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BackgroundDisease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI).Objective and methodsPost hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5-1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNβ-1a), or placebo.ResultsAt 8 years' follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%-43.1%) of assessed participants in the IFNβ-1a-fingolimod switch group and 41.9% (36.6%-47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNβ-1a-fingolimod switch group than on continuous fingolimod (5.4% [3.0%-9.5%] vs 14.2% [10.8%-18.4%], p = 0.01).ConclusionCDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

Neurological immune-related adverse events (irAEs) are rare toxicities that occur following immune checkpoint inhibitor therapy. We propose that patients with thymic malignancies and graft-versus-host disease (GVHD) are predisposed to irAEs. We present two asymptomatic patients, one with thymoma and another with GVHD, who developed abnormal brain MRIs after treatment with programmed cell death protein 1 inhibitors. The first patient, with thymic cancer and thymoma, developed pontine enhancing MRI lesions following treatment with pembrolizumab. The second patient, with prior GVHD, developed pachymeningeal enhancement following treatment with nivolumab. IrAEs with abnormal MRI studies, despite asymptomatology, have significant impact on the treatment strategy for these patients.

Multiple sclerosis (MS) is an inflammatory disease of the CNS. In this issue of The JCI, Ma and Sannino et al. show that two strains of intestinal Clostridium perfringens, known to produce epsilon toxin (ETX), were frequently found in patients with MS. Tiny amounts of this toxin added to immunization with myelin antigens provoked MS-like brain lesions in mice. The distribution of these lesions was diffuse, as in MS, in contrast to the spinal cord- restricted lesions of most animal models. ETX bound to endothelial cells of the CNS to enhance immune cell trafficking through the blood-brain barrier into inflammatory brain lessons. ETX also binds to human, but not murine, white blood cells, perhaps altering immune responses. Barrier disruption and changes in immunity due to the toxin could alter the benefits of immune- modulatory MS therapies and are likely to interact with the complex genetics and environmental influences seen in MS., Brain inflammation without a cause describes multiple sclerosis Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord. The genesis of MS is complex, with multiple virus [...]

BackgroundRelapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-inflammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.MethodsWe did a randomised, double-blind, placebo-controlled phase 2 trial at 16 academic neurology centres in the USA, between June 28, 2007, and Jan 9, 2014. Women aged 18-50 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1) with a random permuted block design to either daily oral estriol (8 mg) or placebo, each in combination with injectable glatiramer acetate 20 mg daily. Patients and all study personnel, except for pharmacists and statisticians, were masked to treatment assignment. The primary endpoint was annualised relapse rate after 24 months, with a significance level of p=0.10. Relapses were confirmed by an increase in Expanded Disability Status Scale score assessed by an independent physician. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00451204.FindingsWe enrolled 164 patients: 83 were allocated to the estriol group and 81 were allocated to the placebo group. The annualised confirmed relapse rate was 0.25 relapses per year (95% CI 0.17-0.37) in the estriol group versus 0.37 relapses per year (0.25-0.53) in the placebo group (adjusted rate ratio 0.63, 95% CI 0.37-1.05; p=0.077). The proportion of patients with serious adverse events did not differ substantially between the estriol group and the placebo group (eight [10%] of 82 patients vs ten [13%] of 76 patients). Irregular menses were more common in the estriol group than in the placebo group (19 [23%] vs three [4%], p=0.0005), but vaginal infections were less common (one [1%] vs eight [11%], p=0.0117). There were no differences in breast fibrocystic disease, uterine fibroids, or endometrial lining thickness as assessed by clinical examination, mammogram, uterine ultrasound, or endometrial lining biopsy.InterpretationEstriol plus glatiramer acetate met our criteria for reducing relapse rates, and treatment was well tolerated over 24 months. These results warrant further investigation in a phase 3 trial.FundingNational Institutes of Health, National Multiple Sclerosis Society, Conrad N Hilton Foundation, Jack H Skirball Foundation, Sherak Family Foundation, and the California Community Foundation.

