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Disease modifying therapies use associated with comorbid autoimmune diseases in multiple sclerosis patients
Multiple Sclerosis and Related Disorders (available online 27 February 2015)
The relation between the use of disease modifying therapies (DMT׳s) and the occurrence of comorbid autoimmune diseases (AID׳s) in multiple sclerosis (MS) patients is still unclear.
To investigate the difference in duration from MS symptom onset to first reported AID in subjects using DMT׳s vs. DMT naïve. Type and prevalence of comorbid AID׳s was also investigated.
Data was extracted from the New York State MS Consortium (NYSMSC) registry and comprised of MS patients with a minimum of 5 years follow-up. After exclusion, 1792 patients were enrolled in the study, 1478 had no AID, and 314 patients had comorbid AID׳s that developed after the initial enrollment. Patients who had an AID were divided into two groups: those with an AID after DMT initiation (n=281) and patients with an AID who were DMT naïve (n=33). Logistic regression analysis was used to test differences in duration between MS symptom onset and the development of AID between the two groups while adjusting for confounders
DMT use did not change the frequency of self-reported AID (17.2 vs. 20.4%). However, the duration between first MS symptom onset and the initial reported occurrence of a comorbid AID was significantly shorter in the DMT user group (192 months±115) compared to the DMT naïve group (262 months±107,p=.002).
There were no group differences between DMT users vs. DMT naïve subjects with regards to AID frequency. The DMT user group reported the development of an AID earlier than the DMT naïve group. Further studies that can identify patients with higher risk for developing AID׳s is warranted.
- We studied the type and prevalence of comorbid autoimmune diseases (AIDs) occurring in multiple sclerosis (MS) patients.
- We know of no previous studies that evaluated the duration from MS symptom onset to first comorbid autoimmune disease.
- Duration from symptom onset and comorbid autoimmune disease was significantly shorter in DMT group compared to naïve group.
- Most frequent autoimmune diseases were thyroid ,irritable bowel syndrome, psoriasis and rheumatoid arthritis in DMT group.
Keywords: Multiple sclerosis, Autoimmune disease, Disease modifying therapy, Thyroid disease, Interferon-Beta.
Multiple sclerosis (MS) is the most common disease of the central nervous system (CNS) affecting young adults and causing chronic disability. It is strongly believed that MS is an organ-specific autoimmune disease (AID) ( Ramagopalan and Sadovnick, 2011 ) targeting the CNS. Studies have suggested genetic, environmental and infectious agents as interacting factors influencing the risk for development of MS (Ramagopalan and Sadovnick, 2011 and Giovannoni and Ebers, 2007).
The classification of autoimmune diseases has varied over time, with the overall estimated prevalence in the general population being 4.5% ( Hayter and Cook, 2012 ). An increased number of AID׳s are reported in people diagnosed with MS compared to the general population (Henderson et al, 2000, Somers et al, 2009, and Dobson and Giovannoni, 2013). Examples of comorbid AID׳s in MS patients reported in the literature include: systemic lupus erythematosus (SLE), thyroid diseases, rheumatoid arthritis, active hepatitis, type 1 diabetes mellitus, uveitis, psoriasis, inflammatory bowel disease (IBD), pemphigus and myasthenia gravis (Bagir et al, 2009, Belniak et al, 2007, Nielsen et al, 2006, Kimura et al, 2000, and Basiri et al, 2009).
As MS is a heterogeneous disease and the response to therapy varies between patients, an individualized therapeutic approach should be tailored on a well-defined risk–benefit balance for each therapeutic intervention. According to current literature, autoimmune complications associated with IFN-β therapy are rare and no significant autoimmune complications have been reported during the large phase III pivotal studies of IFN-β-1a and INF-β-1b in relapsing-remitting MS (RRMS) (Jacobs et al, 1995 and IFNB, 1993), perhaps related to the short time period (18–24 months) the studies were carried out.
An increase in AID cases was found to be associated with the use of Alemtuzumab (Campath), a very potent treatment with increased efficacy for RRMS patients (Cohen et al, 2012, Coles et al, 2012, Daniels et al, 2014, and Aranha et al, 2013). AID׳s including thyroid disease, as well as a few cases of idiopathic thrombocytopenic purpura, were more commonly seen in patients treated with Alemtuzumab compared to subjects treated with IFN-β-1a.
