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Autoimmune Comorbid Conditions in Multiple Sclerosis


The effect of GA on autoimmune conditions comorbid to MS has been studied in experimental animal models. GA has been found to alter the clinical course of type 1 diabetes in animal models,50 beneficial effects on uveoretinitis in rodents,51 models of systemic lupus erythematosus (SLE)52 exacerbate RA.53


but had no effect on rodent and was found to


These variable results in animal models suggest that GA may exert its immunomodulatory effect in an antigen-independent manner.


As discussed above, IFNβ therapy can precipitate immune-mediated abnormalities or exacerbate an existing autoimmune tendency. Following reports of autoimmune thyroid and liver disorders in two MS patients treated with IFNβ,54


of evidence suggests that Th17 cells, along with Th1 cells, play a major role in the pathogenesis of MS.64


and has exerted


Th1 and Th17 responses


counter-regulate each other. Both Th1 and Th17 cells have the capacity to cause autoimmunity independently of each other. These findings are important in understanding the role of IFNβ in the treatment of MS and MS-associated comorbidities. In animal model studies, it was found that treatment with IFNβ reduced EAE symptoms induced by Th1 cells, but exacerbated symptoms induced by Th17 cells. Furthermore, non-responsiveness to IFNβ in patients with relapsing-remitting multiple sclerosis (RRMS) was associated with high serum levels of the TH17 cytokine IL-17F.65


the thyroid and liver function and the serum level of 12 autoantibodies against organ-specific (thyroid, gastric, pancreatic) and non-organ-specific antigens were serially monitored. In contrast to control patients, autoantibodies (anti-nuclear, anti-smooth muscle or anti-thyroid antigens) were detected in 13 patients treated with IFNβ and, in many cases, these were associated with thyroid or liver function alteration.55


In


a separate study of MS patients treated with IFNβ, serum anti-microsomal and anti-thymocyte globulin autoantibodies were detected, with one case of autoimmune hepatitis reported.56


Since these studies were completed, several major autoimmune comorbidities have been found to be associated with IFNβ treatment, including SLE,57


RA,58 UC,59 and myasthenia gravis.60


thyroiditis has been reported in MS patients receiving IFNβ, but not in those receiving GA.61


IFNβ and other type I IFNs appear to be immunomodulatory in diseases driven predominantly by Th1, but inflammatory in diseases resulting from a Th17 response.67


High serum levels of IL-7, particularly when paired with low serum levels of IL-17F, are predictive of response to IFNβ.66


Summary and Future Directions


Autoimmune comorbidities are an important component of the range of comorbid conditions seen in MS and contribute to the substantial disease burden experienced by many MS patients. Autoimmune comorbidities are often associated with MS and can worsen the impact of the disease. These conditions need to be treated and managed by neurologists and specialist MS nurses in collaboration with other specialists.


Autoimmune In 2010, we presented to the American Academy


of Neurology four clinical cases of comorbid MS and psoriasis; all four patients had previously not responded to treatment with IFNβ and, later, all four responded to treatment with natalizumab.62


The


association of IFNβ treatment with systemic autoimmune diseases may be explained in several ways. IFNβ modulates gene expression and the immune system, providing pathogenic influences in some cases, while in other cases providing protection.63


Recent studies have enhanced our understanding of the role of T-helper type 1 (Th1) and T-helper type 17 (Th17) effector cells. A growing body


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It is important to be aware that the predisposition of MS patients to autoimmune comorbidities is not uniform across all diseases. Further studies are required to establish which genetic and environmental factors influence autoimmune comorbidities in MS. More standardized methods of measuring and analysing autoimmune comorbidities and their associations with MS are needed. More studies are also needed to address the effects of autoimmune comorbidities on MS. These future studies should assess a wider range of comorbidities and examine how the frequency of comorbidities changes over time. Finally, the effects of MS treatments on autoimmune comorbidities can potentially inform choices about therapeutic regimens, and more research in this area is greatly needed. n


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