Background: Anti-CD20 is a highly effective therapy for multiple sclerosis (MS), a disease with multiple abnormalities in function of B and T cells and innate immune cells. Anti-CD20 therapy depletes B cells, which alters antibody production and has diverse effects on B cell immunity. These changes potentially affect immunity beyond B cells in MS. Objective: Determine if anti-CD20 therapy effects non-B cell, as well as B cell, gene expression, and serum protein levels. Methods: Samples were collected from 10 healthy controls and from clinically stable relapsing-remitting MS - 10 untreated, 9 interferon-β-treated, and 15 ocrelizumab-treated patients were studied before, and 2 weeks and 6 months after, the first anti-CD20 infusion. Peripheral blood mononuclear cells (PBMC) were analyzed with sensitive, 135,000-transcript RNA expression microarrays, using stringent criteria. Gene expression was compared to 43 MS-relevant serum immune and neurotrophic proteins, using multiplex protein assays. Results: Anti-CD20 therapy reduced expression of 413 total genes and 185 B-cell-regulated genes at 2 weeks vs. pre-therapy. Expression of 19 (15%) of these B cell genes returned toward baseline by 6 months, including genes for the B cell activation protein, CD79A, and for immunoglobulin A, D, and G heavy chains. Expression pathways for Th17 and CD4 regulatory T-cell (Treg) development, differentiation, and proliferation also quieted. In contrast, expression increased in Th1 and myeloid cell antiviral, pro-inflammatory, and toll-like receptor (TLR) gene pathways. Conclusion: These findings have clinical implications. B cell gene expression diminishes 2 weeks after anti-CD20 antibody infusion, but begins to rebound by 6 months. This suggests that the optimum time for vaccination is soon before reinfusion of anti-CD20 therapy. In addition, at 6 months, there is enhanced Th1 cell gene expression and induction of innate immune response genes and TLR expression, which can enhance anti-viral and anti-tumor immunity. This may compensate for diminished B cell gene expression after therapy. These data suggest that anti-CD20 therapy has dynamic effect on B cells and causes a compensatory rise in Th1 and myeloid immunity. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a neurological disorder marked by accumulating immune-mediated damage to the central nervous system. The dysregulated immune system in MS combined with immune effects of disease-modifying therapies (DMTs) used in MS treatment could alter responses to infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Most of the literature on immune response to SARS-CoV-2 infection and COVID-19 vaccination, in both the general population and patients with MS on DMTs, has focused on humoral immunity. However, immune response to COVID-19 involves multiple lines of defense, including T cells. Objective and Methods: We review innate and adaptive immunity to COVID-19 and expand on the role of T cells in mediating protective immunity against SARS-CoV-2 infection and in responses to COVID-19 vaccination in MS. Results: Innate, humoral, and T cell immune responses combat COVID-19 and generate protective immunity. Assays detecting cytokine expression by T cells show an association between SARS-CoV-2-specific T cell responses and milder/asymptomatic COVID-19 and protective immune memory. Conclusion: Studies of COVID-19 immunity in people with MS on DMTs should ideally include comprehensive assessment of innate, humoral, and T cell responses. [ABSTRACT FROM AUTHOR]

Background: Many patients with multiple sclerosis (MS) experience suboptimal disease control despite the use of disease-modifying therapy (DMT). Objective: To assess the efficacy and safety of ocrelizumab (OCR) in patients with relapsing-remitting MS (RRMS) and suboptimal response to prior DMTs. Methods: Patients with RRMS and suboptimal responses (one clinically reported relapse and/or lesion activity) after ⩾ 6 months on another DMT were enrolled. OCR 600 mg was given intravenously every 24 weeks. The primary outcome was no evidence of disease activity (NEDA), defined as the absence of protocol-defined relapse, confirmed disability progression (CDP), T1 Gd-enhancing lesions, and new/enlarging T2 lesions. Results: The intention-to-treat (ITT) population included 608 patients; NEDA was analyzed in a modified ITT (mITT) population (n = 576 (94.7%)). Over 96 weeks, 48.1% of mITT patients achieved NEDA, and most were free from protocol-defined relapse (89.6%), CDP (89.6%), and T1 Gd-enhancing lesions (95.5%); 59.5% had no new/enlarging T2 lesions. Safety observations were consistent with findings in the pivotal trials. Conclusion: Consistent efficacy of OCR on clinical and magnetic resonance imaging (MRI) disease activity measures and progression was shown in patients with RRMS and a suboptimal response to prior DMTs; no new safety signals were observed. [ABSTRACT FROM AUTHOR]