As most cases reported in the literature refer to sporadic instances of AID׳s associated with MS, we aimed to investigate the difference in duration from MS symptom onset to first reported comorbid AID in a group of subjects using DMT׳s in comparison to a DMT naïve group. We also evaluated the type and frequency of AID׳s in our large cohort followed prospectively as part of a multicenter MS patient registry. In order to investigate a potential influence of DMT use related to an occurrence of a comorbid AID, we compared the prevalence and types of AID between a DMT users group and a DMT naïve group.
2.1. Study population
State MS Consortium (NYSMSC) registry. Informed consent according to Institutional Review Board policy was obtained for all patients who contributed data. Only patients with at least five years of follow-up from baseline were included. The NYSMSC database contains patient-reported and physician-reported follow-up data from 12 MS centers throughout New York State over a period from 1996 through 2011. Data from 11 centers fulfilled the inclusion criteria. MS patients with clinically definite MS according to McDonald criteria, including patients with RRMS, secondary progressive (SPMS), primary progressive (PPMS), progressive relapsing (PRMS) types of MS were included in the study. Exclusion criteria included patients with unknown DMT use prior to enrollment, patients who had an AID at registration, those with less than 5 years of follow up, and patients with Devic׳s disease, leaving a sample size ofn=1792 of which 314 subjects reported having an AID.
2.2. AID groups
The AID and no AID groups were compared on basic demographic and clinical characteristics to identify the presence of any inherent differences between the groups. To further ascertain the influence of DMT׳s on AID׳s, patients were divided into two groups: those with a comorbid AID after DMT initiation as DMT use was prior to reporting AID (n=281) and patients who developed AID while being DMT naive (n=33). Self-reported AID׳s included: Crohn׳s disease, SLE, myasthenia gravis, irritable/inflammatory bowel syndrome (IBS combined), psoriasis, rheumatoid arthritis, thyroid disease, and type I diabetes mellitus. DMT types included IFN-β-1a (Avonex, Rebif), IFN-β-1b (Betaseron), glatiramer acetate (Copaxone), natalizumab (Tysabri), and combinations with add-on cyclophosphamide (Cytoxan) azathioprine (Imuran), methotrexate, and mitoxantrone (Novantrone).
2.3. Statistical analyses
Statistical analyses were conducted using SPSS 21.0 software package (SPSS Inc., Chicago, IL, USA). Allp-values reported were two-tailed andp<.05 was considered significant. Chi-square tests were used to determine whether categorical variables were significantly different between the groups. To examine differences in means for continuous variables, independent samplest-tests were used. A logistic regression model was used to test differences in duration between symptom onset and first AID diagnosed between the DMT user group and DMT naïve group, while adjusting for sex, age at symptom onset, Expanded Disability Status Scale (EDSS) at enrollment, year of enrollment and number of follow-ups.
3.1. Demographic characteristics between AID and no AID groups
The majority of patients (1478 out of 1792, 82.1%) did not report a comorbid AID. Those with a comorbid AID were older at MS symptom onset and were more likely to be females. No other significant group differences were reported (see Table 1 ).
|Age MS symptom onset||32.0 (9.2)||33.5 (10.0)||31.7 (8.9)||.004|
|EDSS at registration||3.3 (2.1)||3.2 (2.0)||3.4 (2.2)||.135|
|Disease duration until registration (years)||10.6 (8.9)||10.5 (9.0)||10.6 (8.9)||.854|
|Sex, female, n||1353 (75.5%)||269 (85.7%)||1084 (73.3%)||<.001|
|DMT use, yes, n||1630 (91%)||281 (89.5%)||1349 (91.3%)||.317|
|Caucasian||1687 (94.2%)||301 (96.2%)||1386 (93.8%)|
|African-American||93 (5.2%)||12 (3.8%)||81 (5.5%)|
|Other||11 (.6%)||0||11 (.7%)|
EDSS=expanded disability status scale, DMT=disease modifying therapy
p-values were derived using chi-squared tests and independent samplest-tests.p<.05 was considered statistically significant.
