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Selective depletion of CD20+ B cells by anti-CD20 monoclonal antibodies as monotherapy in multiple sclerosis (MS) profoundly suppresses acute inflammatory disease activity and signifies an important advance in the treatment of relapsing-remitting MS. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, is also the first proven therapy to lessen disability progression in primary progressive MS—a breakthrough for patients with a disease that had no proven therapy. Ocrelizumab is generally well tolerated, with the most common adverse events experienced being infusion reactions and infections. In ocrelizumab trials in MS a numerical imbalance in the risk of malignancies was observed. In this article, we review advances in anti-CD20 B-cell-depleting biological therapies for MS, including ocrelizumab, rituximab, and ofatumumab.

Four sphingosine 1‐phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head‐to‐head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real‐world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.

The recent TOPIC trial found that teriflunomide could prevent relapses in patients with clinically isolated syndrome (CIS). Many other multiple sclerosis (MS) therapies are effective for CIS, because CIS is the first clinical manifestation of MS for most patients. Questions remain over the utility of future trials like TOPIC.

This post hoc analysis of the randomized, placebo‐controlled N‐MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B‐cell subsets and aquaporin‐4 immunoglobulin G (AQP4‐lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B‐cell counts were modestly increased from the pre‐attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre‐attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B‐cell subset counts decreased and did not increase with attacks. No difference in change of AQP4‐IgG titers from baseline to time of attack was observed.

Objective The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9‐Hole Peg Test, or Timed 25‐Foot Walk Test) were evaluated as an endpoint in relapsing multiple sclerosis (RMS) trials using the ENSEMBLE (NCT03085810) and pooled OPERA I/II (NCT01247324/NCT01412333) studies. Methods We evaluated: (i) different definitions and the impact of rebaselining post‐relapse on cPIRA, (ii) cPIRA and biomarkers (MRI activity and serum neurofilament light [sNfL] levels), (iii) sustainability of cPIRA events, and (iv) cPIRA impact on future outcomes, in patients treated with ocrelizumab (600 mg, OPERA I/II [n = 827] and ENSEMBLE [n = 1225]) or interferon β‐1a (44 μg, OPERA I/II [n = 829]). Results Low disease activity (relapses/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in > 95% of ocrelizumab‐treated participants, and variations of cPIRA definitions yielded similar event rates. In OPERA I/II and ENSEMBLE ocrelizumab arms, cPIRA events were independent of MRI activity (86.5% and 95.5%, respectively), and occurred when sNfL was low (risk of cPIRA, hazard ratio [HR]: 0.67; p = 0.11 and 0.57; p = 0.003); more cPIRA events were sustained until study end with interferon β‐1a (80.3% OPERA I/II) vs. ocrelizumab (63.2% OPERA I/II, 56.6% ENSEMBLE). Across studies and treatments, cPIRA was associated with an increased risk of subsequent worsening on the EDSS (HR, 1.62–1.74; p = 0.121–0.037), Symbol Digit Modalities Test (HR, 1.16–2.62; p = 0.54–0.009), and Multiple Sclerosis Impact Scale‐29 physical scale (HR, 1.76; p = 0.064). Interpretation cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials. Trial Registration ClinicalTrials.gov identifiers: OPERA I (NCT01247324; https://clinicaltrials.gov/study/NCT01247324); OPERA II (NCT01412333; https://clinicaltrials.gov/study/NCT01412333); ENSEMBLE (NCT03085810; https://clinicaltrials.gov/study/NCT03085810)

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10–15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.

The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4⁺CD25⁺ T cells and IL-10⁺FoxP3⁺ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10⁺ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect disability.