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  1. Staying Ahead of Multiple Autoimmune Disorders Healio Rheumatology, August 2016 There is a well-established body of evidence cataloguing the co-occurrence of autoimmune disorders. Patients with rheumatoid arthritis, multiple sclerosis, autoimmune thyroiditis, Sjögren’s syndrome or a host of other such conditions carry a substantially increased risk for another autoimmune disease. Although some pairings are reported more frequently than others, the likelihood that a patient with any autoimmune disorder will ultimately acquire another autoimmune disorder is high. The question, then, is why. Regina Berkovich, PhD, MD assistant professor of clinical neurology at Keck Medicine at the University of Southern California, laid out some of the principal arguments. “It is a case of mistaken and activated immune system,” she said. “If the immune system already follows the autoimmune pattern, it is just a higher possibility that there will be another target.” This seems to be the main reason autoimmune disorders tend to coincide, according to Berkovich, who has studied multiple sclerosis (MS) extensively. “A second scenario is that when we use immunomodulatory drugs to treat MS, the initial landscape of the immune system changes,” she said. “When we create changes to the immune system, it may predispose them to further complications.” Other researchers, including Emily C. Somers, PhD, ScM an associate professor of internal medicine, environmental health sciences and obstetrics and gynecology at the University of Michigan, have suggested genetic factors are in play. However, untangling the myriad genetic associations in patients who have multiple disorders has remained elusive to the clinical and research communities. “A current line of thinking is there are certain genetic and environmental factors that may disrupt the immune system in a manner that may set the stage for future development of autoimmune diseases,” she said. However, she noted there are no concrete answers on the genetic front. Regina Berkovich Healio Rheumatology lays out the issues and associations, beginning with a look at trends in comorbid autoimmune diseases. Overview of Associations Cojocaru and colleagues outlined factors involved in multiple autoimmune syndrome, which they defined as the existence of three or more of these conditions. “Disorders of autoimmune pathogenesis occur with increased frequency in patients with a history of another autoimmune disease,” they wrote, suggesting the rate of a second disorder may be about 25%. “At least one of them is usually a skin disease, such as psoriasis or scleroderma.” Although some patients may experience as many as five of these conditions, it is unlikely, according to Cojocaru and colleagues. Multiple autoimmune disorder may be the result of familial or genetic factors, along with immunological or psychological factors. However, environmental triggers may set in motion the occurrence of a second disorder. “The pathogenesis of multiple autoimmune disorders is not known,” they wrote. Multiple autoimmune syndrome can be classified into three types, according to the authors. “Type 1 [multiple autoimmune syndrome] includes myasthenia gravis, thymoma, polymyositis and giant cell myocarditis,” they wrote. “Type 2 [multiple autoimmune syndrome] includes Sjögren’s syndrome, [rheumatoid arthritis] RA, primary biliary cirrhosis, scleroderma and autoimmune thyroid disease. Type 3 [multiple autoimmune syndrome] groups together autoimmune thyroid disease, myasthenia gravis and/or thymoma, Sjögren’s syndrome, pernicious anemia, idiopathic thrombopenic purpura, Addison’s disease, type 1 diabetes mellitus, vitiligo, autoimmune hemolytic anemia, [systemic lupus erythematosus] SLE and dermatitis herpetiformis.” Antoine G. Sreih, MD, assistant professor of clinical medicine in rheumatology at the University of Pennsylvania, echoed this point. “Clusters of autoimmune disorders can occur together, such as Schmidt syndrome or other autoimmune polyendocrine syndromes, which are often due to genetic predisposition,” he said. “Once the immune system loses its tolerance to self, it becomes more prone to causing other autoimmune diseases.” Eric Matteson Speaking more specifically, researchers have suggested inflammatory bowel disease is commonly associated with autoimmune comorbidities. For example, hypothyroidism, primary sclerosing cholangitis, vitiligo and alopecia areata frequently occur in ulcerative colitis. Multiple sclerosis is common in the third type of multiple autoimmune disorder, according to Cojocaru and colleagues. An association of Reynolds syndrome and the lupus erythematosus/lichen planus-overlap syndrome is a hallmark of the second type of this disorder. Overall, vitiligo is often the first autoimmune disease diagnosed, while bullous pemphigoid is the most common blistering skin disease. “The significance of the association of bullous pemphigoid with other autoimmune diseases is still unknown,” they wrote. “The most frequent associations are those with [primary biliary cirrhosis] PBC, psoriasis.” Sjögren’s syndrome frequently occurs with SLE and RA, according to Cojocaru and colleagues. “The presence of Sjögren’s syndrome influences the expression of the other autoimmune disease to some degree, for instance