular the MHC region on chromosome 6.34–38


Although epidemiological data have suggested an inverse association between MS and RA, genome-wide association studies (GWASs) have found that MS and RA share many genetic factors.39


However,


certain genetic loci for susceptibility to autoimmune disease, delineated in GWASs, are not associated with both MS and other autoimmune diseases; for example, the PTPN22 risk allele has been strongly associated with type 1 diabetes, RA, and thyroiditis, but not with MS.40


In addition to genetic factors, synergistic interactions between environmental factors that trigger autoimmunity—such as Epstein–Barr virus infection or vitamin D deficiency—may underlie comorbidities.18 Vitamin D receptor knockout and vitamin D-deficient mice have a surplus of a type of effector T-cell that has been implicated in the pathology of MS and IBD.41


increased risk of comorbid autoimmune disease in MS.3


Effects of Disease-modifying Drugs on Autoimmune Comorbidities


Some of the autoimmune conditions more frequently associated with disease-modifying agents used in MS are shown in Table 2, and isolated cases are summarized in Table 3. These and other autoimmune comorbidities could possibly serve as biological markers predicting good response to GA and unfavourable response to IFNβ.


First-line agents approved for the treatment of MS include IFNβ and GA.42–45


Reference Neumann, et al., 200746 Bonaci-Nikolic, et al., 200992 Alsalameh, et al., 199858 Cicek, et al., 200849


In addition, smoking is associated with an


It is evident from Tables 2 and 3 that there are more reported cases of autoimmune comorbidities in MS patients treated with IFNβ than in those treated with GA. There have been individual case reports of exacerbation of autoimmune conditions—e.g., autoimmune hepatitis—in patients treated with GA.46


Other reported conditions that


may have an autoimmune basis and are associated with GA include necrotising cutaneous lesions,47 vasculitis.49


panniculitis,48 from single case studies. US NEUROLOGY and urticarial It must be emphasized, however, that these reports are


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