Real-world infection risk in multiple sclerosis patients on long-term immunomodulatory treatments.

Introduction: Numerous immunomodulatory treatments exist for multiple sclerosis (MS), including those that deplete immune cells (e.g. anti-CD20 medications), relocate immune cells (e.g. natalizumab, S1P modulators), or modulate immune subsets (e.g. fumarates). All disease-modifying treatments (DMTs) can increase infection risk which could worsen with prolonged use.

Methods: This is a retrospective, single-center, observational cohort study. We analyzed medical records of adult people with MS who took natalizumab, S1P modulators, fumarates or anti-CD20 medications for over two years between January 2013 and April 2021 at Yale. We identified severe infections (requiring hospitalization) and mild infections (identified through outpatient antibiotic prescriptions or chart reference to "infection"). We used a zero-inflated negative binomial regression to assess the effects of DMT use, treatment duration, and patient characteristics on infection likelihood and frequency, while controlling for biologic sex, body mass index, ambulatory status, Charlson Comorbidity Index (CCI), diagnosis, disease modifying therapy and treatment duration.

Results: 104 patients received natalizumab, 61 fumarates, 17 S1P modulators and 291 anti-CD20 medications, with significant baseline differences in age, diagnosis, duration of DMT use, and CCI. Mild infection rates did not differ across DMTs, but severe infections were more common in patients on fumarates. Patients with longer DMT duration or requiring a walking aid had higher mild infection rates, while those with progressive MS or on long-term fumarates had higher severe infection rates, even after controlling for other variables.

Discussion: This study demonstrates how real-life practice patterns, patient factors and DMT choice can influence infection rates, differing from randomized trial patterns. Natalizumab appears safe over extended use, while fumarates were linked to more severe infections, potentially due to the clinical selection of patients with poorer baseline health. The duration of DMT use may predict mild infection rates.