While rituximab treatment puts patients at a higher risk for infectious disease in general, use of such treatment poses particular risk for severe COVID-19 infections in patients with MS.
A population-based study on the Swedish multiple sclerosis (MS) population identified treatment with rituximab as an indicator for more severe COVID-19 infections and subsequent hospitalization, when compared to other disease-modifying therapies (DMTs).
According to the Swedish MS registry (SMSreg), of the 476 reported COVID-19 cases in patients with MS, 292 (61.3%) had confirmed COVID-19, 68 (23.2%) of which required hospitalization. Of the 292 confirmed cases, 164 (56.2%) MS patients were being treated with rituximab at baseline, and 49 (29.9%) of this subgroup required hospitalization due to the COVID-19 infection. In comparison, 15 (12.7%) patients treated with other DMTs required hospitalization. Rituximab was the most frequently reported drug at baseline, showing significant association with hospitalization at 2.95 times the odds of hospitalization, in comparison to treatment with other DMTs (odds ratio [OR], 2.95 [95% CI, 1.48-5.87]).
“Our findings are consistent with most, but not all, of previously published reports on the influence of DMT exposure on severe COVID-19 outcomes in MS patients,” lead author Tim Spelman, PhD, MBBS, research coordination, department of clinical neuroscience, Karolinska Institutet, et al wrote. “Recently, a large multi-site study from Italy reported that MS patients receiving anti-CD20 therapies (either rituximab or ocrelizumab) were at nearly 4 times the odds of severe COVID-19, relative to MS patients receiving no DMT. This is consistent [with] our sensitivity analysis of anti-CD20 therapies, which saw odds of 3.00 and 3.38 times the odds of hospitalization in confirmed COVID-19 and all reported COVID-19, respectively.”
The mean value age at infection was 44.4 years (standard deviation [SD], 11.6), mean value for duration of MS disease at the time of COVID-19 infection was 12.8 years (SD, 9.2), and median Expanded Disability Status Scale at baseline was 2.0 (IQR, 1.0-3.0). The majority of those with confirmed infections were patients with relapsing remitting MS (n = 245; 83.9%), followed by secondary progressive MS, accounting for 33 (11.3%) patients.
When individually compared to other DMTs, such as interferon β, glatiramer acetate, dimethyl fumarate, and teriflunomide (Aubagio; Sanofi), rituximab treatment resulted in higher rates of hospitalization, although none were statistically significantly different. However, when natalizumab (Tysabri; Biogen) was compared to rituximab, investigators found a significant reduction in the weighted odds of hospitalization (OR, 0.24 [95% CI, 0.07-0.83). Fingolimod (Gilynea; Novartis) notably recorded 0 hospitalizations, and when pooled with a group of other DMTs, namely glatiramer and cladribine (Mavenclad; EMD Serono), investigators saw a 76% reduction in the odds of hospitalization (OR, 0.24 [95% CI, 0.07-0.84]).
Off-label use of rituximab, a B-cell depleting agent, is the most common DMT strategy used for patients with MS in Sweden, where the study was based. Following its significant association with hospitalization due to COVID-19, investigators concluded B-cells may actually play a role in defense against the infection itself. Additionally, when analyzing the subgroup of rituximab-treated patients, each additional year of rituximab therapy was associated with 1.24 times the odds of hospitalization (weighted OR, 1.24 [95% CI, 1.04-1.48), as opposed to duration of DMTs combined, which showed no association with increased likelihood of hospitalization.
“An interesting observation is that a longer duration of rituximab treatment significantly increased the risk of severe COVID-19 among the MS patients (yearly OR, 1.24 [95% CI, 1.04-1.48]). Although it is well established that rituximab often induces hypogammaglobulinemia which develops with time, immunoglobulin levels were not available for this study, so we can only hypothesize on such a mechanism driving this observation,” Spelman et al wrote. “However, it is tempting to speculate that previously reported differences between rituximab and ocrelizumab for risk of severe COVID-19 can be influenced by differences in treatment duration due to the more recent introduction of ocrelizumab in MS treatment.”
The unknown degree of coverage for the COVID-19 SMSreg module was identified as the chief limitation, in relation to incomplete reporting and potential for differing follow-up procedures. Key confounders, namely smoking and body mass index, were also unavailable to investigators. While findings suggest the increased risk for severe COVID-19 when MS patients are treated with rituximab, additional studies will be necessitated to exercise better control over confounders to estimate their association with infection rates.