ÌÇÐÄvlog

Key Points

QuestionÌý Is intrathecal immunoglobulin synthesis associated with disability worsening in patients with multiple sclerosis?

FindingsÌý This cohort study included 673 patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome. Patients with intrathecal IgG synthesis were found to have a higher risk of and shorter time to Expanded Disability Status Scale score worsening in the 4 years after study entry.

MeaningÌý Intrathecal IgG synthesis is associated with disability worsening in patients with multiple sclerosis; it may be of use for early treatment decisions.

ImportanceÌý Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed.

ObjectiveÌý To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome.

Design, Setting, and ParticipantsÌý Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018.

ExposureÌý Patients were offered standard immunotherapies per national treatment guidelines.

Main Outcomes and MeasuresÌý A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated.

ResultsÌý Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found.

Conclusions and RelevanceÌý Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.

The disease course of relapsing-remitting multiple sclerosis (RRMS) is highly variable, with benign, almost subclinical courses, as well as highly active courses with rapid disability progression.^1,2 Established early clinical factors associated with disability worsening are older age at disease onset, male sex, multifocal symptoms or incomplete remission of the first relapse, shorter time to the second relapse, and a high brain magnetic resonance imaging (MRI) lesion load at diagnosis.^3-8 Different routine cerebrospinal fluid (CSF) parameters have been suggested as factors associated with the disease course. The presence of oligoclonal bands (OCBs) in the CSF, a qualitative measure of intrathecal IgG synthesis, is a known risk factor for conversion to multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS).^8-11 The same applies to quantitative measures of IgG synthesis in the CSF compartment. Some studies^8,12-14 have also suggested that patients with IgG or IgM OCBs in their CSF might have a higher risk for disability worsening, which has not been confirmed.^15,16

The aim of this study was to investigate a possible association of intrathecal IgG synthesis with disability worsening in a large, highly controlled prospective cohort of patients with new diagnoses of MS and CIS. The association of intrathecal IgG synthesis for disability worsening 4 years after study inclusion was the primary end point. This was based on the broad availability of the test, higher reliability of quantitative Ig testing, and a higher frequency of intrathecal IgG synthesis compared with IgM and IgA synthesis in patients with MS. Associations of other CSF parameters on disability worsening and relapse occurrence were exploratory end points.

Patients from the German national MS cohort, a prospective observational study of patients with newly diagnosed relapsing-remitting MS (RRMS) or CIS, were included in this analysis.¹⁷ Inclusion criteria for the German national MS cohort are (1) an age at study inclusion of 18 years or older, (2) a point of diagnosis not more than 6 months prior to inclusion in patients with CIS and not more than 2 years prior to inclusion in patients with RRMS, and (3) no previous treatment with disease-modifying drugs. The diagnosis of RRMS was based on the 2005 revised McDonald criteria, while CIS diagnosis was defined as a single clinical event and fulfillment of 3 of the 4 Barkhof criteria¹⁸ or 2 Barkhof criteria with supportive findings from a CSF analysis (intrathecal IgG synthesis or positive OCBs) or visual-evoked potential testing. Information on participant sex was either self-reported or determined by investigator observation. Of the 1376 patients in the German national MS cohort on August 13, 2018, after equivocal cases removed, 703 patients with missing CSF or EDSS data were excluded (eFigure 1 in the Supplement). All other patients from 18 different centers were included in the study. There were no differences in sex, age, T2 lesion load at baseline, or disease duration between the patients selected for this study and the German national MS cohort (eTable 1 in the Supplement).

The German national MS cohort study was approved by the ethics committee of the medical faculty of the Ruhr-Universität Bochum (which was the lead institution) and the ethics committee of all participating centers. Written informed consent was obtained from all participants.