3.2. Demographic characteristics between those with an AID who were DMT naïve and those who used DMT׳s
Of the 1630 subjects who used a DMT, 281 (17.2%) had an AID, while of the 162 DMT naïve subjects, 33 (20.4%) had an AID (p=.317). Of the 314 subjects with an AID, 33 reported comorbid AIDs while remaining DMT naive (10.5%) whereas 281 subjects used DMT׳s (89.5%). Females represented 90.9% of the DMT naïve group and 85.1% of the DMT group.
The DMT naïve group was older at both MS symptom onset (mean age: 36.9±8.6) compared to the DMT users group (mean age: 33.1±10.2) as well as at most recent follow-up (60.8±10.2 vs. 52.2±10.0). Although RRMS was the MS type most frequently reported in both groups, there was a significant difference in the proportions reported (p<.001). The DMT naïve group included 17 RRMS cases (51.5%) and 9 SPMS cases (27.3%), compared to 221 (78.9%) and 39 (13.9%) in the DMT users group. EDSS scores at registration were significantly higher in the DMT naïve group (4.0±2.5) compared to the DMT users group (3.1±1.9). There were no differences in sex, race, marital status or education between the DMT naïve and DMT user group. For an overview of characteristics, see Table 2 .
|Characteristics||DMT naïve||DMT user||p -value|
|n =33||n =281|
|Sex, female||30 (90.9%)||239 (85.1%)||.364|
|Age at MS symptom onset||36.9 (8.6)||33.1 (10.2)||.050|
|Age at MRF||60.8 (10.2)||52.2 (10.0)||<.001|
|Caucasian||32 (97.0%)||269 (96.1%)|
|African American||1 (3.0%)||11 (3.9%)|
|Single||5 (15.2%)||42 (15.1%)|
|Married/cohabitating||18 (54.5%)||181 (65.1%)|
|Divorced/separated||8 (24.2%)||45 (16.2%)|
|Widowed||2 (6.1%)||10 (3.6%)|
|<12 years||3 (9.1%)||18 (6.4%)|
|High school||13 (39.4%)||74 (26.3%)|
|Some college/tech school||7 (21.2%)||77 (27.4%)|
|College/university||5 (15.2%)||66 (23.5%)|
|Post graduate||5 (15.2%)||46 (16.4%)|
|Type of MS at registration||<.001|
|RRMS||17 (51.5%)||221 (78.9%)|
|SPMS||9 (27.3%)||39 (13.9%)|
|PRMS||1 (3.0%)||12 (4.3%)|
|PPMS||6 (18.2%)||6 (2.1%)|
|EDSS at registration||4.0 (2.5)||3.1 (1.9)||.017|
|EDSS at most recent follow up||4.5 (2.6)||4.2 (2.2)||.551|
|Duration of follow-up (months)||92 (28)||111 (32)||.001|
|Time symptom onset to registration (months)||195 (114)||118 (104)||<.001|
|Time symptom onset to first comorbid AID (months)||262 (107)||192.1 (115)||.002|
MS=multiple sclerosis, MRF= most recent follow-up, RRMS=relapsing remitting MS, SPMS=secondary progressive MS, PRMS=primary relapsing MS, PPMS=primary progressive MS, EDSS=expanded disability status scale.
3.3. Time to first AID between in DMT naïve and DMT users group
The duration between MS symptom onset until first reported comorbid AID was calculated for both groups. The DMT users group had a significant shorter time from MS symptom onset to first reported comorbid AID (192±115 months vs. 262±107 months,p=.002) compared to the DMT naive group. This effect was still observed after adjusting for sex, age at symptom onset, EDSS at registration, year of registration, and number of follow-ups (p<.001).
3.4. Most commonly reported AID׳s
The most commonly reported AID in the DMT naïve group was thyroid disease (n=11, 33.3%), and rheumatoid arthritis (n=7, 21.2%), followed by psoriasis (n=5, 15.2%) and IBS (5, 15.2%). For subjects who reported an AID after DMT use, the most frequently reported AID was “thyroid” (n=95, 33.8%), while IBS was the second most commonly reported AID (n=68, 24.2%) followed by psoriasis (n=50, 17.8%) and rheumatoid arthritis (n=28, 10.0%). None of these differences reached statistical significance. See Fig. 1 for an overview
To the best of our knowledge, there are no previous studies that evaluated the duration of time to development of comorbid AID relative to DMT use. Our study is unique in investigating type and prevalence of AID׳s occurring in MS patients followed from DMT initiation and compared to patients who remained DMT naïve in this retrospective longitudinal study.
