What's new in critical illness and injury science? An evidence-based analysis of the impact of Janus Kinase inhibitors on 28-day mortality in patients admitted with COVID-19

Since emerging in December 2019, the coronavirus disease 2019 (COVID-19) pandemic caused by the beta-coronavirus severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) virus has resulted in over 219 million cases and 4.55 million deaths globally (as of September 9, 2021). Roughly 20% of patients require hospitalization, with an associated mortality of 11% among admitted patients in the United States.[1] Consensus is lacking on how to characterize the severity and nature of the inflammatory response induced by SARS-CoV-2 infection; however, perturbations interleukin (IL)–1 β, IL-6, IL-10, tumor necrosis factor–α, and other cytokine and cellular mediators may play a significant role in pathophysiology, disease progression, and patient outcomes.[2]In recent issues, we have discussed the evidence of therapies such as intravenous immunoglobulin,[3]convalescent plasma,[4]and anti-IL 6[5]in the treatment of hospitalized and critically ill patients with COVID-19. This editorial will explore the effects of Janus Kinase inhibitors (JAKis) on mortality in patients hospitalized with COVID-19. Early in the pandemic, a study using Benevolent AI's proprietary artificial intelligence (AI) knowledge graph query identified agents that block clathrin-mediated endocytosis as potential therapeutic targets against SARS-CoV-2 cellular infection.[6]Subsequent mechanistic data have supported the AI predictions.[78] JAKi interfere with the Janus Kinase (JAK)-signal transducers and activators of transcription (STAT) pathways involved in processes such as immunity, cell division, cell death, and tumor formation.[9]The JAK-STAT pathways transduce signals through >50 cytokine and growth factor receptors. In addition, JAK 1,2-selective inhibitors (e.g. Baricitinib, Fedratinib, Ruxolitinib, and Tofacitinib) may also have direct anti-viral effects by inhibiting AP2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK).[8]AAK1 and GAK are involved in triggering clathrin coating of membrane pits during endocytosis; the mechanism by which SARS-CoV2 is internalized following binding of its spike protein to angiotensin-converting enzyme 2 (ACE2) on the cell surface.[8]In addition, JAKi may paradoxically enhance the anti-viral response through various mechanisms including (1) reduction of interferon-mediated ACE2 upregulation or (2) limitation of lymphopenia arising from over-dominance of myelopoiesis in excessive acute-phase response, and (3) reducing activated T-lymphocytes and NK cells which may limit cytotoxic tissue damage.[9] A number of observational and nonrandomized studies have reported that the treatment of COVID-19 patients with JAKi's is safe, well-tolerated, and may potentially improve patient outcomes ranging from pulmonary function and recovery times to intensive care unit (ICU) admission rates and mortality.[10111213]Based on the data from the adaptive COVID-19 treatment trial-II,[14]it received an Emergency Use Authorization from the United States Food and Drug Administration in November 2020, in combination with Remdesivir for the treatment of hospitalized individuals with COVID-19. This editorial will explore the effects of JAKi on mortality in patients hospitalized with COVID-19. For this analysis, prospective human randomized controlled trials (RCTs) of adult patients (age ≥18 years) hospitalized COVID-19 and treated with a JAKi were considered for the inclusion. All trials were required to compare JAKi therapy with usual care (UC) ± placebo. The primary outcome of interest for this analysis was 28-day mortality, however that need not be the primary endpoint of the study. A comprehensive literature search strategy was developed of the following databases: China National Knowledge Infrastructure, Cochrane CENTRAL, CINAHL, Directory of Open Access Journals, Embase, Korean Journal Database, Latin American and Caribbean Health Sciences Literature (LILACS), IEEE-Xplorer, information/Chinese Scientific Journals database, Google Scholar, Magiran, PsycInfo, PubMed, Scopus, Scientific Electronic Library Online, Scientific Information Database, Turkish Academic Network and Information Center (TÜBİTAK ULAKBİM), Research Gate, Russian Science Citation Index, and Web of Science. Only RCTs were included; cross-over studies, observational studies, and nonrandomized designs were excluded. Searches were not limited by date, language, or publication status. Preprints were excluded as they have not undergone peer review. To limit publication bias, relevant bibliographies were searched as well as clinical trial registries: ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Australian New Zealand Clinical Trials Registry. Gray literature was excluded. Risk-of-bias was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method. Statistical analysis was performed using RevMan 5.4 (The Cochrane Collaboration, London, United Kingdom). A listing of included RCTs is presented in Table 1.[141516]The results for 28-day mortality are presented in Table 2. When compared to UC + placebo, JAKi treatment for hospitalized COVID-19 patients showed statistically significant improvement in 28-day mortality (3 studies, 1365 patients, JAKi 30/681 [4.4%] vs. UC 51/684 [7.45%]; odds ratio 0.58 [95% confidence interval 0.36, 0.91]; absolute risk difference: 3.13%, NNT: 32; evidence certainty by GRADE criteria: High).Table 1: Summary of included Janus Kinase inhibitor studies in patients hospitalized with coronavirus disease 2019 pneumoniaTable 2: Impact of Janus Kinase inhibitors on mortality in patients hospitalized with coronavirus disease 2019 pneumoniaIn conclusion, available evidence suggests that treatment with JAKis for patients hospitalized with COVID-19 pneumonia may improve 28-day mortality, with roughly 32 fewer deaths per 1000 cases admitted with COVID-19. Additional RCT data will further help clarify this finding, as well as any impact JAKi may have on other metrics including illness severity, ICU admission rates, ICU and hospital length of stay, and mechanical ventilation requirements. Research quality and ethics statement This report was exempt from the requirement of approval by the Institutional Review Board/Ethics Committee. The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines; however, no specific guideline is available for editorials.