Participation in the German national MS cohort involves regular standardized study visits (including at baseline and years 1, 2, and 4). For some patients, intermediate visits were recorded. Data from visits up to 4 years after study inclusion were considered for this study. The Kurtzke Expanded Disability Status Scale (EDSS) score,¹⁹ a clinical score used to measure disability in patients with MS, was assessed at each study visit by trained physicians. The EDSS scores taken during relapses were not included; whether patients experienced a relapse at the time point of EDSS scoring was determined and recorded by the physicians.

We defined EDSS worsening as an increase of the EDSS score of 1.5 for patients with a baseline EDSS of 0; an increase of 1.0 for patients with baseline EDSS between 1 and 5, and an increase of 0.5 for patients with baseline EDSS of more than 5. Because patients were not scheduled for follow-up visits after EDSS worsening, confirmed EDSS worsening at 12 or 24 weeks could not be analyzed. The occurrence of relapses was recorded by the treating physicians at each study visit.

The analysis of CSF samples was performed at each center independently. For patients who underwent more than 1 lumbar puncture, data from the sampling closest to study inclusion were considered. Both CSF and serum concentrations for albumin and the 3 Ig classes (IgG, IgM, and IgA) were measured in parallel by standard nephelometric or turbidimetric assays (depending on the study center), and the CSF-to-serum quotients (QIgG, QIgM, QIgA, and Qalb [CSF-to-serum albumin]) were calculated. Determination of quantitative intrathecal immunoglobulin synthesis of the 3 Ig classes was based on the calculation by Reiber,²⁰ in which intrathecal Ig synthesis is considered in samples with QIgX greater than Qlim (IgX) with Equation 1:

Equation 2:

and Equation 3:

Any intrathecal Ig synthesis was defined as intrathecal synthesis of at least 1 of the 3 Ig classes (IgG, IgA, and IgM). The IgG index was calculated as QIgG/Qalb, and an IgG index of greater than 0.70 was considered elevated. Detection of OCBs was performed using isoelectric focusing followed by immunoblotting, immunofixation, or (rarely) silver staining (depending on the study center). Testing of OCBs were considered positive if patterns 2 or 3 were present.^21,22 The Qalb value was included as a measure of the blood-CSF barrier function. Because the Qalb is age dependent, we calculated it with Equation 4 (in which LP indicates lumbar puncture); patients with Qalb greater than the resulting value were considered to have a dysfunction of the blood-CSF barrier:

Cranial MRIs (cMRIs) were performed at each scheduled study visit, and the number of T2 lesions was recorded by neuroradiologists. The cMRI T2 lesion load was coded as a binary variable (0 for 1 to 8 lesions; 1 for 9 or more lesions).

Based on previous studies and the higher frequency of intrathecal IgG synthesis compared with IgM and IgA synthesis, we defined the association of intrathecal IgG synthesis with risk of disease worsening over 4 years as the primary end point. All other end points and the association of CSF parameters with EDSS worsening over 2 years from study inclusion were exploratory. Associations of CSF parameters with the risk of EDSS worsening at 2 and 4 years were investigated by multivariable binomial regression models with adjustments made for sex, age at lumbar puncture, the occurrence of relapses, disease-modifying therapy (DMT) within 2 or 4 years or before the last EDSS scoring and the cMRI T2 lesion load at baseline, because these might influence disability worsening in patients with MS. All CSF parameters except for the leukocyte count, the cMRI T2 lesions load, the DMT treatment status, the occurrence of relapses, and the EDSS worsening were coded as binary variables. Odds ratios and 95% CIs were calculated.

Only patients with a study inclusion before November 12, 2016, or November 12, 2014, were included in the 2-year and 4-year regression analyses, respectively. Missing 2-year and/or 4-year EDSS worsening status data were imputed by logistic regression using the R package mice with the independent variables sex, age, the baseline cMRI T2 lesions load, the occurrence of relapses within 2 or 4 years, multifocality of the first symptoms, the baseline EDSS score, the last recorded EDSS score, DMT treatment within 2 years or 4 years or before the last recorded visit within 2 or 4 years and the analyzed CSF parameter. For each analysis, 15 imputed data sets were created, and the regression models were fitted on each of the imputed data sets. The estimates from each model were combined by the Rubin rule using the pool() function of the mice package.