As expected, females were more likely to have an AID than males, as AID׳s are known to be more prevalent in women ( Quintero et al., 2012 ). There were no differences in AID occurrence between subjects who used a DMT compared to those who did not. However, when evaluating the time to the occurrence of a comorbid AID within our registry we found that it took a shorter time for subjects in the DMT user group to report their first comorbid AID as compared to subjects in the DMT naïve group. The reason why subjects in the DMT group reported having a DMT earlier than those who remained DMT naïve remains unclear. It may be due to a bias in frequency of follow-ups, as subjects using a DMT may have more frequent lab checks as compared to subjects who were DMT naïve. Patients with MS have an increased risk for developing other AID׳s for which use of DMT may only hasten the development of AID׳s without changing the general risk.
EDSS was lower for DMT users compared to DMT naïve subjects at registration, but at most recent follow up, both groups had similar EDSS scores which might suggest a more aggressive and rapid progressing disease type among DMT users. Interferon therapies were the DMT type most frequently observed in our sample, followed by glatiramer acetate. Reports of comorbid AID following combination therapies including the use of immunosuppressive therapies were rare.
AID׳s are likely caused by a defect of the human immune system characterized by an inability to recognize their own antigens. Although the exact etiology of these diseases are unknown, there are a number of cellular and molecular mechanisms which can underlie these reactions ( Belniak et al., 2007 ), like molecular mimicry, T cell B cell discordance, epitope spreading and dendrites cell apoptosis (Kubach et al, 2005 and Matsui, 2013).
The increased prevalence of comorbid AID׳s in MS patients is well known (Dobson and Giovannoni, 2013 and Marrie et al, 2014). At the same time, a few case reports and retrospective studies have reported about the development of AID׳s after treatment with certain DMT׳s ( Durelli et al., 1999 ). A recent study published by Perez-Alvarez et al. (2013) showed paradoxical development of AID׳s in patient on different biologics. During 5 years; more than 1500 cases of different systemic and organ-specific AID׳s have been reported in patients with underlying AID׳s treated with biological therapies ( Perez-Alvarez et al., 2013 ). IFN-β was the first FDA approved therapy for MS. It was shown to reduce relapse rate, decrease disability progression, and MRI evidence of disease activity. The exact mechanism of action of IFN-β in MS is not fully understood although its immunomodulatory activity, reducing inflammatory damage and stabilizing the blood brain barrier, is probably the best known ( Kraus and Oschmann, 2006 )
Crispin and Diaz-Jouanen, (2005) have described a case of SLE that occurred after 3 years from starting interferon therapy . Occasional cases of myasthenia gravis following IFN-β therapy have also been described ( Dionisiotis et al., 2004 ). These AID׳s, except for autoimmune thyroiditis, are rare events among IFN therapy users ( Okanoue et al., 1994 ). A new case control study published by Fellner et al. (2014) showed that 4 MS patients with psoriasis experienced exacerbation of psoriasis during exposure to interferon-beta. The concern of possible psoriasis exacerbation during interferon-beta use was raised ( Fellner et al., 2014 ).
Similarly, sporadic cases of Crohn׳s disease, myasthenia gravis and arthritis have been reported in patients on GA, which is a random polymer of glutamic acid, lysine, alanine and tyrosine therapy (Charach et al, 2008, Zheng et al, 2008, Frese et al, 2000, and Heesen et al, 2001). Petrova et al. (2010) studied changes in thyroid function in a sample of 158 people on GA therapy, and showed the relative safety of copaxone in respect to changes in thyroid gland.
