To evaluate whether initiation of systemic corticosteroids after Amyotrophic lateral sclerosis (ALS) diagnosis associates with improved survival, and to assess the feasibility of virtual trial simulation using large, multicenter, real-world longitudinal datasets.

 ALS is a fatal neurodegenerative disorder with limited disease-modifying treatments. Emerging evidence suggests that immune modulation may influence disease progression and survival. Systemic corticosteroids represent a pragmatic yet understudied immunomodulatory therapy with potential relevance in ALS.

Retrospective cohorts were created using real world longitudinal datasets between 1990-2025. ALS cases (age >18 years) were identified using ICD-9/10 codes (335.20, G12.21). Immunotherapy exposures using RxNorm codes for 16 commonly prescribed immunotherapies, including systemic corticosteroids. Eligible patients had no exposure to immunotherapies during the two years preceding ALS diagnosis. Cohort A: corticosteroids initiated ≤1 year after diagnosis; Cohort B: no immunotherapy ≤1 year after diagnosis. To minimize indication bias, patients with common autoimmune diseases were excluded. Survival up to five years was assessed using Kaplan–Meier methods, with 1:1 propensity score matching (caliper 0.2) adjusting for demographics.

Among 15,634 total ALS patients, 3500/4097 (85.4%) immunotherapy exposures were systemic corticosteroids. 1418/3500 patients (40.5%) received at least one corticosteroid exposure of which 127 were initiated within one year of diagnosis (Cohort A), compared to 13,448 with no immunotherapy exposure (Cohort B). Corticosteroid initiation was associated with reduced mortality at two years (14% reduction, HR 0.58, 95% CI 0.40–0.86, p=0.0052) and at five years (21.6% reduction, HR 0.53, 95% CI 0.38–0.74, p=0.00014). These benefits were similar after propensity matching. Further, corticosteroid exposure without riluzole conferred a significant two-year survival advantage compared with riluzole alone (23.7% reduction, HR 0.38, 95% CI 0.23–0.63, p=0.000078).

Early systemic corticosteroid exposure following ALS diagnosis associated with improved survival in immunotherapy-naïve patients. Multicenter real-world longitudinal data support virtual trial simulations and highlight the need for confirmatory randomized controlled trials in ALS.