Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). In recent years, vitamin D has gained attention, as low serum levels are suspected to increase the risk for MS. Cholecalciferol supplementation has been tested in several clinical trials, since hypovitaminosis D was linked to higher disease activity and may even play a role in long-term outcome. Here, we review the current understanding of the molecular effects of vitamin D beyond calcium homeostasis, the potential beneficial action in MS and hazards including complications of chronic and high-dose therapy. In clinical trials, doses of up to 40,000 IU/day were tested and appeared safe as add-on therapy for short-term periods. A recent meta-analysis of a randomized, double-blind, placebo-controlled clinical trial investigating vitamin D as add-on therapy in MS, however, suggested that vitamin D had no therapeutic effect on disability or relapse rate. We recognize a knowledge gap for chronic and high-dose therapy, which can lead to life-threatening complications related to vitamin D toxicity including renal failure, cardiac arrythmia and status epilepticus. Moreover, vitamin D toxicity may manifest as fatigue, muscle weakness or urinary dysfunction, which may mimic the natural course of progressive MS. Given these limitations, vitamin D supplementation in MS is a sensitive task which needs to be supervised by physicians. While there is strong evidence for vitamin D deficiency and the development of MS, the risk-benefit profile of dosage and duration of add-on supplementation needs to be further clarified.

The chemokine C-X-C- ligand 13 (CXCL13) is a major B cell chemoattractant to B cell follicles in secondary lymphoid organs (SLO) that proposedly recruits B cells to the cerebrospinal fluid (CSF) during neuroinflammation. CXCR5, the cognate receptor of CXCL13, is expressed on B cells and certain T cell subsets, in particular T follicular helper cells (Tfh cells), enabling them to follow CXCL13 gradients towards B cell follicles for spatial proximity, a prerequisite for productive T cell–B cell interaction. Tfh cells are essential contributors to B cell proliferation, differentiation, and high-affinity antibody synthesis and are required for germinal center formation and maintenance. Circulating Tfh cells (cTfh) have been observed in the peripheral blood and CSF. Furthermore, CXCL13/CXCR5-associated immune activities organize and shape adaptive B cell-related immune responses outside of SLO via the formation of ectopic lymphoid structures in inflamed tissues, including the central nervous system (CNS). This review summarizes the recent advances in our understanding of the CXCL13/CXCR5 immune axis and its role in vaccination, autoimmunity, and infection with a special focus on its relevance for intrathecal B cell activities in inflammatory CNS diseases.

Therapeutic plasma exchange (TPE) is a well-established method of treatment for steroid-refractory relapses in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Little is known about indications and clinical responses to TPE in autoimmune encephalitis and other immune-mediated disorders of the central nervous system (CNS). We performed a retrospective chart review of patients with immune-mediated disorders of the CNS undergoing TPE at our tertiary care center between 2003 and 2015. The response to TPE within a 3- to 6-month follow-up was scored with an established rating system. We identified 40 patients including 21 patients with multiple sclerosis (MS, 52.5%), 12 with autoimmune encephalitis (AE, 30%), and 7 with other immune-mediated CNS disorders (17.5%). Among patients with AE, eight patients had definite AE (Immunolobulin G for N-methyl-D-aspartate receptor n = 4, Leucine-rich, glioma inactivated 1 n = 2, Ma 2 n = 1, and Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid n = 1). Intravenous immunoglobulins had been given prior to TPE in all but one patient with AE, and indications were dominated by acute psychosis and epileptic seizures. While TPE has a distinct place in the treatment sequence of different immune-mediated CNS disorders, we found consistent efficacy and safety. Further research should be directed toward alternative management strategies in non-responders.