by increasing fatigue and lymphoma risk,” they wrote. “The underlying mechanisms for this syndrome are not yet understood, but it may be more prevalent than currently recorded.” “Overlapping syndromes between two or more autoimmune diseases in rheumatology are not uncommon,” Sreih said. “We see this with SLE, RA, scleroderma, Sjögren’s syndrome, vasculitis and polymyositis.” Other common combinations include pemphigus and autoimmune thyroid disease in type 1 [multiple autoimmune syndrome]; chronic active hepatitis, SLE, pemphigus, bullous pemphigoid, [autoimmune hemolytic anemia], [idiopathic thrombopenic purpura], alopecia areata and Addison’s disease in type 2 [multiple autoimmune syndrome]; and acquired primary hypogonadism, hypophysitis, RA, PBC, relapsing polychondritis, multiple sclerosis, [congenital adrenal hyperplasia] CAH, ulcerative colitis and scleroderma in type 3 [multiple autoimmune syndrome],” they wrote. Cojocaru and colleagues suggested clinicians may find the pathogenesis of ulcerative colitis in clusters of autoimmune diseases, and the presence of one of these disorders may likely lead to discovery of another. They urged ongoing surveillance. “The underlying mechanisms for this syndrome are not yet understood, but it may be more prevalent than currently recoded,” they wrote. “I would point out that only some, but certainly not all, of the clustering they suggest is based on pathophysiological understanding of the diseases and so is in the end opinion of the authors,” Eric Matteson, MD, a rheumatologist at the Mayo Clinic in Rochester, Minn., told Healio Rheumatology. “The practical clinical implications of the clustering could include making clinicians aware of certain associations, such as Sjögren’s syndrome and rheumatoid arthritis as they follow patients, and may be helpful in unraveling some of the common pathophysiological basis for them. Some other associations may not have a practical value in terms of understanding the disease causation of management.” A number of data sets validate the findings described by Cojocaru and colleagues. Sardu and colleagues described the prevalence of 12 autoimmune diseases in a general population sample from Sardinia, Italy that included data for more than 25,000 individuals. Results were calculated in terms of prevalence per 100,000. Investigators found RA occurred in 552 individuals per 100,000, while the rate was 124 for ulcerative colitis, 15 for Crohn’s disease, 464 for type 1 diabetes, 81 for SLE, 124 celiac disease, 35 for myasthenia gravis, 939 for psoriasis/psoriatic arthritis, 35 for systemic sclerosis, 224 for MS, 31 Sjögren’s syndrome and 2,619 for autoimmune thyroiditis. “An overall association between autoimmune disorders was highlighted,” the researchers wrote. “People already affected by a first autoimmune disease have a higher probability of being affected by a second autoimmune disorder.” Antoine G. Sreih “This paper recapitulates findings from other populations which also show this interrelatedness of autoimmune diseases, and is not surprising,” Matteson said. “It is necessary to keep in mind that some of the autoimmune diseases have low frequencies, so that lack of an association can be real or spurious.” Sreih built on this point. “The findings in this paper support the notion that having one autoimmune disease increases the risk of having another autoimmune disease and that the majority of the autoimmune diseases examined in this paper are more common in women than men,” he said. “It is important, however, to indicate that findings in one specific population — in this case South Sardinia — may not apply to another population because of differences in genetic composition.” Another caveat is that despite the broad nature of the study, there are still a finite number of autoimmune disorders that underwent analysis, according to Sreih. “Therefore, the findings apply only to those studied autoimmune diseases,” he said. “Also, observation bias may exist since patients with an autoimmune disease are frequently seen and tested by their physicians and therefore more diseases can be detected.” Autoimmune Therapies Berkovich and colleagues investigated the frequency of comorbid diseases in MS. They suggested certain MS drugs may be preferable to others when comorbid autoimmune conditions are present. Moreover, comorbid autoimmune conditions could predict response to MS therapies. “Treatment with interferon beta has been reported to precipitate immune-mediated abnormalities or to exacerbate existing autoimmune diseases,” they wrote. “In comparison, there are fewer reported cases of treatment-associated comorbidities linked with autoimmune disease in patients taking glatiramer acetate. Knowledge of the factors influencing autoimmune comorbidities may provide insights into the complex pathogenesis of MS and help inform treatment choices.” “According to what we know, some immunomodulatory therapies may contribute to a second autoimmune disorder,” Berkovich told Healio Rheumatology. “The association has been noticed with interferon-based therapies. Another more recent medication that may predispose patients to autoimmune complications is alemtuzumab (Lemtrada, Genzyme). We found that if patients already had MS and one other autoimmune condition, such as psoriasis or lupus, interferon was not