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

22 Pages Posted: 14 Oct 2019

See all articles by Jun Keng Khoo

Jun Keng Khoo

Alfred Hospital

Hayley Barnes

Alfred Hospital

Seraphina Key

Monash University - Central Clinical School

Ian N. Glaspole

Alfred Hospital; Monash University - Central Clinical School

Andrew Ostor

Monash University - Central Clinical School; Cabrini Medical Centre

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Abstract

Background: Small molecule tyrosine kinase inhibitors (smTKI) modulate the cytokine receptor-mediated intracellular signal cascade, and are an effective treatment for autoimmune diseases and malignancies. As smTKI are novel, long-term safety is uncertain. As the use of smTKI is increasing, characterisation of their true adverse event profile is critical.

Methods: We performed a systematic review and meta-analysis of all published trial data on the pulmonary adverse effects of smTKIs. EMBASE, MEDLINE, CENTRAL, and Pneumotox databases were searched up to April 2019 for randomised controlled trials, observational studies, 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 (URTI, LRTI), influenza, pneumonia, opportunistic respiratory infections, drug-induced interstitial lung disease, pulmonary embolism, and lung neoplasm.
Findings: We identified 4667 citations for screening, and selected 319 studies for full text review. Seventy-nine studies were analysed, including 47 RCTs, 25 observational studies, and seven post-marketing surveillance studies, comprising 159,652 participants.

There was a significantly increased risk of URTI (RD 0·03; 95% CI 0·01- 0·05; p=0·00; 36 studies, 14,724 participants), LRTI (RD 0·01; 95% CI 0·00-0·02; p=0·02; 24 studies, 12,302 participants), influenza (RD 0·01; 95% CI 0·00-0·01; p=0·04; 22 studies, 10,684 participants), and pneumonia (RD 0·00; 95% CI 0·00-0·01; p=0·02; 33 studies, 15,511 participants). No significantly increased risk was found for other respiratory complications, including pulmonary embolism.

Interpretation: SmTKI increases the risk of non-opportunistic respiratory infections compared with placebo. The risk of any serious pulmonary adverse events is low.

Funding Statement: There was no funding source for this study.

Declaration of Interests: The authors declare no competing interests.

Ethics Approval Statement: (Prospero ID: CRD42019133752).

Keywords: JAK inhibitors, Tyrosine kinase inhibitors, Tofacitinib, Baricitinib, Lung toxicity, Pulmonary adverse events, Pulmonary embolism

Suggested Citation

Khoo, Jun Keng and Barnes, Hayley and Key, Seraphina and Glaspole, Ian N. and Ostor, Andrew, Pulmonary Adverse Events of Small Molecule Tyrosine Kinase Inhibitors: Meta-Analysis and Systematic Review (October 9, 2019). Available at SSRN: https://ssrn.com/abstract=3467017 or http://dx.doi.org/10.2139/ssrn.3467017

Jun Keng Khoo

Alfred Hospital

Melbourne
Australia

Hayley Barnes

Alfred Hospital

Melbourne
Australia

Seraphina Key

Monash University - Central Clinical School

Clayton
Australia

Ian N. Glaspole

Alfred Hospital

Melbourne
Australia

Monash University - Central Clinical School

Clayton
Australia

Andrew Ostor (Contact Author)

Monash University - Central Clinical School ( email )

Clayton
Australia

Cabrini Medical Centre ( email )

Malvern
Australia

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