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

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.

Improvement in Obstructive Sleep Apnea With Weight Loss is Dependent on Body Position During Sleep.

Study Objectives: Weight loss fails to resolve obstructive sleep apnea (OSA) in most patients; however, it is unknown as to whether weight loss differentially affects OSA in the supine compared with nonsupine sleeping positions. We aimed to determine if weight loss in obese patients with OSA results in a greater reduction in the nonsupine apnea/hypopnea index (AHI) compared with the supine AHI, thus converting participants into supine-predominant OSA. Methods: Post hoc analysis of data from a randomized controlled trial assessing the effect of weight loss (bariatric surgery vs. medical weight loss) on OSA in 60 participants with obesity (body mass index: >35 and <55) with recently diagnosed (<6 months) OSA and AHI of ≥ 20 events/hour. Patients were randomized to very low calorie diet with regular review (n = 30) or to laproscopic adjustable gastric banding (n = 30) with follow-up sleep study at 2 years. Results: Eight of 37 (22%) patients demonstrated a normal nonsupine AHI (<5 events/hour) on follow-up compared to 0/37 (0%) patients at baseline (p = .003). These patients were younger (40.0 ± 9.6 years vs. 48.4 ± 6.5 years, p = .007) and lost significantly more weight (percentage weight change -23.0 [-21.0 to -31.6]% vs. -6.9 [1.9 to -17.4], p = .001). The percentage change in nonsupine AHI was greater than the percentage change in supine AHI (-54.0 [-15.4 to -87.9]% vs -33.1 [-1.8 to -69.1]%, p = .05). However, the change in absolute nonsupine AHI was not related to change in absolute supine AHI (p = .23). Conclusions: Following weight loss, a significant proportion (22%) of patients with obesity have normalization of the nonsupine AHI. For these patients, supine sleep avoidance may cure their OSA.