the best choice of drug.” This information can have practical implications for the clinic, according to Berkovich. “The evidence tells us that interferon may exacerbate the conditions,” she said. “Evidence of those complications should be used as a surrogate biomarker to be careful when using interferon in these patients.” That said, Berkovich is hopeful novel therapies, such as teriflunomide (Aubagio, Genzyme) or, dimethyl fumarate (Tecfidera, Biogen) or glatiramer acetate injection (Copaxone, Teva), may improve this situation. “Some of these new immunomodulatory therapies have known risks,” she said. “The symptomatology of MS can overlap with other conditions.” Clinicians weight the benefit-risk ratioassociated with treating a primary autoimmune disorder, according to Berkovich. “Treatment is justified, first, by the efficacy of the drugs for the primary potentially progressive condition — MS,” she said. “If we give medicine to treat MS, we are well aware that it has associated risks, and always discuss this with patients. It is worth it because if we do not treat the MS, patients are highly likely to progress and develop advanced disability. We have no choice but to address the primary condition. The risk for a second condition is relatively minor and manageable when compared to what happens when MS takes its natural course, which may be a grave prognosis.” Genetic Factors Many experts, including Sreih, have suggested genetic factors may be worth investigating. “Patients with one autoimmune disease may be predisposed to acquiring another autoimmune disease,” he said. “Genetic predispositions to having an autoimmune disorder can be common among several autoimmune diseases.” Somers acknowledged the understanding of these associations is increasing, albeit slowly. “Over the last decade, several genetic factors have been found in common between multiple autoimmune diseases,” she said. “However, the particular combinations of genetic and environmental factors will influence the way that autoimmunity is expressed, or what we refer to as the disease phenotype.” Matteson agreed. “This is likely because in some cases common genetic predisposition exposures, such as possibly infections, and common inflammatory pathways of many of these diseases also have overlapping features, like rheumatoid arthritis, Sjögren’s syndrome, and lupus erythematous, to name three,” he said. Conflicting Data Although the overwhelming consensus is that autoimmune diseases co-occur, there are data sets that show the opposite or at least muddy the picture. Farez and colleagues suggested results investigating comorbid autoimmune disorders have been “controversial.” They added this phenomenon has not been studied in patients in Latin America. Results from their case-control study indicated no significant differences in autoimmune disease prevalence in patients with MS compared to controls. Patients with one or more autoimmune disorders did not experience an increased likelihood of acquiring MS (odds ratio = 0.85), according to their findings. “Our results indicate absence of increased comorbid autoimmune disease prevalence in MS patients, as well as of increased risk of MS in patients suffering from other autoimmune disorders,” they concluded. Somers and colleagues conducted a series of population-based cohort studies with data from the United Kingdom General Practice Research Database between 1990 and 1999. The aim was to evaluate risks for co-occurrence of RA, autoimmune thyroiditis, MS and insulin-dependent diabetes mellitus. The analysis included outcomes for 22,888 patients with RA, 26,198 patients with autoimmune thyroiditis, 4,332 patients with MS and 6,170 patients with diabetes whose outcomes were compared with those reported in the general population. Among patients in the diabetes group, adjusted rates of autoimmune thyroiditis were increased among men (standardized incidence ratio[SIR] = 646) and women (SIR = 409.6). Rates of RA also were higher among women with diabetes (SIR = 181.6). Autoimmune thyroiditis and RA showed a trend for coexistence regardless of the disease sequence (sex-specific SIRs = 130.4 to 162). However, the researchers noted an inverse relationship between RA and MS. “The strongest association we found was between type 1 diabetes and autoimmune thyroiditis, with rates of coexistence up to six-times higher than expected,” Somers said. “Since these are both endocrine disorders, this indicates that they may share risk factors relevant to disruption of the endocrine system.” Somers noted that RA and autoimmune thyroiditis are among the most common autoimmune disorders in the general population. “Therefore, detection of comorbidity between this pair of diseases is easiest to detect statistically,” she said. “We found that for someone with RA or autoimmune thyroiditis, their risk of developing the other one is approximately 1.5-times higher than expected by chance.” The inverse relationship in this data set should not be ignored, according to Somers. “The inverse association between RA and MS is puzzling and we do not have a firm explanation for this, although genetic variants have been reported that are negatively correlated between these two diseases,” she said. “That is, variants associated with increased susceptibility for one but decreased susceptibility for the