Atypical adverse events in a real-world study of long-term immunomodulation for multiple sclerosis and neuromyelitis optica spectrum disorder.

Background: Immunotherapies are integral in managing multiple sclerosis (MS) and related demyelinating diseases, but adverse drug reactions significantly affect the tolerability of disease-modifying therapies (DMTs). Objectives: This study aims to assess the safety profile of DMTs within a real-world cohort affected by MS and related diseases and to identify atypical adverse events (AEs) and those of exceptional severity. Methods: A retrospective analysis was conducted on 3850 patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and related conditions (2009-2022). Demographic and clinical data were analyzed for patients treated with DMTs. Parameters included prior treatments, AEs, treatment durations, and reasons for discontinuation. Results: Of the cohort, 1989 patients (71.1% female) with a median follow-up of 46.3 months during DMT use were included. Monotherapy was employed in 987 patients, while 1002 received sequential DMTs, totaling 3850 treatments. Adverse reactions led to discontinuation in 24.2% of cases, while disease progression accounted for 22.9%. Among 1878 AEs, 31 (1.7%) were atypical, and 59 (3.1%) were unusually severe, which was systematically categorized based on type, timing, and remission. Conclusion: Within the confines of this real-world study, DMT administration emerged as generally well tolerated in MS, related demyelinating diseases and NMOSD. The identification of a limited number of atypical AEs, nevertheless, broadens the spectrum of potential complications associated with DMTs. Although weaker evidence for causal associations between drug exposure and observed AEs remains a limitation in observational studies without comparable control groups, this study underscores the value of real-world investigations in offering insights into the long-term safety of DMTs, particularly for rare events.