Pulmonary adverse events of small molecule JAK inhibitors in autoimmune disease: systematic review and meta-analysis

Abstract

Objectives Small molecule tyrosine kinase inhibitors [smTKI, comprising mostly of Janus kinase (JAK) and to a lesser extent, spleen tyrosine kinase (SyK) inhibitors] 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. Due to increasing use, characterization 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 and serious adverse effects of smTKIs in autoimmune disease. EMBASE, MEDLINE, CENTRAL and Pneumotox databases were searched up to April 2019 for randomized 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. Results We identified 4667 citations for screening, and selected 319 studies for full text review. Seventy-nine studies were analysed, including 47 randomized controlled trials, 25 observational studies and seven post-marketing surveillance studies, comprising 159 652 participants. There were significantly increased risks of URTI [risk difference (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 increased risk was found for other respiratory complications, including pulmonary embolism. Conclusion SmTKI increases the risk of non-opportunistic respiratory infections compared with placebo. The risk of any serious pulmonary adverse events is low.

Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010–2019

“…Using real-world data from the FDA's Adverse Event Reporting System (FAERS), Verden and colleagues found a potentially elevated risk of pulmonary thrombosis with JAKinibs, as well as a potentially increased risk of portal vein thrombosis for ruxolitinib based on available data for tofacitinib, tofacitinib extended release (XR), and ruxolitinib, from their approval dates to 31 March 2017 [7]. It should be noted that the literature remains mixed regarding the relationship between JAKinibs and increased incidence of cardiovascular (CV) events or TEs [15][16][17]. However, a recent meta-analysis found that across seven postmarketing surveillance studies of JAKinibs, pulmonary thromboembolism was the most commonly reported respiratory complication [17].…”

“…It should be noted that the literature remains mixed regarding the relationship between JAKinibs and increased incidence of cardiovascular (CV) events or TEs [15][16][17]. However, a recent meta-analysis found that across seven postmarketing surveillance studies of JAKinibs, pulmonary thromboembolism was the most commonly reported respiratory complication [17]. As the burden of TE events remains a substantial public health concern, it is important to continue to examine the strength of this potential safety signal in real-world data.…”

Chronic Progression of Lung Cancer Recurrence After Surgery: Warning Role of Postoperative Pneumonia

“…Respiratory adverse events (RAE) was de ned upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI), including nasopharyngitis and laryngitis, bronchitis, in uenza, respiratory-related opportunistic infections (OIs), interstitial lung disease (ILD),. pulmonary embolism (PE), including deep vein thrombosis(DVT), or collectively venous thromboembolism (VTE) (13). Laboratory data included white blood cell count, neutrophil ratio and albumin level.…”

COVID-19 Usurps Host Regulatory Networks

“…The potential for additional opportunistic pulmonary infection is also associated with monoclonal antibodies such as tocilizumab. An increased risk of pulmonary infections may also arise in autoimmune patients treated with baricitinib (Khoo et al, 2020) or anti-IL-17 antibodies (ixekizumab) (Mease et al, 2019), suggesting that the use of these drugs requires careful evaluation.…”