{"id":1083,"date":"2012-03-14T19:20:41","date_gmt":"2012-03-14T19:20:41","guid":{"rendered":"https:\/\/touchneurology.com\/2012\/03\/14\/autoimmune-comorbid-conditions-in-multiple-sclerosis\/"},"modified":"2012-03-14T19:20:41","modified_gmt":"2012-03-14T19:20:41","slug":"autoimmune-comorbid-conditions-in-multiple-sclerosis","status":"publish","type":"post","link":"https:\/\/touchneurology.com\/multiple-sclerosis\/journal-articles\/autoimmune-comorbid-conditions-in-multiple-sclerosis\/","title":{"rendered":"Autoimmune Comorbid Conditions in Multiple Sclerosis"},"content":{"rendered":"

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system (CNS). Although it is generally considered to be an autoimmune disease, MS may be a heterogeneous condition incorporating different pathologies. The incidence of autoimmune comorbidities in MS patients may help us elucidate the autoimmune aspects of the disease. Furthermore, the presence of autoimmune comorbidities may help us discover new biomarkers with potential predictive value regarding response to treatment, and understand common factors in pathogenesis. This article aims to review autoimmune comorbidities in MS, their incidence and burden in the MS population, and their possible association with MS treatments. We will address potential measures that might reduce the impact of treatment in triggering comorbidities.<\/p>\n

Multiple Sclerosis as an Autoimmune Disease<\/b>
The most widely accepted hypothesis for the pathogenesis of MS is that it is a primary autoimmune disease. This idea was reinforced following observations on experimental autoimmune encephalomyelitis (EAE) in the late 1960s and early 1970s.1\u20134<\/sup> It has been repeatedly demonstrated that EAE is an autoimmune disorder caused by T-cell sensitization to various myelin proteins capable of triggering encephalomyelitis. The hypothesis is further supported by considerable evidence, such as the presence of elevated lymphocytes, macrophages, and microglia in MS lesions; strong genetic associations with genes in the major histocompatibility complex (MHC) region of chromosome 6; and the efficacy of new treatments that target the immune response. However, there are some aspects of the autoimmune pathogenesis hypothesis of MS that require further clarification. Much of this hypothesis is based on animal models of EAE; however, many agents that can successfully treat EAE have failed to show any clinical benefit in MS. This suggests that EAE is not an accurate model of MS and that the two conditions have some different pathophysiological characteristics.5<\/sup> In order to yield clues to the pathogenesis of MS, EAE experimental models should be critically coupled with actual findings in MS.6<\/sup><\/p>\n

The most compelling evidence that there is an immune pathogenesis in MS comes from the striking benefit seen when lymphocyte migration to the CNS is blocked with natalizumab, or when lymphocytes are trapped n regional lymph nodes with fingolimod.7,8<\/sup> It is difficult to discount the fact that, when monocytes are barred entry to the CNS, the rate of elapse and pace of progression of disability in MS are attenuated.<\/p>\n

A further challenge to the autoimmune pathogenesis hypothesis of MS has arisen following findings that some of the antibodies identified in the cerebrospinal fluid of MS patients are not directed against any of the known myelin proteins.9<\/sup> 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<\/sup> 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<\/sup> 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<\/sup><\/p>\n

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 (IFN\u00e2), 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\u2019s disease). GA shows promise in inflammatory bowel disease.12<\/sup><\/p>\n

Effect of Autoimmune Comorbidities on Multiple Sclerosis Diagnosis, Treatment, and Outcomes<\/b>
Comorbidities are an important issue in MS. They significantly worsen the impact of the disease and some of them (e.g., vascular disease, Alzheimer\u2019s disease) are associated with neurodegeneration in progressive MS.13<\/sup> 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<\/sup><\/p>\n

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<\/sup> 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<\/sup> No direct association has been reported between autoimmune conditions and disability progression;17<\/sup> 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<\/sup><\/p>\n

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<\/sup><\/p>\n

Research into the diagnosis and treatment of autoimmune comorbidities within the MS population has not been given sufficient attention. The 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.<\/p>\n

