Genetic Factors Predisposing to Myasthenia Gravis and Related Autoimmune Disorders

Myasthenia gravis (MG) is an autoimmune disorder in which patients experience weakness of the skeletal or ocular-bulbar muscles. In most patients, anti-AChR antibodies affect the signal across the neuromuscular junction necessary for muscular contraction. It is a complex disorder, wherein multiple genes plus environmental factors are likely necessary for disease manifestation. IgA deficiency (IgAD) is defined as serum IgA levels less than 0.07 g/l with normal levels of IgG and IgM. Due to the role of IgA in mucosal barriers, some patients experience recurrent infections, although many individuals are asymptomatic. Both MG and IgAD patients experience concomitant autoimmunity more often than in the background population, and IgAD may caused by autoimmune mechanisms. Investigations into genetic associations with MG have targeted genes implicated previously in autoimmune disorders. The PTPN22 rs2476601 polymorphism was genotyped in 409 MG patients and 1557 controls, and was associated with the entire cohort (p=2.7x10-4, OR=1.52), as well as with hyperplasia (p=1.4x10-4, OR=1.87), anti-AChR positivity (p=4.9x10-4, OR=1.52), and patients exhibiting both (p=6.6x10-5, OR=1.96). Furthermore, after antigen activation, a significant increase in IL-2 producing cells (p=0.002) and IgG secreting cells (p=0.004) in patients carrying the T allele was observed, indicating that the allele may be a gain-of-function variant in MG. Genotyping of 446 MG patients and 1866 controls for the CIITA rs3087456 was conducted without a statistically significant difference observed between MG patients and controls for either allele frequencies (p=0.092) or genotypes (p=0.251). The control material differed significantly from the original study reporting association of the SNP with several disorders (0.266 and 0.216, respectively, p<10-5). A lack of association in replication cohorts (4 of 26 reported association) may indicate that the SNP does not predispose to autoimmunity. The CD45 SNP rs17612648 was genotyped in 446 MG patients and 2303 matched controls, with no association with MG (p=0.199). A lack of replication in subsequent studies (4 of 24 reported association), as well as the identification of a homozygous blood donor without obvious disease, indicates that this SNP’s role in autoimmunity may have to be reconsidered. The HLA A1, B8, DR3, DQ2 (8.1) haplotype has been associated with several autoimmune disorders, and homozygosity for this haplotype has been reported to impart high risk for IgAD development (RR=77.8). Using 117 identified homozygous individuals, 2 were found to be IgAD (1.7%), indicating that the RR for IgAD for such carriers is estimated to be 11.89. Despite overlapping 8.1 association in IgAD and MG, IgAD is not elevated in MG patients (p=0.14), although concomitant autoimmunity is higher than expected in MG (15.9%). The overlapping effects of the haplotype may be due to an independent association of B8 in MG. Examining overlapping genes in autoimmunity has thus proved to be a valuable method of identifying patterns of predisposition. Using the summary associations to determine complex disease predisposition has proven to be difficult. A method was created to use complex disease MZ and DZ twins concordance to estimate the frequency of the predisposition (1:5240 in MG) and number of overlapping genetic regions contributing to disease (2-4 in MG). This information has made it possible to formulate a model of complex disease which is flexible to the number of underlying genetic subgroups of disease, and future genetic information can be used to predict the probability of disease development

A topological data analysis based classification method for multiple measurements

HR was partly supported by a collaboration agreement between the University of Aberdeen and EPFL. WC was partially supported by VR 2014-04770 and Wallenberg AI, Autonomous System and Software Program (WASP) funded by Knut and Alice Wallenberg Foundation, Göran Gustafsson Stiftelse. JT is fully funded by the Wenner-Gren Foundation. JH is partially supported by VR K825930053. RR is partially supported by MultipleMS. The collaboration agreement between EPFL and University of Aberdeen played a role in the design of the neuron spiking analysis and in providing the data required, i.e. the neuronal network and the spiking activity. Open access funding provided by Karolinska Institute.Peer reviewedPublisher PD

