Nintedanib Therapy Alone and Combined with Mycophenolate in Patients with Systemic Sclerosis-associated Interstitial Lung Disease: Systematic Reviews and Meta-Analysis.

Background: The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with nintedanib alone or with the combination of nintedanib plus mycophenolate. Data Sources: Literature searches were conducted across MEDLINE, EMBASE, and CENTRAL databases through June 2022 for studies using nintedanib or nintedanib plus mycophenolate to treat patients with SSc-ILD. Data Extraction: Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analysis performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group method was used to assess the quality of evidence. Synthesis: For nintedanib therapy alone, the systematic review included three total studies and revealed that disease progression was less in the nintedanib arm (the annual rate of decline in forced vital capacity [FVC] was 44.5 mL less, the absolute change from baseline was 46.4 mL less, and FVC % predicted was 1.2% less in the nintedanib arm) when compared to placebo. However, gastrointestinal side effects and treatment discontinuation were double in the nintedanib arm compared to placebo. For combination therapy, the systematic review also included three total studies and revealed changes in the annual rate of decline in FVC favored combination therapy over placebo (mean difference 79.1 mL). Combination therapy was, however, associated with increased gastrointestinal adverse effects compared to placebo. The quality of evidence for all outcomes was very low as per GRADE. Conclusions: The use of nintedanib alone and in combination with mycophenolate in patients with SSc-ILD is associated with a significant reduction in disease progression compared to placebo but at the cost of increased gastrointestinal side effects and treatment discontinuation. The quality of evidence is very low.