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Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

ABSTRACT: The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

SUBMITTER: de Seze J

PROVIDER: S-EPMC10076836 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

de Sèze Jérôme J Maillart Elisabeth E Gueguen Antoine A Laplaud David A DA Michel Laure L Thouvenot Eric E Zephir Hélène H Zimmer Luc L Biotti Damien D Liblau Roland R

Frontiers in immunology 20230323

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. The ...[more]

PMID: 37033984

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Project description:ImportanceIn patients with multiple sclerosis (MS), factors associated with severe COVID-19 include anti-CD20 therapies and neurologic disability, but it is still unclear whether these 2 variables are independently associated with severe COVID-19 or whether the association depends on MS clinical course.ObjectiveTo assess the association between anti-CD20 therapies and COVID-19 severity in patients with relapsing-remitting MS (RRMS) and progressive MS (PMS).Design, setting, and participantsThis multicenter, retrospective cohort study used data from the COVISEP study, which included patients with MS and COVID-19 from February 1, 2020, to June 30, 2022, at 46 French MS expert centers, general hospitals, and private neurology practices. Eligible patients with RRMS were those treated with high-efficacy MS therapy (ie, anti-CD20, fingolimod, or natalizumab), and eligible patients with PMS were those younger than 70 years with an Expanded Disability Status Scale (EDSS) score of 8 or lower. Patients were monitored from COVID-19 symptom onset until recovery or death.ExposuresCurrent anti-CD20 therapy (ocrelizumab or rituximab).Main outcomes and measuresThe main outcome was severe COVID-19 (ie, hospitalization with any mode of oxygenation or death). All analyses were conducted separately in patients with RRMS and PMS using propensity score-weighted logistic regression. Subgroup analyses were performed according to COVID-19 vaccine status, sex, EDSS score, and age.ResultsA total of 1400 patients, 971 with RRMS (median age, 39.14 years [IQR, 31.38-46.80 years]; 737 [76.1%] female) and 429 with PMS (median age, 54.21 years [IQR, 48.42-60.14 years]; 250 [58.3%] female) were included in the study. A total of 418 patients with RRMS (43.0%) and 226 with PMS (52.7%) were treated with anti-CD20 therapies. In weighted analysis, 13.4% and 2.9% of patients with RRMS treated and not treated with anti-CD20 had severe COVID-19, respectively, and anti-CD20 treatment was associated with increased risk of severe COVID-19 (odds ratio [OR], 5.20; 95% CI, 2.78-9.71); this association persisted among vaccinated patients (7.0% vs 0.9%; OR, 8.85; 95% CI, 1.26-62.12). Among patients with PMS, 19.0% and 15.5% of patients treated and not treated with anti-CD20 had severe COVID-19, respectively, and there was no association between anti-CD20 treatment and severe COVID-19 (OR, 1.28; 95% CI, 0.76-2.16). In PMS subgroup analysis, anti-CD20 exposure interacted negatively with EDSS score (P = .009 for interaction) and age (P = .03 for interaction); anti-CD20 therapies were associated with risk of severe COVID-19 only in patients with less neurologic disability and younger patients with PMS.Conclusions and relevanceIn this cohort study, risk of severe COVID-19 was higher in patients with PMS than in those with RRMS. Use of anti-CD20 therapies was associated with an increased risk of severe COVID-19 among patients with RRMS. In patients with PMS, there was no association between anti-CD20 therapies and risk of severe COVID-19.

