Nintedanib reduces fibrotic markers in the lung in a model of rheumatoid arthritis associated interstitial lung disease

Abstract

RATIONALE: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a progressive and debilitating disease without effective therapies. SKG mice, genetically prone to develop autoimmune arthritis, develop a pulmonary interstitial pneumonia that resembles aspects of human RA-ILD. Nintedanib, a specific tyrosine kinase inhibitor, is approved for the treatment of idiopathic pulmonary fibrosis in several countries including the US and EU. OBJECTIVES: To explore the effect of nintedanib on the RA-ILD-like pathology in SKG mice. METHODS: Nintedanib was explored in SKG mice treated with zymosan to induce arthritis and interstitial pneumonia. Beginning at week 5 or 10 after zymosan, mice received nintedanib (p.o., q.d., 60 mg/kg) or vehicle for 6 weeks. Lung fibrosis was assessed by measuring hydroxyproline levels, static lung compliance and Masson9s trichrome staining. Lung inflammation was assessed by differential cell counts in BAL and digested lungs. Arthritis of joints and digits was scored weekly. RESULTS: Therapeutic delivery of nintedanib (week 10-16) to mice with established arthritis resulted in a reduction in lung collagen (hydroxyproline) and collagen staining. Early treatment (week 5-11) also reduced the arthritis score. Nintedanib seemed to trigger a slight but selective inflammation in the lungs of SKG mice treated with zymosan. CONCLUSIONS: Nintedanib reduced pulmonary fibrosis in arthritic SKG mice, a model that replicates aspects of RA-ILD. Early intervention with nintedanib attenuated the development of arthritis. These findings may support further investigation of nintedanib for the treatment of RA-ILD.