A multiple sclerosis disease progression measure based on cumulative disability

BACKGROUND: Existing severity measurements in multiple sclerosis (MS) are often cross-sectional, making longitudinal comparisons of disease course between individuals difficult. OBJECTIVE: The objective of this study is to create a severity metric that can reliably summarize a patient's disease course. METHODS: We developed the nARMSS - normalized ARMSS (age-related MS severity score) over follow-up, using the deviation of individual ARMSS scores from the expected value and integrated over the corresponding time period. The nARMSS scales from -5 to +5; a positive value indicates a more severe disease course for a patient when compared to other patients with similar disease timings. RESULTS: Using Swedish MS registry data, the nARMSS was tested using data at 2 and 4 years of follow-up to predict the most severe quartile during the subsequent period up to 10 years total follow-up. The metric used was area under the curve of the receiver operating characteristic (AUC-ROC). This resulted in measurements of 0.929 and 0.941. In an external Canadian validation cohort, the equivalent AUC-ROCs were 0.901 and 0.908. CONCLUSION: The nARMSS provides a reliable, generalizable and easily measurable metric which makes longitudinal comparison of disease course between individuals feasible

Accurate classification of secondary progression in multiple sclerosis using a decision tree

BACKGROUND: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult. OBJECTIVE: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes. METHODS: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists. RESULTS: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data. CONCLUSION: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results

Antibodies; Interferon beta; Multiple sclerosisAnticossos; Interferó beta; Esclerosi múltipleAnticuerpos; Interferón beta; Esclerosis múltipleAntibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA

Age Related Multiple Sclerosis Severity Score: Disability ranked by age.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is obtained by normalising the Expanded Disability Status Scale (EDSS) score for disease duration and has been a valuable tool in cross-sectional studies. OBJECTIVE: To assess whether use of age rather than the inherently ambiguous disease duration was a feasible approach. METHOD: We pooled disability data from three population-based cohorts and developed an Age Related Multiple Sclerosis Severity (ARMSS) score by ranking EDSS scores based on the patient's age at the time of assessment. We established the power to detect a difference between groups afforded by the ARMSS score and assessed its relative consistency over time. RESULTS: The study population included 26058 patients from Sweden ( n = 11846), Canada ( n = 6179) and the United Kingdom ( n = 8033). There was a moderate correlation between EDSS and disease duration ( r = 0.46, 95% confidence interval (CI): 0.45-0.47) and between EDSS and age ( r = 0.44, 95% CI: 0.43-0.45). The ARMSS scores showed comparable power to detect disability differences between groups to the updated and original MSSS. CONCLUSION: Since age is typically unbiased and readily obtained, and the ARMSS and MSSS were comparable, the ARMSS may provide a more versatile tool and could minimise study biases and loss of statistical power caused by inaccurate or missing onset dates.Biogen, Neuro Sweden (Neuroförbundet), Cambridge NIHR Biomedical Research Centr

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe:A descriptive study of test results

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA

Lack of association of the CIITA -168A→G promoter SNP with myasthenia gravis and its role in autoimmunity

<p>Abstract</p> <p>Background</p> <p>The major histocompatibility complex class II transactivator (CIITA) regulates MHC class II gene expression. A promoter SNP -168A→G (rs3087456) has previously been shown to be associated with susceptibility to several immune mediated disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS) and myocardial infarction (MI). Myasthenia gravis (MG) is an autoimmune disorder which has previously been shown to be associated with polymorphisms of several autoimmune predisposing genes, including <it>IL-1</it>, <it>PTPN22</it>, <it>TNF-α </it>and the <it>MHC</it>. In order to determine if allelic variants of rs3087456 increase predisposition to MG, we analyzed this SNP in our Swedish cohort of 446 MG patients and 1866 controls.</p> <p>Results</p> <p>No significant association of the SNP with MG was detected, neither in the patient group as a whole, nor in any clinical subgroup. The vast majority of previous replication studies have also not found an association of the SNP with autoimmune disorders.</p> <p>Conclusions</p> <p>We thus conclude that previous findings with regard to the role of the <it>CIITA </it>-168A→G SNP in autoimmunity may have to be reconsidered.</p