Serum neurofilament light chain (sNfL) is an intensely investigated biomarker in multiple sclerosis (MS). The aim of this study was to explore the impact of cladribine (CLAD) on sNfL and the potential of sNfL as a predictor of long-term treatment response. Data were gathered from a prospective, real-world CLAD cohort. We measured sNfL at baseline (BL-sNfL) and 12 months (12Mo-sNfL) after CLAD start by SIMOA. Clinical and radiological assessments determined fulfilment of “no evidence of disease activity” (NEDA-3). We evaluated BL-sNfL, 12M-sNfL and BL/12M sNfL ratio (sNfL-ratio) as predictors for treatment response. We followed 14 patients for a median of 41.5 months (range 24.0–50.0). NEDA-3 was fulfilled by 71%, 57% and 36% for a period of 12, 24 and 36 months, respectively. We observed clinical relapses in four (29%), MRI activity in six (43%) and EDSS progression in five (36%) patients. CLAD significantly reduced sNfL (BL-sNfL: mean 24.7 pg/mL (SD ± 23.8); 12Mo-sNfL: mean 8.8 pg/mL (SD ± 6.2); p = 0.0008). We found no correlation between BL-sNfL, 12Mo-sNfL and ratio-sNfL and the time until loss of NEDA-3, the occurrence of relapses, MRI activity, EDSS progression, treatment switch or sustained NEDA-3. We corroborate that CLAD decreases neuroaxonal damage in MS patients as determined by sNfL. However, sNfL at baseline and at 12 months failed to predict clinical and radiological treatment response in our real-world cohort. Long-term sNfL assessments in larger studies are essential to explore the predictive utility of sNfL in patients treated with immune reconstitution therapies.

Background and purpose: This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)‐associated neurological immune‐related adverse events (nirAE).Methods: A systematic literature review was made, with case observations of a melanoma and a non‐small cell lung cancer (NSCLC) patient who developed ICI‐associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement.Results: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c‐LETM), respectively. Intrathecal inflammation with chemokine C‐X‐C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death‐1 (PD‐1) expression on CSF T cells; the c‐LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first‐line treatment. The NSCLC case improved upon administration of B cell‐depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI‐associated LETM case with intrathecal CXCL13 elevation, three cases with ICI‐associated aquaporin‐4 antibody neuromyelitis spectrum disorder, and evidence of B cell‐mediated toxicity based on antibody‐mediated immune pathologies in ICI‐associated immune‐related adverse events.Conclusions: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI‐associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.

Antibody responses to SARS-CoV-2 vaccination are impaired in people with multiple sclerosis (MS) under anti-CD20 therapies. It is however unclear, whether patients who received the basic immunization prior to anti-B cell medication start respond to the COVID-19 booster dose, once B cells are depleted. To investigate the humoral response to recall antigen by COVID-19 booster vaccines in people with MS (pwMS), who recently started an anti-CD20 therapy compared to people with long-term B cell depletion. We enrolled 15 pwMS who had received booster vaccination on anti-CD20 therapy. Of these, 11 had established anti-CD20 medications and were therefore vaccinated during a continuous state of B cell depletion (CD20-vaccine cohort). Four pwMS had received the basic immunization prior to anti-CD20 therapy commencement and only the booster dose (vaccine-CD20-vaccine cohort) under conditions of B cell depletion. We assessed SARS-CoV-2 specific antibody responses after booster vaccination among both groups and evaluated accompanying B cell numbers and proportions from the peripheral circulation. The booster dose of SARS-CoV-2 vaccination elicited measurable antibody responses in 18% of individuals from the CD20-vaccine cohort compared to 100% from the vaccine-CD20-vaccine cohort. Antibody-levels were significantly higher among patients from the vaccine-CD20-vaccine cohort compared to the CD20-vaccine cohort (mean 951.25 ± 1137.96 BAU/ml, vs mean 12.36 ± 11.94 BAU/ml; mean difference 938 BAU/ml (95% CI: 249–1629 BAU/ml), p <0.0001). Among the vaccine-CD20-vaccine cohort, the booster immunization led to augmentation of spike antibody levels in 75% despite concomitant B cell depletion, and values increased by 3.8 – 9.4-fold compared to basic immunization. We observed no correlation of B cell kinetics and SARS-CoV-2 antibody levels. Our study suggests that antibody production to recall COVID-19 antigens is preserved in pwMS despite concomitant anti-CD20 therapy. If corroborated in bigger cohorts, this could have implications in the management of individuals about to start B cell medications.