Project description:BackgroundAnti-CD20 therapies induce pronounced B-cell depletion and blunt humoral responses to vaccines. Recovery kinetics of anti-CD20 therapy-mediated cellular and humoral effects in people with multiple sclerosis (pwMS) are poorly defined.ObjectiveTo investigate the duration of the anti-CD20 treatment-induced effects on humoral responses to COVID-19 vaccines.MethodsThis retrospective observational study included pwMS who had discontinued anti-CD20 therapy for ⩾12 months and remained without immunomodulation. We retrieved demographics and laboratory parameters including B-cell counts and immunoglobulin (IgG, IgM, IgA) levels prior to anti-CD20 commencement (baseline) and longitudinally after anti-CD20 treatment discontinuation from electronic medical records. Humoral responses to SARS-CoV-2 vaccines were compared with a population of 11 pwMS with ongoing anti-CD20 medication (control cohort).ResultsA total of 24 pwMS had discontinued anti-CD20 therapy for a median of 34 months (range: 16-38 months). Antibody responses to COVID-19 vaccines were available in 17 (71%). Most individuals (n = 15, 88%) elicited a measurable antibody response [mean: 774 BAU/ml (±SD 1283 BAU/ml)] to SARS-CoV-2 immunization on average 22 months (range: 10-30 months) from the last anti-CD20 infusion, which was higher compared with the population with ongoing anti-CD20 therapy (n = 11, mean: 12.36 ± SD 11.94 BAU/ml; p < 0.00001). Significantly increased antibody levels compared with the control cohort were found among pwMS who were vaccinated >18 months after treatment discontinuation (19-24 months: n = 2, p = 0.013; 25-36 months: n = 9; p < 0.001). The interindividual kinetics for B-cell reconstitution were heterogeneous and mean B-cell counts approached normal ranges 18 months after treatment discontinuation. There was no correlation of B-cell repopulation and vaccine responses. Mean total IgG, IgM, and IgA levels remained within the reference range.ConclusionAnti-CD20-induced inhibition of humoral responses to COVID-19 vaccines is transient and antibody production was more pronounced >18 months after anti-CD20 treatment discontinuation. The immunological effect on B-cell counts appears to wane by the same time.

Project description:BackgroundPatients with multiple sclerosis (MS) are commonly treated with anti-CD20 therapies. Reduced seroconversion following COVID-19 vaccination in patients receiving certain anti-CD20 therapies has been reported; however, the immune response following natural infection is poorly characterised. This study aimed to retrospectively evaluate COVID-19 antibody responses after vaccination and natural infection in patients treated with anti-CD20 therapies.MethodsWe performed a retrospective review evaluating COVID-19 seroconversion and anti-spike glycoprotein antibody titres in double-vaccinated patients with MS, or related neuroinflammatory conditions, treated with anti-CD20 therapies (N = 30) with a confirmed history of natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (n = 14) or without infection (control; n = 16). This single-centre study was performed at the Yale Multiple Sclerosis Center, where patients treated with anti-CD20 therapies (ocrelizumab, n = 21; rituximab, n = 5; ofatumumab, n = 4) were systematically checked for SARS-CoV-2 anti-spike antibody levels throughout the pandemic. Data were collected from March 2020 to March 2022. All patients had received at least two doses of a Food and Drug Administration (FDA)-approved COVID-19 vaccine. Qualitative anti-spike antibody seropositivity was determined based on test-specific laboratory reference ranges. For a subset of patients (n = 18), quantitative anti-spike antibody levels were assessed via DiaSorin LIAISON® chemiluminescence immunoassay (positive titre was defined as ≥ 13). Vaccination and infection dates were also recorded, and patients were monitored for adverse COVID-19-related health effects.ResultsOverall, 15/30 (50.0%) patients seroconverted following double vaccination. After infection, 13/14 (92.9%) seroconverted, while 6/16 (37.5%) uninfected patients seroconverted after vaccination. For the 18 patients with quantitative anti-spike antibody titres, mean titre post-vaccination was 37.4. Mean antibody titres were significantly higher after infection: 540.3 versus 20.1 in the control group (p < 0.05). Of the 14 infected patients, 13 had mild COVID-19 symptoms and one was asymptomatic. No hospitalisations or deaths were reported.ConclusionsThis study reports that SARS-CoV-2 anti-spike antibody titres in double-vaccinated MS patients treated with anti-CD20 therapies were significantly increased post-infection compared with the control group. Patients treated with anti-CD20 therapy who had confirmed infections displayed mild or asymptomatic infection. These results provide reassurance that anti-CD20 therapies in double-vaccinated patients do not preclude an appropriate SARS-CoV-2 antibody response post-infection.

Dataset Information

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

Publications

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

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