As neurologic complications of inflammatory bowel disease is not uncommon. A recent study showed that MS patients with concomitant inflammatory bowel disease have a milder disease course ( Zephir et al., 2013 ). The study included three groups (MS-IBD patients, isolated MS cases and isolated IBD cases), after a median of 12 years of disease duration, the median EDSS and the percentages of patients reaching an EDSS of 3.0 and 4.0 were significantly lower in MS-IBD patients than isolated MS patients. A change in the immune balance toward a stronger Th2 milieu may be responsible for this association
Bagir et al. (2009) showed that 20–25% of untreated MS patients have autoimmune thyroiditis (AIT) and/or subclinical hypothyroidism and that the occurrence of thyroid autoimmunity and dysfunction following IFN-β-1a treatment of viral hepatitis and other diseases are known to increase this pathology ( Lange-Asschenfeldt et al., 2004 ). However, conflicting data have been reported on the association between IFN-β therapy of MS patients and thyroid disease development. In MS patients, IFN-β therapy has been reported to induce anti-thyroid antibodies and precipitate thyroid clinical disease in patients with preexisting antibodies (Durelli et al, 1999 and Kreisler et al, 2003).
In our study, thyroid disease was reported most frequently in treated and non-treated groups. We were not able to determine if thyroid disease is a result of using interferon vs. de novo. Rheumatoid arthritis, psoriasis and IBS were also common AID׳s in both groups. An interesting finding is that IBS was more common in the DMT user group compared to those who were DMT naïve, while the opposite was true for rheumatoid arthritis, which was most common in the DMT naïve group compared to the DMT user group. Some patients reported three AID׳s in both the DMT naïve group and DMT user. This is supported by the theory that people with AID׳s are more prone to develop other comorbid AID׳s.
Limitations of our study include self-report of comorbid AID which was limited to AID types listed on the NYSMSC data collection instrument. Reliability of self-reported comorbidities was not addressed in our study, however, a study by Broadley et al. (2000) reported high reliability of self-reported autoimmune assessments finding a positive predictive value of 70% or higher with most autoimmune diseases. Furthermore, IBS was not differentiated from IBD or colitis on the data collection instrument and the actual etiology of IBS as an autoimmune disease is still unclear ( Tur and Montalban, 2012 ). We were not able to further define thyroid disease types by laboratory data.
Because of the shortened time we found for the DMT users to report their first comorbid AID compared to the DMT naïve group, it is important to look closer at DMT׳s in the context of presence or possible occurrence of other AID׳s. Our results support monitoring thyroid function for all patients whether using therapy or therapy naïve. Identifying risk factors associated with the development of comorbid AID in the context of therapy may help in providing a more appropriate personalized therapeutic management of MS patients and better understanding of the pathobiology of the disease.
Conflict of interest
Lynn Chouhfeh, Katelyn Kavak have nothing to disclose
Barbara Teter has received grant and or research support from Biogen Idec, Teva Neurosciences, EMD Serono, Genzyme and Novartis.
Bianca Weinstock-Guttman has participated in speaker׳s bureaus and/or served as a consultant for Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Questcor, Genzyme, Mylan and Acorda. She has also received grant/research support from the agencies listed above as well as Shire.
The authors acknowledge members of the NYSMSC: Keith Edwards (Empire Neurology, PC, Latham, NY), Andrew Goodman (University of Rochester Medical Center, Rochester, NY), Malcolm Gottesman (Winthrop Comprehensive MS Care Center, Mineola, NY), Joseph Herbert and Ilya Kister (NYU Langone Medical Center, New York, NY), Burk Jubelt (SUNY Upstate Medical University, Syracuse, NY), Patricia Coyle and Lauren Krupp (SUNY Stony Brook, Stony Brook, NY), Michael Lenihan (Adirondack Neurology Associates, PC, Albany, NY), Allen Gerber (Albany Medical College, Albany, NY), Allan Perel (Alpha Neurology, PC, Staten Island, NY), and Robert Zivadinov (Jacobs Neurological Institute, SUNY Buffalo, Buffalo, NY) Carl Granger (Uniform Data Management for Rehabilitation, SUNY Buffalo, Buffalo, NY)
Analysis of the NYSMSC registry data for this study was funded by Genzyme 2012–10892
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a Jacobs Comprehensive MS Treatment and Research Center, University at Buffalo, Buffalo, NY, USA
b New York State MS Consortium, University at Buffalo, Buffalo, NY, USA
c Department of Neurology, State University of New York at Buffalo, Buffalo, NY USA
☆ See acknowledgements for a list of participating investigators.
© 2015 Published by Elsevier B.V.