Kaplan-Meier analyses were run to estimate time to EDSS worsening, and all patients were included in these analyses and censored at the point of their last EDSS scoring. Differences in the event distributions between patients with and without intrathecal Ig synthesis, OCBs, or a dysfunction of the blood-CSF barrier were determined using a log rank test.

A P value less than .05 was considered statistically significant for all tests. All statistical analyses were performed using R statistical software version 3.5.1 (R Foundation for Statistical Computing) with the extension packages mice, survival, and survminer.²³ Data analysis was completed from August 2018 to December 2018.

A total of 673 patients with new diagnoses were included in the analyses. Table 1 shows the baseline characteristics of these patients. Of all patients, 459 patients (68.2%) were female; the median age at study inclusion and lumbar puncture was 32 (interquartile range [IQR], 27-41) years. At study inclusion, 319 patients (47.4%) had been diagnosed with CIS and 354 patients (52.6%) with RRMS per the 2005 revised McDonald criteria. The median time from disease manifestation to study inclusion was 3 months. Of the 369 patients with available visit information for 4 years or more, 327 (88.6%) were treated with DMTs during the first 4 years from baseline (eTable 2 in the Supplement). Of all 671 patients with available baseline cMRI data, 453 (67.5%) had more than 9 T2 lesions on baseline cMRI. Demographic data and disease activity measures for patients with RRMS and CIS as well as for patients with CIS with or without OCBs or intrathecal IgG synthesis are shown in eTable 3 in the Supplement.

Of the 638 patients with available data on OCBs, only 78 patients (12.2%) did not have OCBs in the CSF (Table 1). Intrathecal synthesis of IgG was seen in 352 of 605 patients (58.2%), whereas only 123 of 566 (21.7%) and 49 of 559 (8.8%) had intrathecal synthesis of IgM and IgA, respectively. Intrathecal synthesis of at least 1 Ig class could be seen in 392 of 588 patients (66.6%) with available IgG, IgM, and IgA data; intrathecal synthesis of more than 1 Ig class could be seen in 102 of 557 patients (18.3%) with available IgG, IgM, and IgA data. An elevated albumin quotient adjusted for age was observed in 179 of 606 patients (29.5%). The median (IQR) leukocyte count in the CSF was 6 (3-12) per μL. The percentages of patients from each center with OCBs, quantitative intrathecal Ig synthesis, and an elevated Qalb are shown in eFigure 2 in the Supplement.

Four years after study inclusion, 92 of 330 patients (27.9%) with available EDSS scoring data had an EDSS worsening. Possible associations of CSF parameter with risk of EDSS worsening were tested by multivariable binomial regression after imputation of the missing EDSS worsening data, and the analyses were adjusted for factors that might influence EDSS worsening, such as sex, age, relapse occurrence, DMT treatment, and baseline cMRI T2 lesion load. Regression analysis showed that intrathecal IgG synthesis was associated with a higher risk of EDSS worsening 4 years after study inclusion (odds ratio [OR], 2.02 [95% CI, 1.15-3.58]; P = .01; Table 2). Comparable findings were obtained in the 2-year analysis (OR, 1.91 [95% CI, 1.11-3.29]; P = .02; Table 2) and an analysis on a subgroup who fulfilled the 2017 revised McDonald criteria²⁴ (eTable 4 in the Supplement). Additionally, we performed an analysis using the IgG index to determine intrathecal IgG synthesis (when IgG index >0.70) and found a similar association (4-year analysis: OR, 2.27 [95% CI, 1.30-3.97]; P = .004; eTable 5 in the Supplement). When considering intrathecal synthesis of at least 1 Ig class, the association of intrathecal Ig synthesis with risk of EDSS worsening was comparable with the results seen for intrathecal IgG synthesis (4-year analysis: OR, 2.14 [95% CI, 1.13-4.07]; P = .02; 2-year analysis: OR, 2.16 [95% CI, 1.27-3.67]; P = .005; Table 2). There was no association of intrathecal IgA or IgM synthesis itself (Table 2), the presence of OCBs in the CSF, an elevated Qalb (eTable 6 in the Supplement), or the leukocyte count (eTable 7 in the Supplement) with risk of EDSS worsening in this cohort.

