Abstract Background Corticosteroids remain the cornerstone of sarcoidosis therapy but are associated with substantial long-term toxicity. Methotrexate (MTX) is commonly introduced as a steroid-sparing immunosuppressant; however, large-scale real-world data directly comparing prednisone monotherapy versus combination prednisone + MTX regimens remain limited. Methods We conducted a retrospective, multicenter cohort analysis using the TriNetX U.S. Collaborative Research Network (110 healthcare organizations). Adults (≥18 years) with pulmonary sarcoidosis were stratified into two cohorts: prednisone only and prednisone + MTX (MTX within 1 month before to 2 months after prednisone initiation). Outcomes were evaluated from 90 days to 1 year post-index. Propensity score matching was performed using demographic, clinical, and laboratory covariates, including baseline use of systemic immunosuppressive medications (e.g., azathioprine, mycophenolate, leflunomide, hydroxychloroquine, or biologic agents) to account for treatment intensity and prior disease-modifying therapy exposure, yielding 8,119 patients per arm. Primary outcomes included all-cause mortality, hospital admission, and hepatic injury (ALT/AST 3× ULN). Secondary outcomes comprised severe infection and gastrointestinal bleeding. Risk ratios (RR), odds ratios (OR), and hazard ratios (HR) were estimated. Results Before matching, the prednisone-only group included 38,436 patients (mean age 63.0 ± 14.7 years, 58.7 % female) and the prednisone+MTX group included 8,159 patients (mean age 59.6 ± 12.6 years, 57.9 % female). After matching, 8,119 patients remained in each group with balanced baseline covariates (standardized mean differences 0.1). Compared with combination therapy, prednisone monotherapy was associated with higher all-cause mortality (3.6 % vs 2.3 %; RR 1.56, 95 % CI 1.30-1.87; p 0.001) and greater ICU admission risk (1.0 % vs 0.7 %; HR 1.45, 95 % CI 1.04-2.03; p = 0.028). Rates of GI bleeding (2.3 % vs 2.0 %; p = 0.24), hepatic toxicity (ALT/AST ≥ 120 U/L; 3.7 % vs 3.5 %; p = 0.53), and severe sepsis/pneumonia (1.7 % vs 1.6 %; p = 0.58) were comparable. One-year survival probability favored combination therapy (97.4 % vs 95.8 %, log-rank p 0.001). Conclusions In this large real-world, propensity-matched analysis, the addition of methotrexate to prednisone in sarcoidosis was associated with improved one-year survival and reduced ICU admission without increased hepatic or infectious complications. These findings support the safety and potential survival benefit of early steroid-sparing therapy with methotrexate in sarcoidosis and warrant prospective validation. This abstract is funded by: None
Chilingarashvili et al. (Fri,) studied this question.