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Multicenter Study
. 2023 Jun 1;6(6):e2319766.
doi: 10.1001/jamanetworkopen.2023.19766.

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis

Edouard Januel  1   2 , David Hajage  1 , Pierre Labauge  3 , Elisabeth Maillart  2 , Jérome De Sèze  4 , Hélène Zephir  5 , Jean Pelletier  6 , Laurent Guilloton  7 , Caroline Bensa  8 , Olivier Heinzlef  9 , Olivier Casez  10 , Damien Biotti  11 , Bertrand Bourre  12 , Sandra Vukusic  13 , Aude Maurousset  14 , Eric Berger  15 , David Laplaud  16 , Christine Lebrun-Frénay  17 , Anne-Laure Dubessy  18 , Pierre Branger  19 , Eric Thouvenot  20   21 , Pierre Clavelou  22 , François Sellal  23 , Eric Manchon  24 , Thibault Moreau  25 , Caroline Papeix  8 , Florence Tubach  1 , Céline Louapre  2
Affiliations
Multicenter Study

Association Between Anti-CD20 Therapies and COVID-19 Severity Among Patients With Relapsing-Remitting and Progressive Multiple Sclerosis

Edouard Januel et al. JAMA Netw Open. .

Abstract

Importance: In 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.

Objective: To 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 participants: This 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.

Exposures: Current anti-CD20 therapy (ocrelizumab or rituximab).

Main outcomes and measures: The 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.

Results: A 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 relevance: In 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Januel reported receiving personal fees and reimbursement for conference registration fees, travel expenses, and accommodation from Sanofi-Genzyme outside the submitted work. Dr Maillart reported receiving research support from Fondation ARSEP and Biogen Idec and travel funding and/or consulting fees from Alexion, Biogen Idec, Bristol Myers Squibb (BMS), Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, Cellgène, and Teva. Prof Zephir reported receiving consulting fees from Biogen Idec, Sanofi, Merck, Novartis, Roche, Horizon Therapeutics, Alexion, and BMS; grant research support from Roche; and nonfinancial support from BMS, Alexion, and Biogen Idec outside the submitted work. Dr Guilloton reported receiving consulting and/or lecture fees and/or travel funding from Novartis, Merck, Sanofi, BMS, and Biogen and grants from Novartis, Aguettant, Biogen, Merck, Sanofi, and BMS outside the submitted work. Dr Bensa reported receiving consulting honoraria from Alexion, Sanofi, Merck, Biogen, BMS, Novartis, Roche, and Teva. Dr Heinzlef reported receiving consulting and lecture fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and Biogen Idec; travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec; and research support from Roche, Merck, and Novartis. Dr Casez reported receiving personal fees from Biogen, Roche, Merck, Novartis, Janssen, and Sanofi and nonfinancial support from Roche, Merck, and Novartis outside the submitted work. Dr Bourre reported serving on scientific advisory boards for and/or receiving funding for travel and honoraria from Alexion, Biogen, BMS, Janssen, Merck, Novartis, Sanofi, Roche, and Teva; receiving grants from Alexion, Merck, and Novartis; and receiving personal fees from Biogen, Roche, Janssen, and BMS outside the submitted work. Prof Vukusic reported receiving lecturing fees, travel grants, and research support from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Dr Maurousset reported receiving personal fees from Merck, Biogen, Roche, Teva, and Alexion outside the submitted work. Dr Berger reported receiving honoraria and consulting fees from Alexion, Novartis, Sanofi-Aventis, Biogen Idec, Genzyme, Merck, Roche, and Teva. Dr Laplaud reported receiving grants from Roche, Sanofi, the ARSEP Foundation, the EDMUS Foundation, and the National Agency of Research and receiving personal fees from Biogen, Novartis, Alexion, Merck, and MSD outside the submitted work. Dr Dubessy reported participating in paid advisory boards for Merck and Novartis and receiving personal fees from Merck outside the submitted work. Dr Branger reported receiving personal fees from Novartis, Biogen, Merck, BMS, Alexion, and Sanofi outside the submitted work. Prof Thouvenot reported receiving personal fees from Biogen, BMS, Janssen, Horizon, Merck, Novartis, and Sanofi outside the submitted work. Prof Clavelou reported receiving personal fees for board participation from Janssen and Novartis and for board participation and travel from Sanofi and Merck outside the submitted work. Dr Moreau reported receiving travel grants and fees for advisory boards from Biogen, Roche, Novartis, Sanofi, and Teva outside the submitted work. Dr Papeix reported receiving honoraria and consulting fees from Alexion, Biogen, Merck, Horizon, and Roche outside the submitted work and serving as president of the Francophone Multiple Sclerosis Society from 2021 to 2024. Prof Tubach reported being head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique–Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière Hospital, both of which have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies that have contributed indiscriminately to the salaries of the employees; Prof Tubach is not employed by these companies and did not receive any personal remuneration from them. Dr Louapre reported receiving consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva, and Merck Serono and a research grant from Biogen. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Association Between Anti-CD20 Therapies and Severe COVID-19 in All Patients With Relapsing-Remitting Multiple Sclerosis (RRMS) and by Subgroup
Observed numbers of events are reported in the nonweighted population without imputation of missing data. Percentages and odds ratios (ORs) were estimated in the weighted population with imputation of missing data (including outcomes). The analysis was propensity score weighted (average treatment effect estimand). Variables used in the propensity score estimation were age, sex, time since multiple sclerosis onset, Expanded Disability Status Scale (EDSS) score, comorbidities (cardiovascular disease, pulmonary disease, diabetes, obesity, and active tobacco smoking), exposure to high-dose methylprednisolone in the month before COVID-19, postvaccine COVID-19 (infection occurring at least 7 days after the second dose of COVID-19 vaccine), previous COVID-19, COVID-19 variant (original Alpha, Delta, or Omicron), and treatment of COVID-19 with monoclonal antibody. Severe COVID-19 was defined as hospitalization with any mode of oxygenation or death. Age was divided into 2 groups based on the median for patients with RRMS, and subgroup analyses were conducted in age categories defined accordingly. P values for the subgroup analyses are for the interaction. Squares indicate ORs, with horizontal lines indicating 95% CIs.
Figure 2.
Figure 2.. Association Between Anti-CD20 Therapies and Severe COVID-19 in All Patients With Progressive Multiple Sclerosis (PMS) and by Subgroup
Observed numbers of events are reported in the nonweighted population without imputation of missing data. Percentages and odds ratios (ORs) were estimated in the weighted population with imputation of missing data (including outcomes). The analysis was propensity score weighted (average treatment effect estimand). Variables used in the propensity score estimation were age, sex, time since multiple sclerosis onset, Expanded Disability Status Scale (EDSS) score, comorbidities (cardiovascular disease, pulmonary disease, diabetes, obesity, and active tobacco smoking), exposure to high-dose methylprednisolone the month before COVID-19, postvaccine COVID-19 (infection occurring at least 7 days after the second dose of COVID-19 vaccine), COVID-19 variant (original Alpha, Delta, or Omicron), and treatment of COVID-19 with monoclonal antibody. Severe COVID-19 was defined as hospitalization with any mode of oxygenation or death. Age was divided into 2 groups based on the median for patients with PMS, and subgroup analyses were conducted in age categories defined accordingly. P values for subgroup analyses are for the interaction. Squares indicate ORs, with horizontal lines indicating 95% CIs.
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