Age and treatment class modify inflammatory risk after disease-modifying therapy discontinuation in older people with MS

Background The effectiveness of disease-modifying therapies (DMTs) in multiple sclerosis (MS) declines with age, while treatment-related adverse events increase. Although discontinuation is increasingly considered in older patients, factors influencing post-withdrawal inflammatory risk remain incompletely defined. We evaluated whether age, treatment class, treatment duration and prior disease stability modify the risk of disease reactivation after DMT discontinuation. Methods We included individuals aged ≥50 years with MS exposed for ≥6 months to first-line therapies, anti-trafficking agents or anti-CD20 monoclonal antibodies. Discontinuation was defined as treatment cessation for ≥6 months. A propensity score-matched continuation group (1:6) was constructed accounting for demographic, clinical and treatment-related factors. The primary outcome was per-protocol time to inflammatory reactivation (relapse or new MRI lesion), with 48-week confirmed disability worsening (CDW) as a secondary outcome. Prespecified interaction analyses were performed. Results Among 563 treated individuals, 113 (20.1%) discontinued therapy (median age 58 (IQR 54–65) years; 74% female). In the matched cohort (110 discontinuations; 581 continuations; median follow-up 5.1 vs 4.4 years), discontinuation was associated with increased inflammatory activity (HR 2.04; 95% CI 1.33 to 3.14), predominantly subclinical. This association was attenuated in individuals aged >60 years (HR 1.35; 95% CI 0.68 to 2.69) compared with those aged ≤60 years (HR 3.71; 95% CI 1.99 to 6.90; P for interaction=0.027). No difference in 48-week CDW was observed (HR 1.24; 95% CI 0.86 to 1.78). Conclusions In people with MS aged ≥50 years, the inflammatory consequences of DMT discontinuation, mainly driven by MRI, are modified by age, with attenuation in those aged >60 years and no associated increase in mid-term disability progression.