To investigate associations of CSF parameters with time to EDSS worsening, Kaplan-Meier analyses were performed. Four years after study inclusion, the percentage of patients in whom EDSS worsened who also had intrathecal IgG synthesis was 28.4% (95% CI, 22.7%-34.1%). For patients without intrathecal IgG synthesis, it was 18.1% (95% CI, 12.4%-23.9%). Kaplan-Meier curves for EDSS worsening in patients with and without intrathecal IgG synthesis are shown in Figure 1A. Comparable results were obtained in a subgroup of patients fulfilling the 2017 revised McDonald criteria (eFigure 3 in the Supplement), and when the IgG index was used to determine intrathecal IgG synthesis (eFigure 4 in the Supplement). The same association of intrathecal IgG synthesis with time to disability worsening was seen in subgroups of untreated patients (Figure 2A) and patients treated with DMT (Figure 2B), although the analysis in the subgroup of untreated patients did not reach statistical significance. Patients with intrathecal synthesis of at least 1 of the 3 Ig classes showed an earlier EDSS worsening compared with patients without any intrathecal Ig synthesis (Figure 1D). When investigated separately, neither intrathecal IgM nor IgA synthesis was associated with earlier EDSS worsening (Figures 1B and C), and there was no association of the presence of OCBs in the CSF or an elevated Qalb with time to EDSS worsening (eFigure 5 in the Supplement).

We investigated associations of intrathecal Ig synthesis with the occurrence of relapses during a 4-year observation period. Although patients with intrathecal IgG synthesis seemed to have a slightly higher risk of and shorter time to relapse compared with those without intrathecal IgG synthesis (eTable 8 and eFigure 6 in the Supplement), the differences did not reach statistical significance. Furthermore, we performed an exploratory analysis on the association of intrathecal Ig synthesis and the risk of and time to reach EDSS scores of 2.5 or 3 within 4 years of baseline. Patients with intrathecal IgG synthesis had a higher risk of reaching an EDSS score of 2.5 (OR, 3.31 [95% CI, 1.37-7.98]; P = .009) and a higher risk of reaching an EDSS score of 3 (OR, 2.29 [95% CI, 1.02-5.14]; P = .04; eTables 9 and 10 in the Supplement). Similar findings were obtained in the Kaplan-Meier analyses on time to reach EDSS scores of 2.5 and 3, although the analysis regarding a score of 3 did not reach significance (eFigures 7 and 8 in the Supplement).

The disease course in patients with MS is highly variable, and reliable biomarkers for prognostication of disability worsening are lacking. In this study, we analyzed the possible associations of standard CSF parameters with EDSS worsening in patients newly diagnosed with RRMS and CIS. Because in many countries CSF analysis is a standard diagnostic procedure in patients presenting with symptoms suggestive of MS, a prognosis of the disease course based on CSF parameters could be a valuable tool to guide treatment decisions. Indeed, the presence of CSF OCBs seems to be independently associated with the conversion from CIS to clinically definite MS. Accordingly, diagnostic criteria for MS have recently been revised to include OCBs as a parameter of dissemination in time.²⁴ However, the role of CSF parameters as factors associated with disability worsening is less clear.

