Rituximab Infusion Timing, Cumulative Dose, and Hospitalization for COVID-19 in Persons With Multiple Sclerosis in Sweden

Rituximab therapy has been associated with more severe COVID-19 infection in persons with multiple sclerosis,^1,2 although this finding was based on a small number of events. Further research is needed to evaluate the potential increased risk for severe disease. In this study, we examined the association between timing and dose of rituximab and hospitalization for COVID-19 across Sweden.

This nationwide nested case-control study used prospectively collected data from the COMBAT-MS (Comparison Between All Immunotherapies for Multiple Sclerosis) observational drug trial cohort (eMethods in the Supplement). Participants were persons who were receiving ongoing treatment with rituximab and had COVID-19 onset (reported by a neurologist) between March 1, 2020, and April 30, 2021. This study received approval from the Regional Ethics Review Board in Stockholm. Written informed consent was obtained from all participants. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

The odds of hospitalization for COVID-19 were related to (1) the time between the most recent rituximab infusion and the COVID-19 onset date (months) and (2) the total cumulative lifetime dose of rituximab received (grams) using logistic regression. The reference cohort included all participants with mild COVID-19 infection, defined as those who did not require hospitalization. Models were adjusted for age, sex, and prepandemic Expanded Disability Status Scale score (range: 0-10, with the highest score indicating greatest level of disability). Data on race and ethnicity were not collected. A sensitivity analysis included only persons with polymerase chain reaction–confirmed COVID-19 infection.

Findings were reported as odds ratios (ORs) with 95% CIs. A 2-sided P < .05 indicated statistical significance. Pearson χ² or Fisher exact test was used for categorical variables, whereas unpaired, 2-tailed t test or Mann-Whitney test was used for continuous variables. SAS, version 9.4 (SAS Institute), was used for all statistical analyses.

Of the 3391 persons who were enrolled in the COMBAT-MS cohort, 326 (9.6%) contracted COVID-19 infection during the study period. Among these individuals, 172 (52.8%) received rituximab before COVID-19 onset. Twenty-six persons (15.1%) required hospitalization, 5 of whom were admitted to the intensive care unit and 4 of whom required ventilation. No deaths occurred.

No differences were observed in terms of age, disease duration, or disease course between persons with COVID-19 that required hospitalization and those with a mild case (Table 1). The median (IQR) time between the most recent rituximab infusion and COVID-19 onset was 6.1 (3.9-11.0) months among those with a mild case and was 4.6 (3.6-5.6) months among those who were hospitalized (the difference was not significant at P = .16). Persons with mild COVID-19 had a median (IQR) cumulative lifetime rituximab dose of 3.5 (2.5-4.5) grams compared with 3.3 (2.6-4.5) grams for hospitalized cases. Time from the most recent disease-modifying therapy infusion was not associated with the odds of requiring hospitalization (adjusted OR, 0.99; 95% CI, 0.92-1.04) nor was a cumulative lifetime dose of rituximab (adjusted OR, 1.08; 95% CI, 0.83-1.38). After the categorization of rituximab timing, persons with an infusion less than 4 months (vs >8 months) before COVID-19 onset were more likely to be hospitalized, but this association was not significant after adjustment for age, sex, and Expanded Disability Status Scale score. Sensitivity analyses of polymerase chain reaction–confirmed COVID-19 cases revealed comparable results (Table 2).

Among 172 Swedish persons with multiple sclerosis who received rituximab before contracting COVID-19, we found no statistically significant association between the timing of rituximab infusion or cumulative lifetime rituximab dose and the odds of hospitalization for COVID-19, although the study power was limited. Much research has been conducted on the potential risk of severe COVID-19 infection associated with rituximab exposure, but the conclusions have been drawn from small patient populations, and the evidence has been inconsistent overall.^1-4 The findings of the present study do not support a strong temporal association between the most recent dose of rituximab and hospitalization for COVID-19; these findings are similar to the results of a study in Italy¹ but counter those of a study from California.² Both of these previous studies included few cases (<10) with severe COVID-19 infection. Although the present study was larger, its power was limited and thus we were unable to rule out an association of modest-to-moderate size.

The strengths of this study were the prospective collection of data, nationwide study population, and high-quality data.⁵ The limitations included potential ascertainment bias given the awareness of an increased risk of infection associated with rituximab⁶ and missing information on known risk factors for COVID-19 severity, including smoking and comorbidity. In conclusion, large data sets with data capture that is less prone to surveillance bias and with access to a broader range of confounding factors are necessary to settle the question of whether continued use of rituximab during the COVID-19 pandemic increased the risk of severe COVID-19 infection.

Accepted for Publication: October 5, 2021.

Published: December 1, 2021. doi:10.1001/jamanetworkopen.2021.36697

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 McKay KA et al. JAMA Network Open.

Corresponding Author: Thomas Frisell, PhD, Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, T2, Karolinska University Hospital, 171 76 Stockholm, Sweden (thomas.frisell@ki.se).

Author Contributions: Dr McKay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McKay, Piehl, Langer-Gould, Frisell.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: McKay, Piehl.

Critical revision of the manuscript for important intellectual content: Piehl, Englund, He, Langer-Gould, Hillert, Frisell.

Statistical analysis: McKay, Langer-Gould, Frisell.

Obtained funding: Piehl, Langer-Gould, Hillert.

Administrative, technical, or material support: Piehl, He, Frisell.

Supervision: Piehl, Hillert.

Conflict of Interest Disclosures: Dr McKay reported receiving research funding from the Swedish Research Council for Health, Working Life and Welfare. Dr Piehl reported receiving grants from Swedish Medical Research Council, County of Stockholm, Merck KGaA, UCB, and Sanofi-Genzyme as well as personal fees from Parexel and Roche outside the submitted work. Dr Hillert reported receiving grants from Biogen, Celgene, Merck KGaA, Novartis, Bristol Myers Squibb, Roche, and Sanofi-Genzyme; personal fees from Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis, Teva, Janssen, and Sandoz; and research funding from Swedish Research Council and the Swedish Brain Foundation outside the submitted work. Dr Frisell reported receiving research funding from the Swedish Research Council and NEURO Sweden. No other disclosures were reported.

Funding/Support: This study was supported by the Patient-Centered Outcomes Research Institute (PCORI/MS-1511-33196).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.