ArticleNeurology and therapy2026
Divergent Trends in Relapse Activity and Relapse-Independent Progression Over Two Decades in Multiple Sclerosis.
Article in Neurology and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionMultiple sclerosis (MS) management has increasingly favored earlier high-efficacy disease-modifying therapy (DMT). We examined diagnosis-era changes in relapse activity and disability accrual alongside evolving DMT use.
methodsWe retrospectively analyzed two Italian cohorts of adults with MS onset in 2001-2024 across four diagnosis eras. Annualized relapse rate (ARR) was modeled by Poisson regression; confirmed disability accrual (CDA), relapse-associated worsening (RAW), and progression independent of relapse activity (PIRA) by Andersen-Gill Cox models. CDA was classified as RAW when relapse onset occurred from 90 days before through 30 days after the event, otherwise as PIRA. Treatment was time-varying: untreated, low-/moderate-efficacy therapy (LET/MET), or high-efficacy therapy (HET). Inverse probability-weighted models included residual adjustment. Sensitivity analyses examined a strict common 2-year horizon, MRI restriction/adjustment, relapsing-onset MS, first-event analyses, 90-day DMT lag, early-HET exclusion, pre-treatment versus never-treated person-time, visit frequency, and center stratification.
resultsAmong 1096 patients (228, 214, 292, and 362 across eras 1-4), first-line HET use reached 45.9% in era 4. Each later diagnosis year was associated with lower ARR (RR 0.98, 95% CI 0.96-0.99; p < 0.001), with steeper calendar-time declines during LET/MET and HET than untreated person-time (joint interaction p < 0.001). Later diagnosis year was also associated with lower RAW (HR 0.94, 95% CI 0.92-0.97; p < 0.001) and modestly lower CDA over full follow-up (HR 0.98, 95% CI 0.96-1.00; p = 0.026), although CDA attenuated in weighted and common-horizon analyses. PIRA was not associated with diagnosis year (HR 1.01, 95% CI 0.99-1.04; p = 0.262). Lower ARR and RAW persisted across sensitivities, whereas the strict 2-year analysis suggested higher early PIRA in more recent eras.
conclusionLater diagnosis-era cohorts had lower relapse activity and relapse-associated disability accrual, whereas overall disability accrual was less consistent and PIRA did not decline. Improvements in relapse-related disease activity were not accompanied by a comparable reduction in relapse-independent disability accrual.
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