In this prospective cohort, we analyzed associations of CSF parameters at diagnosis for disability worsening over 4 years. Within 4 years, only 28% of all patients had an increase of the EDSS score, which is in accordance with other recent studies showing that a large proportion of patients with MS, especially those with access to DMT, do not develop substantial disability in the first few years after disease manifestation.^25,26

In this cohort, intrathecal production of IgG was associated with a higher risk of and shorter time to EDSS worsening 4 years after study inclusion. This association was independent of the cMRI T2 lesion load at baseline, DMT treatment, and the occurrence of relapses. We used the calculations by Reiber²⁰ to determine intrathecal Ig synthesis because these proved clear cutoff points. However, we saw the same association when using the IgG index with a cutoff of 0.70 for intrathecal IgG synthesis instead.

A prognosticative value of intrathecal IgG synthesis for disability worsening or accumulation in patients with MS has been suggested by previous small studies.^27,28 The presence of OCB in the CSF, as an indication of local production of IgG in the central nervous system, has also been associated with a higher risk of disability worsening in patients with MS.^8,14,28 However, these associations were not confirmed by others.^15,16,29 In contrast with previous studies, we investigated this in a large, prospective, well-controlled, multicenter cohort of patients with newly diagnosed MS or CIS and a standardized EDSS rating every 12 months, and we carefully adjusted the analysis for known factors influencing disease worsening.

While we observed an association of intrathecal IgG synthesis as determined by quantitative IgG testing with disability worsening, there was no association with the presence of OCBs in the CSF. This could be owing to the low number of patients with negative OCB status (12.2%) in this cohort, which differs from the prevalence of patients who were OCB negative in aforementioned studies^8,28 (16%-43%). The low rate of patients with negative OCBs goes along with a low power to detect an association with EDSS worsening in this study; thus, much bigger cohorts would be needed to see this outcome.

Intrathecal synthesis of IgM and IgA can be observed in a small proportion of patients with MS in this study (IgA, 22%; IgM, 9%). Intrathecal IgM synthesis has previously been shown to have a prognosticative value for the conversion to clinically definite MS in patients with CIS and be associated with a more aggressive disease course.^13,30-33 In previous studies, intrathecal IgM synthesis was mainly determined by oligocloncal IgM-band testing, and clinical end points were conversion to clinically definite MS, T2 lesion volume, brain atrophy, risk of relapses, and time to an EDSS score of 4.0. To our knowledge, a correlation of intrathecal IgA synthesis with disease course has been investigated in a few studies^34,35 with low numbers of patients, and no association with disease activity has been reported. In this cohort, there was no association between intrathecal production of IgM or IgA and a risk of or time to EDSS worsening when analyzed separately. This could be owing to the small proportion of patients with intrathecal IgA and IgM synthesis. Thus, much larger cohorts would be needed to detect possible associations with smaller effects.

Because the follow-up in this study was 4 years, this study cannot provide any information about the association of CSF parameters with long-term outcome in patients with RRMS and CIS. Additionally, because the CSF analyses were performed by each center independently, differences in sample handling or analysis could affect results.

The results of this study demonstrate an association of a standard CSF parameter with the disease course of patients newly diagnosed with RRMS and CIS. Patients with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening over 4 years. The association was independent of the occurrence of relapses and DMT treatment. Follow-up studies on this cohort will provide further insights on the association of intrathecal IgG synthesis with long-term outcomes.

Accepted for Publication: February 1, 2019.

Corresponding Author: Bernhard Hemmer, MD, Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str 22, 81675 Munich, Germany (hemmer@tum.de).

Published Online: April 29, 2019. doi:10.1001/jamaneurol.2019.0905

Author Contributions: Drs Hemmer and Gasperi had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Gasperi, Wiendl, Tumani, Gold, Hemmer.

Acquisition, analysis, or interpretation of data: Gasperi, Salmen, Antony, Bayas, Heesen, Kümpfel, Linker, Paul, Stangel, Tackenberg, Then Bergh, Warnke, Weber, Wildemann, Zettl, Ziemann, Zipp, Tumani, Hemmer.