other.” The other noteworthy data from the study involve gender differences in comorbid autoimmune disorders, according to Somers. Emily C. Somers “Females have a much greater risk of autoimmune disease overall compared to males, and the female excess holds true for most individual autoimmune disorders,” she said. “For example, 90% of lupus patients are female. Thus, the risk of developing a second disorder should be examined separately for each sex, given the higher underlying risk among females. We believe that our data support similar patterns of coexistence for both sexes, but given the rarity of autoimmune diseases in males, the associations among males are more challenging to detect.” Regarding other conflicting evidence, there are also data demonstrating that autoimmune therapies may not always lead to increased risk for further disorders. Chouhfeh and colleagues investigated how disease modifying therapies impact comorbid autoimmune diseases in MS using data from a cohort of 1,792 patients in the New York State MS Consortium registry. There were 1,478 patients with no other autoimmune diseases and 314 with a comorbid condition that occurred after enrollment. The researchers grouped the patients into those with a disorder after initiation of disease modifying therapies (n = 281) and patients with a disorder who were naïve to disease modifying therapies (n = 33). Disease-modifying therapies failed to alter the frequency of self-reported autoimmune disorders (17.2 vs. 20.4%), according to the results. However, the duration between initial symptoms of MS and the initial report of a comorbid autoimmune condition was 192 ± 115 months among patients treated with disease-modifying therapies and 262 ± 107 months among those who were not. “The findings of this paper are interesting,” Sreih said. “One would expect that the use of disease-modifying therapies in general would decrease the incidence of autoimmune diseases given that many of these medications are therapies given to autoimmune diseases.” Sreih highlighted this paper also shows that women are at higher risk of developing autoimmune diseases than men. He also had some comments about the limitations of the paper. “The number of patients with autoimmune disorders who are naïve to disease-modifying therapies is relatively small compared to patients with autoimmune disorders who are on those drugs,” he said. “Also, the authors lumped different medications with different mechanisms of action under one category of disease-modifying therapies. However, some medications may cause autoimmune diseases more than others and therefore one cannot generalize to all medications. It would have been interesting to know which medications were more associated with autoimmune disorders or with shorter duration to developing an autoimmune disorder than others.” The final point Sreih made is there may have been a bias by indication of therapy. “Patients who are sicker or have a specific disease receive therapy or certain medications as opposed to patients who are not as sick or have another subtype of multiple sclerosis,” he said. Commonly Reported Associations A number of comorbid autoimmune conditions have been described extensively. Boelaert and colleagues conducted a multicenter, cross-section study that included 2,791 patients with Graves’ disease and 495 patients with Hashimoto’s thyroiditis at a center in the United Kingdom. The aim was to assess prevalence rates of coexisting autoimmune disorders. A second autoimmune disorder occurred in 9.67% of Graves’ disease index cases and 14.3% of Hashimoto’s thyroiditis index cases. RA was the most frequently reported comorbid condition, occurring in 3.15% of Graves’ disease and 4.24% of Hashimoto’s thyroiditis cases. Increases in relative risk for a number of other autoimmune disorders were reported for both Graves’ disease and Hashimoto’s thyroiditis, according to the findings (greater than 10 for pernicious anemia, SLE, Addison’s disease, celiac disease and vitiligo). The parents of index cases also experienced increased relative risks for a number of other coexisting autoimmune disorders. “There was relative ‘clustering’ of Graves’ disease in the index case with parental hyperthyroidism and of Hashimoto’s thyroiditis in the index case with parental hypothyroidism,” the researchers wrote. “These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms.” For Berkovich, this makes clinical decision-making of utmost importance. “We should cooperate and collaborate with other clinicians treating these patients,” she said. “Early screening and diagnosis along with early intervention can mitigate further risk.” Gill and colleagues investigated prevalence of comorbid autoimmune diseases in a cohort of 1,098 patients with vitiligo at Henry Ford Health System in Detroit during January 2002 and October 2012. Around 20% of the group had at least one comorbid autoimmune disease. The researchers reported increased rates of a number of conditions in vitiligo patients compared with the general population, including thyroid disease (12.9%), alopecia areata (3.8%), inflammatory bowel disease (0.9%), pernicious anemia (0.5%), SLE (0.3%), Guillain-Barre syndrome (0.3%), discoid lupus (0.2%), linear morphea (0.2%), myasthenia gravis (0.2%) and Sjögren’s syndrome (0.2%). “We observed a high prevalence