Supplementary Material for: Efficacy and Safety of Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis

Background: Current therapeutic options for atopic dermatitis (AD) are limited. Janus kinase (JAK) inhibitors may be viable alternatives. Objectives: To assess the efficacy and safety of JAK inhibitors for AD treatment. Methods: We searched PubMed, Embase, the Cochrane Controlled Register of Trials, Web of Science, Global Resource of Eczema Trials database, and ClinicalTrials.gov from inception to September 1, 2020. Randomized clinical trials (RCTs) comparing JAK inhibitors with placebo/vehicle treatment for AD patients were included. The primary study outcomes included (1) the change (%) from the Eczema Area and Severity Index (EASI) baseline expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI), and (2) the Investigator’s Global Assessment (IGA) response and safety outcomes expressed as relative risk (RR) and 95% CI. Results: We included 14 RCTs published in 13 studies (3,822 patients). Treatment with JAK inhibitors significantly improved IGA response (RR 2.83, 95% CI 2.25–3.56, p < 0.001) and EASI score (WMD –28.82, 95% CI –34.48 to −23.16, p < 0.001). JAK inhibitor treatment achieved the largest improvement in both IGA response (RR 3.59, 95% CI 2.66–4.84, p < 0.001) and EASI score (WMD –42.00, 95% CI –48.64 to −35.36, p < 0.001) by week 4 of treatment. Topical JAK inhibitors were significantly more efficacious than oral inhibitors. Upadacitinib treatment for 4 weeks was most effective in reducing EASI score (WMD –53.92, 95% CI –69.26 to −38.58, p < 0.001), while abrocitinib for 4 weeks led to the most effective IGA response (RR 5.47, 95% CI 2.74–10.93, p < 0.001). There was no difference in the frequency of adverse events (AEs) leading to discontinuation; however, JAK inhibitors use, especially abrocitinib, led to a higher incidence of treatment-emergent AEs (RR 1.25, 95% CI 1.10–1.42, p = 0.001). Conclusion: Our results imply that JAK inhibitors are an effective and safe AD treatment. Nevertheless, further trials with longer duration and head-to-head comparisons of different JAK inhibitors are needed.背景：目前特应性皮炎（atopic dermatitis，AD）的治疗选择十分有限。贾纳斯激酶（Janus kinase，JAK）抑制剂或可成为可行的替代治疗方案。 目的：评估JAK抑制剂用于AD治疗的有效性与安全性。 方法：本研究检索了PubMed、Embase、Cochrane对照试验注册库、Web of Science、全球湿疹试验资源数据库以及ClinicalTrials.gov自建库至2020年9月1日的文献。纳入以AD患者为研究对象、比较JAK抑制剂与安慰剂/赋形剂治疗的随机对照试验（randomized clinical trial，RCT）。主要研究结局指标包括：(1) 湿疹面积及严重程度指数（Eczema Area and Severity Index，EASI）较基线的变化百分比，以加权均数差（weighted mean difference，WMD）及95%置信区间（95% confidence interval，95% CI）表示；(2) 研究者整体评分（Investigator’s Global Assessment，IGA）应答情况及安全性结局，以相对危险度（relative risk，RR）及95% CI表示。 结果：本研究共纳入13项已发表研究中的14项RCT，共计3822例患者。JAK抑制剂治疗可显著改善IGA应答（RR=2.83，95%CI：2.25~3.56，P<0.001）及EASI评分（WMD=-28.82，95%CI：-34.48~-23.16，P<0.001）。治疗至第4周时，JAK抑制剂在IGA应答（RR=3.59，95%CI：2.66~4.84，P<0.001）与EASI评分（WMD=-42.00，95%CI：-48.64~-35.36，P<0.001）两方面均实现了最大幅度的改善。外用JAK抑制剂的疗效显著优于口服JAK抑制剂。其中，乌帕替尼（Upadacitinib）治疗4周在降低EASI评分方面效果最为显著（WMD=-53.92，95%CI：-69.26~-38.58，P<0.001），而阿布昔替尼（abrocitinib）治疗4周则在改善IGA应答方面效果最优（RR=5.47，95%CI：2.74~10.93，P<0.001）。导致停药的不良事件（adverse event，AE）发生率无组间差异；但使用JAK抑制剂，尤其是阿布昔替尼，会导致治疗期间出现不良事件的发生率升高（RR=1.25，95%CI：1.10~1.42，P=0.001）。 结论：本研究结果表明，JAK抑制剂是一种有效且安全的AD治疗药物。不过，仍需开展更长随访时长、不同JAK抑制剂头对头比较的临床试验以进一步验证其疗效与安全性。