Drafting of the manuscript: Gasperi, Antony, Hemmer.

Critical revision of the manuscript for important intellectual content: Salmen, Bayas, Heesen, Kümpfel, Linker, Paul, Stangel, Tackenberg, Then Bergh, Warnke, Weber, Wiendl, Wildemann, Zettl, Ziemann, Zipp, Tumani, Gold, Hemmer.

Statistical analysis: Gasperi, Hemmer.

Obtained funding: Salmen, Wildemann, Zipp, Hemmer.

Administrative, technical, or material support: Salmen, Antony, Kümpfel, Linker, Paul, Stangel, Tackenberg, Then Bergh, Warnke, Weber, Wildemann, Zettl, Gold.

Supervision: Salmen, Wiendl, Tumani, Hemmer.

Conflict of Interest Disclosures: Dr Salmen has received speaker honoraria and/or travel compensation from Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Dr Bayas has received personal compensation from Merck, Biogen, Bayer Vital, Novartis, Teva Pharmaceutical Industries, Roche, and Sanofi/Genzyme and grants for congress trips and participation from Biogen, Teva Pharmaceutical Industries, Novartis, Sanofi/Genzyme, and Merck. Dr Heesen has received speaker honoraria and grants from Biogen, Genzyme, Roche, and Merck. Dr Kümpfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharmaceutical Industries, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche, and Biogen, as well as grant support from Bayer-Schering AG, Novartis, and Chugai Pharma. Dr Linker received research support and/or personal compensation for activities with Bayer Health Care, Biogen, Genzyme/Sanofi, Merck, Novartis Pharma, Roche, and Teva Pharmaceutical Industries. Dr Paul has served on the steering committee for Novartis Optical Coherence Tomography in Multiple Sclerosis study and MedImmune; has received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva Pharmaceutical Industries, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, and MedImmune; is an academic editor for PLoS One; is an associate editor for Neurology: Neuroimmunology & Neuroinflammation; has consulted for SanofiGenzyme, Biogen Idec, and MedImmune; and has received research support from Bayer, Novartis, Biogen Idec, Teva Pharmaceutical Industries, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research (BMBF Competence Network Multiple Sclerosis), Guthy Jackson Charitable Foundation, National Multiple Sclerosis Society, and Arthur Arnstein Stiftung Berlin. Dr Stangel has received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva Pharmaceutical Industries. Dr Stangel’s institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva Pharmaceutical Industries. Dr Tackenberg has received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva Pharmaceutical Industries, and UCB Pharma. Dr Tackenberg’s university has received unrestricted research grants from Biogen-idec, Novartis, Teva Pharmaceutical Industries, Bayer Healthcare, CSL-Behring, Grifols, Octapharma, Sanofi Genzyme, and UCB Pharma. Dr Then Bergh has received funding from the Deutsche Forschungsgemeinschaft; received, through his institution, research support for investigator-initiated studies from Actelion and Novartis; served on scientific advisory boards for Novartis, Sanofi/Genzyme, and Roche; received support to attend a scientific meeting from Biogen; and received personal honoraria for speaking from Bayer Schering, Biogen, Roche, and Sanofi/Genzyme. Dr Warnke received honoraria and/or research funding from