Rituximab in Progressive Connective Tissue Disease-Associated Interstitial Lung Disease: A Multicenter Real-World Cohort Study.

INTRODUCTION: Rituximab has emerged as a viable rescue therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD), which is resistant to standard immunosuppression. However, real-world data on long-term lung function trajectories following rituximab in individuals with objectively verified progression are sparse. METHODS: We conducted a multicenter retrospective cohort study of patients with progressive connective tissue disease-associated interstitial lung disease (CTD-ILD) despite continuous mycophenolate mofetil or cyclophosphamide therapy. Progression was defined as an absolute decline of ≥ 10% in forced vital capacity (FVC % predicted) over a standardized 6-month pretreatment window. Pulmonary Function Tests (PFTs) were evaluated at 6 months prior to treatment, at rituximab initiation (baseline), early post-rituximab, and at 12 months. RESULTS: Fifty-eight patients were analyzed. During the 6-month pretreatment window, mean FVC significantly declined by 15.8%. Following rituximab initiation, significant functional response was observed. At the early post-rituximab assessment, mean FVC increased by 4.7% from baseline (p < 0.001). At 12 months (n = 56 paired cases) , mean FVC showed a sustained change of 6.8% from baseline (95% CI: +3.9% to +13.7%, p < 0.001). DLCO demonstrated a concordant response with a mean 12-month increase satisfying statistical significance (95% CI: +0.8% to +8.2%, p = 0.018). Exploratory subgroup analyses descriptively suggested more frequent improvements in inflammatory-predominant phenotypes (p = 0.044) and in patients with higher baseline FVC (OR 1.08, p = 0.024). Subgroup and predictor modeling remained otherwise underpowered and hypothesis-generating. Rituximab exhibited a favorable safety profile with no toxicities leading to permanent treatment discontinuation. CONCLUSIONS: In this real-world multicenter cohort of patients with progressive CTD-ILD despite prior immunosuppression, rituximab showed early stabilization and persistent response over a 12 month period. Exploratory findings suggest that clinical benefit may be more pronounced in inflammatory-predominant phenotypes and in patients with more preserved lung volumes at treatment initiation, rather than in end-stage fibrotic disease. These data support the use of rituximab as a rescue therapy in certain patients, while emphasizing the importance of cautious interpretation and prospective validation.