of comorbid autoimmune diseases in patients with vitiligo and report several new associations,” the researchers concluded. “These associations can tell us about the immune landscape we are dealing with in these patients,” Berkovich said. “The presence of multiple conditions gives us valuable information to help define therapies and understand these diseases.” Sreih said vitiligo can accompany many autoimmune diseases and may be associated with many autoimmune polyendocrinopathies. “The study was relatively large, but unfortunately lacked a control group, and used the general population autoimmune diseases’ estimates for comparison,” he said. “One can potentially compare to the general population if the assumption is the population being studied is representative of the general population, which is probably not the case for this study. The studied population in this paper belongs to one hospital and one specific geographic area of Detroit.” Another key point was thyroid disease was the most common comorbid disease in this population, according to Sreih. “However, hypo- and hyperthyroidism, which are not necessarily caused by autoimmune processes, were included in the definition of thyroid disease and therefore lead to possible overestimation of the true number,” he said. Lauret and Rodrigo addressed approaches to dealing with celiac disease, which remains poorly understood. “Remarkable breakthroughs have been achieved in the last decades, due to a greater interest in the diagnosis of atypical and asymptomatic patients, which are more frequent in adults,” they wrote. “The known presence of several associated diseases provides guidance in the search of oligosymptomatic cases, as well as studies performed in relatives of patients with [celiac disease].” However, they cautioned there is diversity in the etiology of associated diseases. “Some share a similar genetic base, like type 1 diabetes mellitus; others share pathogenic mechanisms, and yet, others are of unknown nature,” they wrote, and warned the disease may present with extra-intestinal manifestations. A gluten-free diet has demonstrated the capacity to improve clinical symptoms of celiac disease, including associated conditions, according to Lauret and Rodrigo. This diet may eliminate anemia or offer improved control of type 1 diabetes. Moving Forward “According to data sets in a number of publications, there is strong evidence that patients with one autoimmune disease have a higher probability of developing another,” Berkovich said. “In my professional experience — 95% of my patients have MS — it is common to see coexisting autoimmune conditions, such as psoriasis. The presence of other autoimmune conditions gives us a lot of information about these patients. We should be paying attention to this.” The good news is drug developers are investigating drugs that minimize the risk of a second condition in patients with MS and other primary disorders, according to Berkovich. “This is the high possible priority in the pipeline right now,” she said. “While I believe it is impossible to create a medication without the potential side effect or risks of complications, I believe we learn to mitigate and stratify the risks. Patients’ safety is always our priority – and this means safety from complications of treatment and also safety from the potentially debilitating complications of MS progression.” -by Rob Volansky References: Berkovich R, et al. US Neurology. 2011doi:10.17925/USN.2011.07.02.132. Boelaert K, et al. Am J Med. 2010;doi:10.1016/j.amjmed.2009.06.030. Chouhfeh L, et al. Multiple Sclerosis and Related Disorders.2015;doi:10.1016/j.msard.2015.02.004. Cojocaru M, et al. Maedica (Buchar). 2010;5:132-134. Farez MF, et al. Multiple Sclerosis International. 2014;doi:10.1155/2014/828162. Gill L, et al. J Am Acad Dermatol. 2016;doi:10.1016/j.jaad.2015.08.063. Lauret E, et al. BioMed Research International. 2013;doi:10.1155/2013/127589. Ni C, et al. Clin Cosmet Investig Dermatol. 2014;doi:10.2147/CCID.S44843 Sardu C, et al. Plos. 2012;doi:10.1371/journal.pone.0032487. Somers EC, et al. Am J Epidemiol. 2009:doi:10.1093/aje/kwn408. For more information: Regina Berkovich, PhD, MD, can be reached at 1520 San Pablo St, #3000, Los Angeles, CA 90033; email: regina.berkovich@med.usc.edu. Eric Matteson, MD, can be reached at 701 Fairview Blvd., Red Wing, MN 55066; email: theimer.sharon@mayo.edu. Emily C. Somers, PhD, ScM, can be reached at the Division of Rheumatology, University of Michigan, 3918 Taubman Center, 1500 East Medical Center Dr., Ann Arbor, MI, 48109; email: emsomers@umich.edu. Antoine G. Sreih, MD, can be reached at Perelman Center for Advanced Medicine, South Pavilion, 1st Floor, 3400 Civic Center Blvd., Philadelphia, PA 19104; email: greg.richter@uphs.upenn.edu. Disclosures: Berkovich reports she is a consultant on advisory boards for Acorda, Bayer, Biogen Idec, Questcor and Teva; and receives research support from Biogen Idec, Questcor, Teva and the National Multiple Sclerosis Society. Matteson and Somers report no relevant financial disclosures. Sreih reports research funding from Glaxo SmithKline, Roche/Genentech, Celgene, Chemocentryx and Bristol-Myers Squibb; and has consulted for Genentech, Krogg and Partners, Rupert Case Management and Naxion.
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