Rituximab May Be Linked to Severe COVID-19 Outcomes

Patients with inflammatory rheumatic and musculoskeletal diseases (RMD) treated with rituximab have been shown to exhibit more severe COVID-19 symptoms, which may be related to a drug-induced defect in the antiviral humoral response, according to a study published in The Lancet.¹

“Our findings support the concept that although the innate immune system and T cells are paramount in the early antiviral response, B cells are also crucial,” stated investigators. “Therefore, long-term administration of rituximab might be associated with decreased antibody production through B-cell depletion and reduced viral clearance, which might impair the priming of antibody responses to neutralize viral replication.”

This multicenter, retrospective study (NCT04353609) analyzed national data from the French RMD COVID-19 cohort beween April 15, 2020, and November 20, 2020. Patients studied were aged 18 years or older, with confirmed RMD and either confirmed or suspected COVID-19 diagnosis. Investigators wanted to determine the link between rituximab treatment and severe COVID-19 outcomes. Severity was classified as mild (ambulatory care), moderate (non-intensive hospital treatment), and severe (intensive care unit [ICU] admission or death). Participants were split into 2 groups: those who received rituximab and those who did not. The no rituximab group was further split into 2 subgroups: a no rituximab group (patients with RMD who did not receive rituximab treatment) and a no rituximab subgroup (consisting of patients who did not receive rituximab even though they have diseases in which the medication is used as a common therapeutic option). Additionally, the duration of hospital stay and an analysis of death were secondary objections of the study. Adjustments were made for factors such as age, sex, arterial hypertension, smoking status, body-mass index, cancer, and comorbidities such as cardiovascular disease and other underlying diseases.

Investigators analyzed data for 1090 patients, 137 (13%) of which developed severe COVID-19 symptoms, and 89 (8%) died. The mean age of patients was 55.2 years, 67% (734) were female, and 33% (356) were male. Those in the rituximab group were more likely to experience more severe outcomes when compared with both the no rituximab group as well as the no rituximab subgroup (effect size 3·26, 95% CI 1·66–6·40, p=0·0006). After adjusting for confounders, the risk of death did not increase significantly, despite having more patients die in the rituximab group, which may indicate that comorbidities increase the risk of death. It should be noted that 756 (69%) of patients had at least 1 comorbidity, which included conditions like obesity, respiratory disease, and hypertension. Patients receiving rituximab were more likely to be male, older, and have comorbidities and a history of corticosteroid use.

“One crucial concern is to determine whether this worse outcome is related to rituximab per se or to the specific population that is treated by this medication. Indeed, rituximab is usually used in rheumatic diseases characterized by a higher risk of poor prognosis,” explained investigators. “In addition, the profile of patients receiving rituximab (older age, male sex, higher frequency of comorbidities, and corticosteroid use) is associated with increased risk of severe COVID-19.”

Further, the time between the last infusion and severe symptoms of COVID-19, as measured by the Kruskal-Wallis test, were much shorter for patients with severe COVID-19. Corticosteroids (>10 mg per day) and interstitial lung disease were also linked to severe COVID-19. Hospital stays were longer for the 63 patients in the rituximab group (0·62, 0·46–0·85, p=0·0024) when compared with the 1027 in the control cohorts.

The limitations included the study’s observational nature, which opens the possibility of missing data, a lack of adequate statistical power, and confounding by measured or unmeasured variables, which may introduce an unintentional bias. Additionally, the number of patients with specific rheumatic diseases, such as rheumatoid arthritis with interstitial lung disease, where too small for investigators to analyze separately. It was also theorized that the higher frequencies of severe outcomes in patients receiving rituximab may be confounded by indication, as patients with RMD are generally more medicated and study data did not include disease activity. Lastly, previous medications, ethnicity, information about rituximab dose and duration, and associated hypogammaglobulinaemia were not available.

“The analysis of the French COVID-19 RMD cohort suggests the possibility for differential risk of adverse clinical outcomes among patients with inflammatory rheumatic and musculoskeletal diseases based on the type of biological agents received,” concluded investigators. “In particular, rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases, especially if they have other comorbidities that render them particularly at risk of severe COVID-19 outcomes.”

Reference:

Avouac J, Drumez E, Hachulla E, et al. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study [published online ahead of print, 2021 Mar 25]. Lancet Rheumatol. 2021;10.1016/S2665-9913(21)00059-X. doi:10.1016/S2665-9913(21)00059-X