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Autoimmune Comorbid Conditions in Multiple Sclerosis


cerebrospinal fluid of MS patients are not directed against any of the known myelin proteins.9


A mitigating argument is that some of these


antibodies may be targeting myelin lipids and carbohydrates that are known to play a role in autoimmune inflammation.10


One hypothesis is


that demyelination is caused by oligodendrologlial apoptosis and that inflammation is merely a secondary event initiated to eliminate the products of myelin degeneration.11


Whether it is apoptosis or


infection that triggers the inflammatory response, there is evidence of an unmistakable immune footprint at the site of disease. Inhibiting the entry of immune cells to the brain provides great benefit, as shown by natalizumab, its effects, and its underlying mechanism of action.7


Another confounding factor in the pathogenesis of MS lies in the available treatment options. MS relapse management treatments, such as systemic steroids and adrenocorticotrophic hormone (ACTH), are also widely accepted for other autoimmune conditions, where they can be used for maintenance or treatment of acute exacerbations. The potential disease-modifying role of ACTH in MS needs to be more extensively studied. Disease-modifying treatments for MS, such as interferon beta (IFNβ), glatiramer acetate (GA), natalizumab, fingolimod, and BG-12, have mostly unknown or insufficiently studied applications for other autoimmune conditions (with the exceptions of the BG-12 analog, which is approved for use in psoriasis, and of natalizumab, which is approved for use in Crohn’s disease). GA shows promise in inflammatory bowel disease.12


Effect of Autoimmune Comorbidities on Multiple Sclerosis Diagnosis, Treatment, and Outcomes Comorbidities are an important issue in MS. They significantly worsen the impact of the disease and some of them (e.g., vascular disease, Alzheimer’s disease) are associated with neurodegeneration in progressive MS.13


While


there are many different types of comorbidities in MS, autoimmune conditions are a common feature in many patients, and some occur more often in MS patients than in the general population.3,4,14


It has been shown that autoimmune comorbidities in MS can affect a number of aspects, including diagnosis, clinical phenotyping of the disease, disease and disability progression, quality of life, and treatment decisions.15 A North American registry study found a diagnostic delay of one to 10 years in MS patients who had vascular, autoimmune, musculoskeletal, gastrointestinal, visual, or mental comorbidities.16


No direct association has


been reported between autoimmune conditions and disability progression;17


however, the association between comorbidities and increased disability at diagnosis has led to the suggestion that comorbidities may act pathophysiologically to hasten disease progression.15


The presence of autoimmune comorbidities in MS has important implications for therapeutic decision-making. For example, in the presence of comorbid inflammatory bowel disease or uveitis, the use of anti-tumour necrosis factor (TNF) biologic therapies should be avoided. Likewise, it would be inadvisable to treat MS with natalizumab in a patient previously given immunosuppressive therapy for either MS or a comorbid autoimmune condition.18


Research into the diagnosis and treatment of autoimmune comorbidities within the MS population has not been given sufficient attention. The


US NEUROLOGY B


1 2 3 4 5 6 7 8 9


0


Figure 1: Autoimmune Diseases Reported in Patients with MS (A) and Estimated Prevalence of Autoimmune Disease Among First-degree Relatives (B)


A


0 1 2 3 4 5 6 7 8 9


Women


Men


The data come from a study of 176 families (including 386 individuals with multiple sclerosis and 1,107 first-degree relatives). MS = multiple sclerosis. Source: Barcellos, et al., 2006.23


resulting information gap adds further complexity to disease management. Addressing this gap is important, particularly because early recognition and treatment of the comorbid conditions can improve prognosis, help define the disease course, and allow better informed and more individualized treatment decisions.


133


Alopecia areata Ankylosing spondylitis Autoimmune hepatitis


Ulcerative colitis Crohn’s disease


Guillain–Barré syndrome


Mixed connective tissue disease Type 1 diabetes Menière’s disease


Pernicious anaemia Polymyositis


Raynaud’s disease Systemic lupus erythematosus Psoriasis Inflammatory bowel disease


Ankylosing spondylitis Autoimmune hepatitis


Addison’s disease Alopecia areata


Idopathic thrombocytopenic purpura Guillain–Barré syndrome Type 1 diabetes


Mixed connective tissue disease Menière’s disease


Myasthenia gravis Pemphigus vulgaris Pernicious anaemia


Primary biliary cirrhosis Sjögren’s syndrome


Polymyositis


Raynaud’s disease Rheumatoid arthritis


Systemic lupus erythematosus Psoriasis Sarcoidosis


Hashimoto’s thyroiditis Graves’ disease


Uveitis/iritis Asthma


Rheumatoid arthritis Graves’ disease


Hashimoto’s thyroiditis Uveitis/iritis Asthma


Prevalence (%)


Prevalence (%)


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