Impact of previous treatment history and B-cell depletion treatment duration on infection risk in relapsing-remitting multiple sclerosis: a nationwide cohort study

Abstract

Background: B-cell depletion displays striking effectiveness in relapsing-remitting multiple sclerosis (RRMS), but is also associated with increased infection risk. To what degree previous treatment history, disease-modifying therapy (DMT) switching pattern and time on treatment modulate this risk is unknown. The objective here was to evaluate previous DMT use and treatment duration as predictors of infection risk with B-cell depletion.

Methods: We conducted a nationwide RRMS cohort study leveraging data from the Swedish MS registry and national demographic and health registries recording all outpatient-treated and inpatient-treated infections and antibiotics prescriptions from 1 January 2012 to 30 June 2021. The risk of infection during treatment was compared by DMT, treatment duration, number and type of prior treatment and adjusted for a number of covariates.

Results: Among 4694 patients with RRMS on B-cell depletion (rituximab), 6049 on other DMTs and 20 308 age-sex matched population controls, we found higher incidence rates of inpatient-treated infections with DMTs other than rituximab used in first line (10.4; 95% CI 8.1 to 12.9, per 1000 person-years), being further increased with rituximab (22.7; 95% CI 18.5 to 27.5), compared with population controls (6.6; 95% CI 6.0 to 7.2). Similar patterns were seen for outpatient infections and antibiotics prescriptions. Infection rates on rituximab did not vary between first versus later line treatment, type of DMT before switch or exposure time.

Conclusion: These findings underscore an important safety concern with B-cell depletion in RRMS, being evident also in individuals with shorter disease duration and no previous DMT exposure, in turn motivating the application of risk mitigation strategies.

Keywords: MULTIPLE SCLEROSIS.

Figure 1. Infection rate in rituximab as first or later line therapy compared with alternative DMTs and the general population. DMT, disease-modifying therapy; events, number of patients with infection; HR, HR with 95% CI from Cox proportional hazards model adjusting for age, sex, start year, comorbidities, demographics and (comparison between MS cohorts only) MS clinical characteristics; IR, incidence rate per 1000 PYR; N, number of patients; PYR, person-years of follow-up.

Figure 2. Infection rate in rituximab switching from natalizumab compared with switches from injectables, dimethyl fumarate and fingolimod. DMF, dimethyl fumarate; events, number of patients with infection; FGL, fingolimod; HR, HR with 95% CI from Cox proportional hazards model adjusting for age, sex, start year, comorbidities, demographics, MS clinical characteristics and treatment history; INJ, injectables; IR, incidence rate per 1000 PYR; N, number of patients; NTZ, natalizumab, PYR, person-years of follow-up; RTX, rituximab.

Figure 3. Cumulative incidence (95% CI) and hazard of serious infection while on rituximab.

Figure 4. Infection rate in rituximab by time on treatment. events, number of patients with infection; IR, incidence rate per 1000 PYR; N, number of patients; PYR, person-years of follow-up; HR, HR with 95% CI from Cox proportional hazards model adjusting for age, sex, start year, comorbidities, demographics and MS clinical characteristics.