Bayer, Biogen, Novartis, and Teva Pharmaceutical Industries. Dr Weber received honoraria from Genzyme, Novartis, Teva Pharmaceutical Industries, Pfizer, Merck-Serono, and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono, Bayer Healthcare, and Novartis and grant support from Merck-Serono, Novartis, and the Federal Ministry of Education and Research (BMBF; Projects Biobanking and Omics in ControlMS, as part of the Competence Network Multiple Sclerosis). Dr Wiendl receives honoraria for acting as a member of scientific advisory boards and a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, and Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, Teva Pharmaceutical Industries, and WebMD Global; acts as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society; and receives research funding from the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaftt, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, North Rhineland–Westphalia Ministry of Education and Research, Interdisciplinary Center for Clinical Studies Muenster and RE Children's Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme. Dr Wildemann has received grants from the German Ministry of Education and Research, Dietmar Hopp Foundation, and Klaus Tschira Foundation; grants and personal fees from Biogen, Merck Serono, Sanofi Genzyme, Novartis pharmaceuticals, and Teva Pharmaceutical Industries; and personal fees from Bayer Healthcare. Dr Ziemann has received speaker honoraria and/or travel compensation from Biogen Idec GmbH, Bayer Vital GmbH, Bristol Myers Squibb GmbH, CorTec GmbH, Medtronic GmbH, Pfizer, and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV, outside of the submitted work. Dr Zettl has received speaking fees, travel support, and/or financial support for research activities from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharmaceutical Industries. Dr Zipp has received funds for research grants, consultation fees, or travel compensation from Deutsche Forschungsgemeinschaft, German Ministry of Education and Research, International Progressive MS Alliance, Novartis, Octapharma, Merck-Serono, Ono Pharmaceutical, Biogen, Genzyme, Celgene, Roche, and Sanofi Aventis. Dr Tumani has received speaker honoraria from Bayer, Biogen, Fresenius, Genzyme, Merck, Novartis, Roche, Siemens, and Teva Pharmaceutical Industries; serves as section editor for the Journal of Neurology, Psychiatry and Brain Research; and receives research support from Fresenius, Genzyme, Merck and Novartis. Dr Gold has received speaker's and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris, and Teva Pharmaceutical Industries; and grant support (via his department) from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, and Teva Pharmaceutical Industries. Dr Hemmer has served on scientific advisory boards for F. Hoffmann–La Roche Ltd, Novartis, Bayer AG, and Genentech; data safety monitoring board member for AllergyCare and TG Therapeutics; and has received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann–La Roche Ltd. Dr Hemmer’s institution has received research support from Chugai Pharmaceuticals and holds part of 2 patents, 1 for the detection of antibodies and T cells against KIR4.1 in a subpopulation of patients with MS and 1 for genetic determinants of neutralizing antibodies to interferon β. No other disclosures were reported.