Studies of Autoimmune Comorbidities in Multiple Sclerosis<\/b>
Until recently, clinical data relating to the co-occurrence of autoimmune diseases in MS have been predominantly based on uncontrolled case series or small case-control studies, with few studies accounting for confounding factors such as age and sex. There are many difficulties inherent to such studies, such as selection or ascertainment bias. Results may differ depending on which conditions are included and how the diagnosis is reached.18<\/sup> In ethnically-mixed populations such as that of North America, the use of spouses as controls allows ethnic matching19 (the use of such controls is fairly common in genetic studies but much less widespread in clinical trials20\u201322<\/sup>). However, since MS is significantly more prevalent in females, this approach can increase a potential gender imbalance between cases and controls.<\/p>\n

In a study of families in which several members had been diagnosed with MS (176 families, 386 individuals with MS, and 1,107 first-degree relatives), participants were studied for a history of coexisting autoimmune disorders (see Figure 1<\/i>).23<\/sup> Of the 386 individuals with MS, 26 % had a coexisting autoimmune disorder. Of the 1,107 first-degree relatives, 64 % had a history of autoimmune conditions. The most commonly reported autoimmune conditions in MS patients and their relatives were Hashimoto\u2019s thyroiditis, psoriasis, and inflammatory bowel disease (IBD).<\/p>\n

A recent American population-based case-control study using a large database (5,296 MS cases and 26,478 matched controls) found that individuals with MS were more likely than controls to have uveitis, IBD, and Bell\u2019s palsy prior to MS diagnosis.24<\/sup> They were also more likely to develop Guillain\u2013Barr\u00e9 syndrome and bullous pemphigoid. However, the study found no increased likelihood of MS patients having or developing rheumatoid arthritis (RA), lupus, or thyroiditis. The study concluded that MS may share environmental triggers, genetic susceptibilities, and\/or alterations in immune homeostasis with IBD and uveitis, but not with other autoimmune disorders. The study had limitations relating to its methodology and reliance on electronic patient records. By grouping certain diseases together, opportunities to gain valuable information were lost; for example, IBD incorporates Crohn\u2019s disease and ulcerative colitis (UC), which have immunopathological differences, and to differentiate between the two might have given clues to shared mechanisms with MS.<\/p>\n

A Danish registry study showed that autoimmune disorders tended to co-occur with MS and to occur in MS patients\u2019 families, but that this was not a uniform phenomenon across all diseases.25<\/sup> Patients with type 1 diabetes were found to have more than a threefold increased risk of developing MS. Compared with the general Danish population, MS patients were found to have increased incidences of type 1 diabetes, UC, autoimmune thyroiditis, and pemphigoid, but a decreased incidence of RA. MS and RA appear to have a reduced likelihood of co-existence.26<\/sup> This inverse association between MS and RA has also been found in a population-based cohort study using the UK General Practice Research Database.27<\/sup><\/p>\n

While the above studies show similarities, there are inconsistencies in the data regarding the association between thyroiditis and MS. Autoimmune thyroiditis was found to be significantly more prevalent in male MS patients than in male controls (9.4 versus 1.9 %; p=0.03). However, there was no significant difference in the prevalence of autoimmune thyroiditis in female MS patients and female controls (8.7 versus 9.2 %). Further studies are required to determine the cause of this increased prevalence of autoimmune thyroiditis in males with MS.28<\/sup> This finding illustrates the importance of avoiding gender bias in studies of comorbidities in MS.<\/p>\n

A large North American study found no association between MS and asthma,24<\/sup> although asthma associated with chronic obstructive pulmonary disease was excluded from the study\u2014presumably 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\u20130.77).29<\/sup> 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<\/sup> 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<\/sup> 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 \u03b2-2 adrenergic receptor) in asthmatics may support this.32<\/sup> This link, however, is controversial, and much more data are needed to clarify putative associations and possible common mechanisms.<\/p>\n

In summary, the data published to date show a marked association between MS and certain autoimmune comorbidities. Table 1<\/i> 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<\/sup><\/p>\n

Autoimmune Comorbidities in Multiple Sclerosis\u2014Genetic and Environmental Factors<\/b>
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<\/sup> 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: <\/p>\n