Solitano Virginia, Ahuja Dhruv, Lee Han Hee, Gaikwad Ritu, Yeh Kuan-Hung, Facciorusso Antonio, Singh Abha G, Ma Christopher, Ananthakrishnan Ashwin N, Yuan Yuhong, Singh Namrata, Jairath Vipul, Singh Siddharth
Division of Gastroenterology and Gastrointestinal Endoscopy, IRCCS Ospedale San Raffaele, University Vita-Salute San Raffaele, Milan, Italy.
Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
JAMA Netw Open. 2025 Sep 2;8(9):e2531204. doi: 10.1001/jamanetworkopen.2025.31204.
Janus kinase (JAK) inhibitors are highly effective medications for several immune-mediated inflammatory diseases (IMIDs). However, safety concerns have led to regulatory restrictions.
To compare the risk of adverse events with JAK inhibitors vs tumor necrosis factor (TNF) antagonists in patients with IMIDs in head-to-head comparative effectiveness studies.
For this systematic review and meta-analysis, the Ovid Medline, Ovid EMBASE, and Web of Science databases were searched from inception to June 25, 2025.
Head-to-head comparative effectiveness studies of adults (aged ≥18 years) with IMIDs (including rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, or spondyloarthropathy) treated with either JAK inhibitors or TNF antagonists were included. Randomized clinical trials, noncomparative observational studies, studies not reporting outcomes of interest or focused solely on specific safety events, and studies with a sample size of less than 500 were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed.
Four investigators independently, and in pairs, abstracted data from included studies. A random-effects meta-analysis was conducted to obtain incidence rates (IRs) and hazard ratios (HRs) for JAK inhibitors vs TNF antagonists for each safety outcome (serious infections, malignant neoplasms, major cardiovascular events [MACEs], or venous thromboembolism [VTE]), adjusting for key confounding variables. Heterogeneity was quantified using the I2 statistic. Risk of bias was assessed by 2 investigators independently using the Newcastle-Ottawa Scale.
The primary outcome was risk of serious infections, malignant neoplasms, MACEs, or VTE.
This meta-analysis of 42 studies with low to moderate risk of bias included 813 881 patients (median age, 55.7 years [IQR, 53.0-59.0 years] for JAK inhibitor users and 51.5 years [IQR, 42.7-57.4 years] for TNF antagonist users; 76.5% female). For patients using JAK inhibitors vs TNF antagonists, there was no significant difference in risk of serious infections (IR, 3.79 [95% CI, 2.85-5.05] vs 3.03 [2.32-3.95] per 100 person-years; pooled HR, 1.05 [95% CI, 0.97-1.13]), malignant neoplasms (IR, 1.00 [0.77-1.31] vs 0.94 [0.72-1.22] per 100 person-years; pooled HR, 1.02 [0.90-1.16]), or MACEs (IR, 0.72 [0.56-0.92] vs 0.66 [0.49-0.89] per 100 person-years; pooled HR, 0.91 [0.80-1.04]), with minimal to moderate heterogeneity. There was a slightly higher risk of VTE with JAK inhibitors vs TNF antagonists (IR, 0.57 [95% CI, 0.40-0.82] vs 0.52 [0.37-0.73] per 100 person-years; pooled HR, 1.26 [95% CI, 1.03-1.54]). Effect estimates were largely stable across subgroups and on meta-regression.
The head-to-head studies in this systematic review and meta-analysis did not identify any meaningful difference in the risk of serious infections, malignant neoplasms, or MACEs with JAK inhibitor vs TNF antagonist use across all IMIDs, with low overall incidence. JAK inhibitor use was associated with a slightly higher risk of VTE. Further research, especially long-term studies, is needed to fully elucidate the safety of JAK inhibitors and TNF antagonists across diverse populations and optimize clinical use.
Janus激酶（JAK）抑制剂是治疗多种免疫介导的炎症性疾病（IMID）的高效药物。然而，安全问题导致了监管限制。
在头对头比较有效性研究中，比较JAK抑制剂与肿瘤坏死因子（TNF）拮抗剂在IMID患者中发生不良事件的风险。
对于本系统评价和荟萃分析，检索了Ovid Medline、Ovid EMBASE和Web of Science数据库，检索时间从数据库创建至2025年6月25日。
纳入了对使用JAK抑制剂或TNF拮抗剂治疗的成人（年龄≥18岁）IMID（包括类风湿性关节炎、炎症性肠病、银屑病或银屑病关节炎或脊柱关节炎）进行头对头比较有效性研究。排除随机临床试验、非对照观察性研究、未报告感兴趣结局或仅关注特定安全事件的研究以及样本量小于500的研究。遵循系统评价和荟萃分析的首选报告项目（PRISMA）报告指南。
四名研究人员独立且成对地从纳入研究中提取数据。进行随机效应荟萃分析，以获得JAK抑制剂与TNF拮抗剂在每种安全结局（严重感染、恶性肿瘤、主要心血管事件[MACE]或静脉血栓栓塞[VTE]）方面的发病率（IR）和风险比（HR），并对关键混杂变量进行调整。使用I²统计量对异质性进行量化。两名研究人员使用纽卡斯尔-渥太华量表独立评估偏倚风险。
主要结局是严重感染、恶性肿瘤、MACE或VTE的风险。
这项对42项偏倚风险低至中度的研究进行的荟萃分析纳入了813881名患者（使用JAK抑制剂的患者中位年龄为55.7岁[四分位间距，53.0 - 59.0岁]，使用TNF拮抗剂的患者中位年龄为51.5岁[四分位间距，42.7 - 57.4岁]；76.5%为女性）。对于使用JAK抑制剂与TNF拮抗剂的患者，严重感染风险无显著差异（每100人年IR，3.79[95%CI，2.85 - 5.05]对比3.03[2.32 - 3.95]；合并HR，1.05[95%CI，0.97 -1.13]）、恶性肿瘤（每100人年IR，1.00[0.77 - 1.31]对比0.94[0.72 - 1.22]；合并HR，1.02[0.90 - 1.16]）或MACE（每100人年IR，0.72[0.56 - 0.92]对比0.66[0.49 - 0.89]；合并HR，0.91[0.80 - 1.04]），异质性最小至中度。与TNF拮抗剂相比，JAK抑制剂导致VTE的风险略高（每100人年IR，0.57[95%CI，0.40 - 0.82]对比0.52[0.37 - 0.73]；合并HR，1.26[95%CI，1.03 - 1.54]）。效应估计在各亚组和meta回归中基本稳定。
本系统评价和荟萃分析中的头对头研究未发现，在所有IMID中，使用JAK抑制剂与TNF拮抗剂相比，严重感染、恶性肿瘤或MACE风险存在任何有意义的差异，总体发病率较低。使用JAK抑制剂与略高的VTE风险相关。需要进一步研究，尤其是长期研究，以充分阐明JAK抑制剂和TNF拮抗剂在不同人群中的安全性，并优化临床应用。