Funding/Support: The German National MS cohort and the German Competence Network of Multiple Sclerosis are supported by the German Federal Ministry for Education and Research (grants 01GI0914 [Bochum, Germany], 01GI0916, 01GI1601G [Lübeck, Germany], 01GI1601B [Marburg, Germany], and 01GI1601D [Munich, Germany]); the Transregional Collaborative Research Center SFB CRC TR-128 (Drs Hemmer, Wiendl, Zipp, and Gold), and the the MultipleMS EU project (Dr Hemmer).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The German Competence Network of Multiple Sclerosis members are Orhan Aktas, MD, Department of Neurology, University Hospital, Medical Faculty Heinrich Heine University, Düsseldorf, Germany; Gisela Antony, DiplPsych, Central Information Office German Competence Network of Multiple Sclerosis, Philipps University Marburg, Marburg, Germany; Ilya Ayzenberg, MD, Ralf Gold, MD, Kerstin Hellwig, MD, and Anke Salmen, MD, Department of Neurology, and Carsten Lukas, MD, Diagnostic and Interventional Radiology and Nuclear Medicine, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany; Erik Bahn, MD, and Wolfgang Brück, MD, Institute of Neuropathology, Alexander Flügel, MD, Institute for Neuroimmunology and Multiple Sclerosis Research, Tim Friede, PhD, Department of Medical Statistics, Dmitri Lodygin, PhD, Institute for Neuroimmunology and Multiple Sclerosis Research, and Tina Meißner, Msc, Department of Medical Informatics, University Medical Center Göttingen, Göttingen, Germany; Klaus Berger, MSc, MPH, Institute of Epidemiology and Social Medicine, University Münster, Münster, Germany. Dorothea Buck, MD, and Bernhard Hemmer, MD, Department of Neurology, Mark Mühlau, MD, NeuroImaging Center, and Thomas Korn, MD, Department of Experimental Neuroimmunology and Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; Manuel Friese, MD, Christoph Heesen, MD, and Jan-Patrick Stellmann, MD, Institute of Neuroimmunology and Multiple Sclerosis and Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Sergiu Groppa, MD, and Felix Lüssi, MD, Department of Neurology, University Medical Center of the Johannes Gutenberg-University Mainz, and Frauke Zipp, MD, Department of Neurology, Focus Program Translational Neurosciences and Research Center for Immunotherapy, Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; Catharina Groß, PhD, and Luisa Klotz, MD, Clinic of Neurology with Institute of Translational Neurology, and Sven Meuth, MD, Tobias Ruck, MD, and Heinz Wiendl, MD, Department of Neurology, University Hospital Münster, Münster, Germany; Jürgen Haas, PhD, and Brigitte Wildemann, MD, Molecular Neuroimmunology Group, Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany; Reinhard Hohlfeld, MD, Martin Kerschensteiner, MD, Tania Kümpfel, MD, and Edgar Meinl, MD, Institute of Clinical Neuroimmunology and Biomedical Center (BMC), Ludwig Maxilimians University of Munich, Germany; Reinhard Hohlfeld, MD, Martin Kerschensteiner, MD, Thomas Korn, MD, and Bernhard Hemmer, MD, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Inke König, PhD, Institute of Medical Biometry and Statistics, University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Markus Kowarik, MD, Department of Neurology, and Ulf Ziemann, MD, Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, Tübingen, Germany; Gurumoorthy Krishnamoorthy, PhD, Max Planck Institute of Biochemistry, Martinsried, Germany; Bertram Müller-Myhsok, PhD, and Sandra Nischwitz, MD, Max Planck Institute of Psychiatry, Munich, Germany; Bertram Müller-Myhsok, PhD, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Marco Prinz, MD, Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, Centre for Integrative Biological Signaling Studies, and Center for NeuroModulation, Faculty of Medicine, University of Freiburg, Frieburg, Germany; Anke Salmen, MD, Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland; Martin Stangel, MD, and Corinna Trebst, MD, Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany; Hayrettin Tumani, MD, Department of Neurology, University of Ulm, Ulm, Germany, and Clinic of Neurology Dietenbronn, Schwendi, Germany. Associated members: Antonios Bayas, MD, Department of Neurology, Klinikum Augsburg, Augsburg, Germany; Hans-Peter Hartung, MD, Department of Neurology, University Hospital, Medical Faculty Heinrich-Heine-University, Düsseldorf, Germany; Ralf Linker, MD, Department of Neurology, University of Regensburg, Regensburg, Germany; Sandra Nischwitz, MD, Max Planck Institute of Psychiatry, Munich, Germany; Friedemann Paul, MD, NeuroCure Clinical Research Center, Charité–Univeritätsmedizin Bering, corporate member of Freie Universität Berin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, and Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité–Universitätsmedizin Berlin, Berlin, Germany; Björn Tackenberg, MD, Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, Marburg, Germany; Florian Then Bergh, MD, Department of Neurology and Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany; and Uwe Zettl, MD, Department of Neurology, University of Rostock, Rostock, Germany.

Meeting Presentation: The data presented in this article has been presented in part as a poster at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis Meeting; October 26, 2017; Paris, France.

Additional Contributions: The authors and representatives of the German Competence Network of Multiple Sclerosis express their deep thankfulness to all contributors of the study, especially the study nurses, for their motivated collaboration and recruitment efforts, all patients and relatives for their participation and support and the data monitoring and administrative personnel of the study. Personnel received no compensation from a funding sponsor for their contributions.