Objective In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D 3 in patients with RRMS. Methods Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D 3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48. Results At 48 weeks, 36.3% of patients who received high-dose vitamin D 3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D 3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: −0.074; p = 0.035). Conclusions SOLAR did not establish a benefit for high-dose vitamin D 3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS. Clinicaltrials.gov identifier NCT01285401. Classification of evidence This study provides Class II evidence that for patients with RRMS treated with SC IFN-β-1a, 48 weeks of cholecalciferol supplementation did not promote NEDA-3 status.

Epstein-Barr virus (EBV) has long been suggested as a pathogen in multiple sclerosis (MS).Here, we used high-throughput sequencing to determine the diversity, compartmentalization, persistence, and EBV-reactivity of the T-cell receptor (TCR) repertoires in MS. TCR-β genes were sequenced in paired samples of cerebrospinal fluid (CSF) and blood from patients with MS and controls with other inflammatory neurological diseases. The TCR repertoires were highly diverse in both compartments and patient groups. Expanded T-cell clones, represented by TCR-β sequences >0.1%, were of different identity in CSF and blood of MS patients, and persisted for more than a year. Reference TCR-β libraries generated from peripheral blood T cells reactive against autologous EBV-transformed B cells were highly enriched for public EBV-specific sequences and were used to quantify EBVreactive TCR-β sequences in CSF. TCR-β sequences of EBV-reactive CD8 + T cells, including several public EBV-specific sequences, were intrathecally enriched in MS patients only, whereas those of EBV-reactive CD4 + T cells were also enriched in CSF of controls. These data provide evidence for a clonally diverse, yet compartmentalized and persistent, intrathecal T-cell response in MS. The presented strategy links TCR sequence to intrathecal T-cell specificity, demonstrating enrichment of EBV-reactive CD8 + T cells in MS. Keywords:Cerebrospinal fluid r Epstein-Barr virus r High-throughput sequencing r MS r TCR Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Andreas Lossius e-mail: andreas.lossius@rr-research.no * These authors contributed equally to this work as senior authors. Eur. J. Immunol. 2014. 44: 3439-3452 Introduction T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS) [1]. The T cells access the central nervous system (CNS) via the cerebrospinal fluid (CSF) or cross the blood-brain barrier through the perivascular spaces, which communicate with the CSF [2]. The CSF is also contiguous with the extracellular fluid of the brain and is believed to reflect inflammation within the CNS better than blood [3]. Although moderately increased in MS [4], the low numbers of T cells in CSF have complicated the characterization of these cells. Thus, the clonal composition of T cells in the CSF and their relationship to T cells in the blood is poorly understood. Cloning and sequencing of individual T-cell receptors (TCRs) [5], spectratyping [6,7], or flow cytometric staining for TCR variable (V) β-chain families [8] has previously permitted mapping of only a narrow part of the intrathecal TCR repertoire. These studies have yielded partly conflicting results with respect to clonal diversity and TCRV β-chain usage, and the overlap between the T-cell populations in CSF and blood has not been quantified. Epstein-Barr virus (EBV) has consistently been associated with MS in epidemiological studies [9], and MS patients display a perturbed immune respo...

In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.

Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity.