key: cord-0967202-7axpo9tq authors: Lin, Zhiwei; Niu, Jianyi; Xu, Yifan; Qin, Lijie; Ding, Jiabin; Zhou, Luqian title: Clinical efficacy and adverse events of baricitinib treatment for coronavirus disease‐2019 (COVID‐19): A systematic review and meta‐analysis date: 2021-12-13 journal: J Med Virol DOI: 10.1002/jmv.27482 sha: a579722889c16210d1b92a07c607e925836f41e8 doc_id: 967202 cord_uid: 7axpo9tq The benefits of baricitinib in coronavirus disease‐2019 are inadequately defined. We performed a systematic review and meta‐analysis of studies of baricitinib to determine its clinical efficacy and adverse events in patients with COVID‐19. Databases were searched from their inception to September 5, 2021. The primary outcome was the coefficient of mortality. We also compared secondary indicators and adverse events between baricitinib treatment and placebo or other treatments. Twelve studies of 3564 patients were included and assessed qualitatively (modified Jadad and Newcastle–Ottawa Scale scores). Baricitinib effectively improved the mortality rate (relative risk of mortality = 0.56; 95% confidence interval: 0.46–0.69; p < 0.001; I (2) = 2%), and this result was unchanged by subgroup analysis. Baricitinib improved intensive care unit admission, the requirement for invasive mechanical ventilation, and improved the oxygenation index. Data from these studies also showed that baricitinib slightly reduced the risk of adverse events. Regarding the choice of the drug dosage of baricitinib, the high‐dose group appeared to have additional benefits for clinical efficacy. Our study shows that baricitinib may be a promising, safe, and effective anti‐severe acute respiratory syndrome‐coronavirus‐2 drug candidate, with the advantages of low cost, easy production, and convenient storage. respiratory distress syndrome. 2 Upon viral infection, sustained excessive secretion of proinflammatory cytokines leads to dysregulation of the innate immune system, and this cytokine storm attracts large numbers of inflammatory cells to infiltrate the lungs, ultimately causing immune damage. 3 Secretion of cytokines, such as interleukin (IL)−1β, IL-6, tumor necrosis factor-α, and IL-1,8, is significantly increased in patients with Signal transducer and activator of transcription (STAT) signaling is a major cellular signaling pathway involved in the inflammatory response. 5 Accordingly, effective inhibition of cytokine storms is crucial for preventing severe COVID-19 complications and reducing mortality. Baricitinib appears to be a safe and efficacious drug for treating COVID-19 infections. Baricitinib is a Janus kinase (JAK1/JAK2) inhibitor developed to treat patients suffering from rheumatoid arthritis. 6 JAK-STAT signaling is critical to multiple cellular processes, including survival, differentiation, and proliferation. 7 The JAK-STAT pathways control the magnitude and duration of cytokine signaling to Type I and Type II cytokine receptors. Several inflammatory factors are involved in the pathogenesis of malaria through JAK-STAT pathways, including IL-6 and granulocyte-macrophage colony-stimulating factors. JAK1 and JAK2 inhibitors target these signaling pathways, which suppress the activation of inflammatory cells and reduce acute inflammatory responses. On November 19, 2020, baricitinib received emergency authorization from the US Food and Drug Administration for use in combination with Remdesivir to treat hospitalized or suspected patients with COVID-19. This emergency Food and Drug Administration authorization was based on a clinical trial conducted by the National Institute of Allergy and Infectious Diseases (ACTT-2). 8 This trial showed that the combination of baricitinib and Remdesivir reduced mortality over a 28-day treatment period compared with Remdesivir alone. Recently, new data from a randomized, controlled trial (RCT) showed that the 28-day all-cause mortality rate was 8% (n = 62) for baricitinib and 13% (n = 100) for placebo (hazard ratio [HR] = 0.57; 95% confidence interval [CI]: 0.41-0.78; p = 0.0018), with a 38.2% relative reduction in mortality. 9 This result supports the use of baricitinib in patients with COVID-19. The clinical use of baricitinib in patients with COVID-19 remains questionable. Although previous meta-analyses of JAK inhibitors have been published, 10-12 none of them examined the clinical efficacy and adverse events of baricitinib, and only one RCT 8 was included in these studies. Therefore, the clinical efficacy and adverse events of baricitinib still need to be investigated. This is a systematic review and meta-analysis study of clinical trials and observational studies. Append research in this systematic review and meta-analysis were chosen as most likely attaining the coming criteria: follow the PICO framework (P, Populations-hospitalized coronavirus disease 2019 patients; I, Interventions-treatment with baricitinib; C, Comparator/Control-a group of patients who only receive standard of care therapy or any other medications as control/placebo and did not receive treatment with baricitinib; O, Outcomes-mortality, intensive care unit admission, the requirement for invasive mechanical ventilation, the oxygenation index, choice of the drug dosage, and the risk of adverse events), The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria 13 were followed. Studies that met all the following criteria were included: (1) the studies were in the English language, and baricitinib was used alone or with other therapies in patients with COVID-19; (2) the efficacy and safety of baricitinib were investigated in adults with COVID-19; (3) clinical outcomes of interest (all-cause mortality, disease severity, intensive care unit [ICU] admission, invasive mechanical ventilation, and adverse events) were reported; (4) case-control, cohort, and randomized or non-randomized clinical trial research were contained; (5) all studies besides correspondence or review articles, case-series or case report studies, studies reported other than in English language, research focusing on children below 18 years old were excluded. Three authors (ZL, JN, and YX) extracted data independently using predefined standardized forms. Each full article that met the inclusion criteria was carefully reviewed, and the following baseline information was extracted: first author, publication year, study type, number of total participants, number of participants receiving baricitinib, number of participants receiving other drugs, and the modified Jadad 14 or Newcastle-Ottawa Scale (NOS) score. 15 The outcome measures were mortality, intensive care unit admission, the requirement for invasive mechanical ventilation, the oxygenation index, choice of the drug dosage, and the risk of adverse events. Three authors assessed the quality of each study involved in this review independently. Randomized studies and clinical trials included in the final analyses were scored by one investigator (ZL) to formally assess the risk of bias using the modified Jadad score. Non-randomized studies included in the final analyses were scored by one investigator (JN) using the Newcastle-Ottawa Scale (NOS). There was adjudication by one investigator (YX) when there was disagreement. The modified Jadad scale was used to evaluate the quality of clinical trials, including the randomization (0 or 2), blinding (0 or 2), description of withdrawals and dropouts (0 or 1), inclusion/exc1usion criteria (0 or 1), adverse effects (0 or 1), and statistical analysis (0 or 1) of each study. The studies were scored from 0 to 8, and 1-3 signified low-quality while 4-8 signified high-quality. 16 NOS was used to evaluate the quality of observational studies. The representativeness of the exposed cohort (0 or 1), selection of the nonexposed cohort (0 or 1), ascertainment of exposure (0 or 1), none of the subjects had the disease they were studying at the start of the study (0 or 1), comparability (0 or 1), noncomparability (0 or 1), method (0 or 1), follow-up time (0 or 1), and adequacy of follow-up of cohorts (0 or 1) were reported for the NOS score. Research is graded as good quality if it scores ≥7. 17 Forest plots were generated using Review Manager V.5.3 software (Cochrane Collaboration). To calculate the risk ratio (RR) and its 95% 95% CI for the mortality, ICU admission, mechanical ventilation, and adverse events outcomes, we utilize Mantel-Haenszel's formula. We used the Inverse Variance method to obtain the mean difference (MD) and its standard deviations (SDs) for the oxygenation index outcome. The I 2 statistic was exerted to assess the heterogeneity with a value of <25% considered a low degree of heterogeneity, 26%-50% moderate degree of heterogeneity, and >50% considered a high degree of heterogeneity. Because of the small number of studies, we did not test publication bias as any test would have low power to distinguish chance from real asymmetry. 18 3 | RESULTS The PRISMA flow diagram is shown in Figure 1 . We initially identified 512 articles. We then identified 46 highly relevant articles by searching titles and abstracts and eliminating repetitions. After examining the content further, 12 studies comprising 3564 patients 8, 9, [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] remained. Out of 12 pieces of research, two were double-blind, randomized clinical trials, four were non-randomized clinical trials, and six were prospective cohort research and retrospective cohort research Figure 2 . The quality assessment is shown in Figure 3A ,B. The studies included data on the first author, publication year, study type, number of total participants, number of participants receiving baricitinib, and number of participants receiving other drugs ( Figure 2 ). See Figure 3 , for the modified Jadad scale and NOS scale. The outcome of mortality in the baricitinib group versus the control groups is shown in Figure 4A . Nine studies 8, 9, 19, 20, [23] [24] [25] 27, 28 including 3827 patients reported the mortality rate. Pooled results showed that baricitinib had a lower mortality rate compared with that in the control groups (relative risk [RR] = 0.56; 95% CI: 0.46-0.69; p < 0.001; I 2 = 2%; Figure 4A ). Three studies of 2632 patients 8, 9, 27 reported the effect of baricitinib versus placebo in patients (RR = 0.63; 95% CI: 0.49-0.81; p < 0.001; I 2 = 0%; Figure 4B ). Three studies of 582 patients 20, 25, 28 reported the effect of baricitinib versus hydroxychloroquine in patients (RR = 0.29; 95% CI: 0.14-0.60; p < 0.001; I 2 = 49%; Figure 4B ). (RR = 0.67; 95% CI: 0.49 -0.91; p < 0.01; I 2 = 0%; Figure 5B ). Pooled data from two studies 8, 23 of 903 patients showed that the requirement of noninvasive mechanical ventilation was similar between the baricitinib group and the control groups (RR = 1.50; 95% CI: 0.40-5.55; p = 0.54; I 2 = 87%; Figure 5C ). Six studies 8, 9, 19, 23, 27 including 3132 patients investigated the effect of baricitinib on infections. In the baricitinib group, the risk of infections was marginally reduced compared with that in the control groups (RR = 0.80; 95% CI: 0.66-0.96; p < 0.05; I 2 = 45%; Figure 6 ). In two RCTs 8,9 with 2558 participants, baricitinib decreased the risk of serious adverse events compared with controls (RR = 0.81; 95% CI: 0.68-0.96; p < 0.05; I 2 = 0%; Figure 6 ). Four studies 8, 9, 19, 23 Previous studies 21, 22 To the best of our knowledge, this is the first systematic review and meta-analysis of the efficacy and safety of baricitinib as a potential therapeutic candidate for SARS-CoV-2. We found that baricitinib use was associated with a significant reduction in mortality in patients with COVID-19. Baricitinib reduced the risk of death in patients compared with patients with placebo and hydroxychloroquine, which further validated our findings. Additionally, the risk of ICU admission, the requirement for invasive mechanical ventilation, and the discharge oxygenation index were significantly improved after using baricitinib in patients with COVID-19. Moreover, benefits were observed with baricitinib treatment 4 mg daily, but a more robust benefit was observed with baricitinib 8 mg daily. We also found no clinically meaningful differences in safety between the baricitinib group and the control groups. Baricitinib also had a reduced risk of new infections and serious adverse events compared with that in controls. In contrast to three previously published meta-analyses 10-12 that summarized published studies of JAK inhibitors, in our study, we specifically focused on the clinical efficacy and adverse events of baricitinib. We included two recent multicenter, double-blind, randomized, placebo-controlled trials, and several recent high-quality, observational studies of baricitinib to improve the validity of our conclusions. We also performed a detailed analysis of the rates of adverse events and serious adverse events and the effect of different baricitinib doses. This more detailed analysis has more clinical significance compared with other related studies. Previous studies [10] [11] [12] have suggested that new-onset infections and thrombotic events are the main adverse events with baricitinib treatment. However, our meta-analysis showed that the incidence of new-onset infections was reduced by baricitinib treatment compared with controls. This may be due to the accelerated recovery of patients using baricitinib, 29, 30 or to the fact that the included studies used baricitinib for a short period of time, and we look forward to more studies in the future. Similar results were also shown in two RCTs, COV-BARRIER and ACTT-2, which included 2558 patients, especially regarding the incidence of serious adverse events. However, our study showed no significant difference in other common adverse reactions between baricitinib treatment and controls. Baricitinib (C 16 H 17 N 7 O 2 S), an adenosine triphosphate competitive kinase inhibitor that selectively, strongly, and reversibly inhibits JAK1 and JAK2 enzymes, was predicted to be a potential therapeutic agent against SARS-CoV-2 using artificial intelligence algorithms. 31 Baricitinib inhibits the intracellular signaling pathway of cytokines that are elevated in severe COVID-19, including IL-2, IL-6, IL-10, interferon-γ, and granulocyte-macrophage colony-stimulating factor. 32 Baricitinib acts against SARS-CoV-2 by impairing AP2associated protein kinase 1 and preventing SARS-CoV-2 cellular entry and infectivity. 33 Baricitinib also improves the lymphocyte count in patients with COVID-19. 34 Furthermore, baricitinib has few interactions with other drugs, and excretion rates are largely unchanged, making it useful for older adults with underlying disease. 35 JAK inhibitors (JAKinibs) are biological agents that inhibit Type I/II cytokine receptors. They are currently used to treat a number of diseases, and second-generation selective Jakinibs are being designed and studied. 36 | 1531 available in tablet form, which is convenient for transport and storage. Otherwise, low-dose consumption of baricitinib (2-10 mg orally once a day) in comparison to fedratinib (400 mg orally once a day) makes it have better medication compliance. Baricitinib also has the advantages of oral administration, a simple route of administration, and a reasonable price, making it suitable for use in low-and middleincome countries. Both chloroquine and the derivative molecule hydroxychloroquine have in vitro activity against SARS-CoV and SARS-CoV-2. 45 Hydroxychloroquine is thought to impair the terminal glycosylation of the angiotensin-converting enzyme 2 (ACE2) receptor, which is the binding site for the envelope spike glycoprotein and has been shown to inhibit endolysosome function. In addition, hydroxychloroquine may have greater in vitro activity against SARS-CoV-2 than chloroquine. 46 There are many limitations to our study as follows. First, although two high-quality, multicenter RCTs were included, we also included some high-quality observational studies. More multicenter, doubleblind, randomized trials are required to validate our results. Second, the method of assessing the severity of patients at baseline was not uniform across studies. Therefore, more studies using uniform evaluation methods for severity are still required. Third, the effect of baricitinib treatment may be affected by other drugs taken simultaneously, and the results do not only reflect the clinical effect of baricitinib. Fourth, most of the current studies on the safety of baricitinib were short-term. Therefore, the incidence of more long-term adverse reactions still needs to be further investigated. Finally, there have been few studies on the optimal dose of baricitinib for SARS-CoV-2. This optimal dose needs to be further explored in future studies. Our study systematic review and meta-analysis that baricitinib may represent a promising, safe, and effective anti-SARS-CoV-2 drug candidate, with the advantages of a low cost, easy production, and convenient storage. In the future, investigation of the clinical effects and safety of baricitinib in patients with SARS-CoV-2 and investigation of different levels of severity and novel variant strains will likely lead to the widely available precise use of baricitinib. 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The data that support the findings of this study are available from the corresponding author upon reasonable request.