Background B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation. Methods The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer–BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov , NCT04877496 . Findings The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57–72) and of controls was 54 years (45–62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48–2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50–5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16–2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17–2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19 + cell count (>27 cells per μL; positive predictive value 0·70), and CD4 + lymphocyte count (>653 cells per μL; positive predictive value 0·71) were ...

ObjectiveAlthough the prognosis of natalizumab-associated progressive multifocal leukoencephalopathy (PML) seems to be better than HIV-associated PML, little is known about the long-term functional outcome in multiple sclerosis (MS) patients and the subsequent return of MS disease activity. We evaluated retrospectively 15 patients with natalizumab-associated PML treated at our centre.Patients and methodsFifteen MS-PML patients (nine women, six men) were referred to us from adjacent local centres. The patients had a median natalizumab exposure of 34 months at PML diagnosis. They received standardised treatment as described in previous work. Expanded Disability Status Scale (EDSS) and Karnofsky score in the year pre-PML, at PML-diagnosis (pre-immune reconstitution inflammatory syndrome (IRIS)) and post-PML were determined in 3–6 monthly intervals.ResultsThe median follow-up of these 15 patients was 21.5 months. None of the 15 patients died. Three patients had a Karnofsky score of 80 or higher, nine patients between 50–70 and three patients of 40 or lower at latest examination. Eight of the 15 patients developed seizures during acute PML phase. Fifty percent of those patients were not seizure-free one year post PML, despite continuation of antiepileptic treatment. The median EDSS in the year pre-PML was 2.5, 4.5 at PML diagnosis, 6.5 post-IRIS and 5.5 at latest examination. CSF became virus-free in eight of the 15 patients after a median time of 4.5 months. In nine patients, disease reappeared after a median time of seven months from PML diagnosis.ConclusionsAlthough the clinical outcome of natalizumab-treated PML patients is much better than in patients with HIV-associated PML, this may be further improved by treatment at reference centres using standardised therapy regimens and transient intensive care if needed. Systematic studies of appropriate MS immunotherapies after PML are critically needed.

Objective Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in patients receiving natalizumab for multiple sclerosis (MS). JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy, is required for probable or definite diagnosis of PML. However, in some patients only low levels of JCV DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging. Our objective was to assess the complementary value of a CSF JCV antibody index (AIJCV) in the diagnosis of natalizumab-associated PML. Methods AIJCV was assessed in 37 cases of natalizumab-associated PML and 89 MS-patients treated with natalizumab without PML. Sera and CSF were tested in a capture enzyme-linked immunosorbent assay, using JCV-VP1 fused to glutathione S-transferase as antigen. Albumin levels and total immunoglobulin G concentration were determined by immunonephelometry, and the AIJCV was calculated as published. Results Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV > 1.5, whereas this was seen in none of the controls (p < 0.0001). At time of the first positive qPCR for JCV DNA, 11 of 20 (55%) patients with natalizumab-associated PML had an AIJCV > 1.5. JCV DNA levels of <100 copies/ml were seen in 14 (70%) of these 20 patients, of whom 8 (57%) demonstrated an AIJCV > 1.5. Interpretation Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.

The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH) 2 D 3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG 35–55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8 + T cells was analyzed by microarray ( n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8 + T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy. Electronic supplementary material The online version of this article (10.1007/s00401-019-02018-8) contains supplementary material, which is available to authorized users.

Multiple sclerosis (MS) is characterized as an autoimmune disease affecting the central nervous system. It is one of the most common neurological disorders in young adults. Over the past decades, increasing evidence suggested that hypovitaminosis D is a contributing factor to the risk of developing MS. From different risk factors contributing to the development of MS, vitamin D status is of particular interest since it is not only a modifiable risk factor but is also associated with MS disease activity. MS patients with lower serum vitamin D concentrations were shown to have higher disease activity. However, this finding does not demonstrate causality. In this regard, prospective vitamin D supplementation studies missed statistical significance in its primary endpoints but showed promising results in secondary outcome measures or post hoc analyses. An explanation for missed primary endpoints may be underpowered trials. Besides vitamin D supplementation as a potential add-on to long-term immunotherapeutic treatment, a recent laboratory study of our group pointed toward a beneficial effect of vitamin D to improve the efficacy of glucocorticoids in relapse therapy. In the following article, we will briefly review the effects of vitamin D on MS by outlining its effects on the immune and nervous system and by reviewing the association between vitamin D and MS risk as well as MS disease activity. We will also review the effects of vitamin D supplementation on MS risk and MS disease activity.

Natalizumab (Nat) is a humanized monoclonal antibody used for the treatment of relapsing multiple sclerosis (MS). Nat inhibits lymphocyte migration via the blood brain barrier (BBB) by blockage of an integrin adhesion molecule, very late antigen 4. During the phase III clinical trials, it was shown that Nat reduces disease activity and prevents disability progression. In addition, several smaller studies indicate a positive influence of Nat on cognition, depression, fatigue, and quality of life (Qol). Therapeutic efficacy has to be weighed against the risk of developing potentially fatal progressive multifocal leukoencephalopathy (PML), an opportunistic infection by JC-virus (JCV) with an incidence of 3.4/1000 (95% CI 3.08–3.74) in Nat treated MS patients. In this review article, we will review data on the presumed mechanism of Nat action, clinical and paraclinical efficacy parameters, and adverse drug reactions with a special focus on PML.

Background: Fingolimod (FTY) is the first oral medication approved for multiple sclerosis therapy. Until now, little has been known about the effects of FTY withdrawal regarding disease activity and development of tumefactive demyelinating lesions (TDLs), as already described in patients who discontinue natalizumab. Methods: In this study we present the clinical and radiological findings of two patients who had a severe rebound after FTY withdrawal and compare these with patients identified by a PubMed data bank analysis using the search term 'fingolimod rebound'. In total, 10 patients, of whom three developed TDLs, are presented. Results: Patients suffering from TDLs were free of clinical and radiological signs of disease activity under FTY therapy (100% versus 57%, compared with patients without TDLs) and had rebounds after a mean of 14.6 weeks (standard deviation 11.5) [patients without TDLs 11.7 (standard deviation 3.4)]. Conclusion: We propose that a good therapeutic response to FTY might be predisposing for a severe rebound after withdrawal. Consequently, therapy switches should be planned carefully with a short therapy free interval.

Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1-phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-β-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer’s disease, and other neurodegenerative disorders.