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.