Pulmonary Adverse Events of Small Molecule Tyrosine Kinase Inhibitors: Meta-Analysis and Systematic Review

Abstract

Background Small molecule tyrosine kinase inhibitors (smTKI) are signalling molecules, which modulate the cytokine receptor-mediated intracellular signal cascade, and is an effective treatment for several autoimmune diseases and malignancies. As smTKI are novel, long-term safety is uncertain. Commonly reported side effects include infections, typically pulmonary and herpes zoster. As published data mainly examines tofacitinib trials, the class effect of smTKI is unknown. Methods We performed a meta-analysis of all published trial data on the pulmonary adverse effects of smTKIs. EMBASE, MEDLINE, and CENTRAL databases were searched up to September 2018 for randomized controlled trials, observational studies, case reports, and post marketing surveillance, comparing any smTKI with placebo or another therapy, or as monotherapy at different doses. Primary outcomes comprised of any respiratory complications including upper and lower respiratory tract infections, influenza, opportunistic respiratory infections, pneumonia, interstitial pneumonitis, pulmonary embolism, and lung neoplasm. Findings We identified 2253 citations for screening, and selected 150 for full text review. Seventy-five studies were analyzed, including 49 RCTs, 16 observational studies, three case reports, and seven post-marketing surveillance studies, comprising 153,942 participants. Median duration of RCTs was 24 weeks. The overall risk of any pulmonary adverse event with smTKI is low across RCTs and observational studies. There was significantly increased risk of developing upper respiratory tract infections (URTI) (RD 0·03, 95% CI 0·02 to 0·04, p<0·00001, 36 trials, 16419 participants), pneumonia (RD 0·0032; 95% CI 0·0003 to 0·0060, p=0·03, 31 trials, 15001 participants) and influenza (RD 0·0078; 95% CI 0·0031, 0·0126; p=0·001, 5 trials, 16395 participants) after smTKI exposure. No significantly increased risk was found for other respiratory complications. Interpretation SmTKI increases risk of URTI, pneumonia and influenza compared with placebo or conventional agents. The risk of any pulmonary adverse event with smTKI is low. Funding Nil