The choice of advanced therapies for immune-mediated inflammatory disorders (IMIDs) needs to balance efficacy with safety. Janus kinase (JAK) inhibitors provide rapid and targeted immunomodulation, but safety concerns arose following the 2019 ORAL surveillance trial. This clinical trial compared tumor necrosis factor (TNF)-α antagonists with tofacitinib in older rheumatoid arthritis patients who had cardiovascular risk factors. This study showed raised risks of cancer, venous thromboembolism (VTE), and major adverse cardiovascular events (MACEs) as well as mortality. Accordingly, regulatory agencies restricted JAK inhibitor use, especially in high-risk groups. A recent systematic review and meta-analysis was published in JAMA Network Open, aimed to compare the safety of TNF antagonists and JAK inhibitors in patients with IMIDs.
This review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using different databases like Web of Science and Ovid (Medline and Embase). Studies published up to June 25, 2025, evaluating the safety outcomes in IMID patients treated with TNF antagonists or JAK inhibitors were included. Non-comparative studies, randomized clinical trials, and studies with less than 500 patients that did not report the predefined safety parameters were excluded from this analysis.
The primary safety endpoints were VTE (deep venous thrombosis and pulmonary embolism), malignancy, MACEs (stroke, cardiovascular death, and myocardial infarction), and serious infections. Random-effects meta-analysis estimated the hazard ratio (HR) and incidence rate (IR). Risks of bias and heterogeneity were evaluated using the Newcastle-Ottawa scale and I2 Statistics, respectively. All statistical analysis was carried out through R version 4.3.2.
In this meta-analysis, 42 studies (low to moderate risk of bias) were finalized in this review. A total of 813,881 patients (females = 76.5%) were included. The median age was found to be 51.5 years for TNF antagonist users and 55.7 years for JAK inhibitor users. Compared with TNF antagonists, JAK inhibitors showed no significant difference in risk of MACEs (pooled HR = 0.91 [95% confidence interval (CI): 0.80-1.04]), malignant neoplasm (n = 3467, pooled HR = 1.02 [95% CI: 0.90-1.16]), and serious infections (pooled HR = 1.05 [95% CI: 0.97-1.13]) with minimum to moderate heterogenicity.
However, treatment with JAK inhibitors was associated with a modest but meaningful increase in the risk of VTE compared with 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]), with effect estimates remaining consistent across subgroup analysis.
The study’s limitations include a lack of randomization, variable confounder adjustments, a shorter follow-up period, heterogeneous patient populations, inconsistent outcome definitions, a selective reporting method, and an inability to assess differences in drug-specific safety outcomes.
In conclusion, this systematic review and meta-analysis found no significant difference in the risk of cancer, MACEs, and serious infection between TNF antagonists and JAK inhibitors. However, a modest increase in VTE risk with JAK inhibitors was observed. These findings support careful use of JAK inhibitors with ongoing monitoring and highlight the need for further long-term research.
References: Solitano V, Ahuja D, Lee HH, et al. Comparative Safety of JAK Inhibitors vs TNF Antagonists in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(9):e2531204. doi:10.1001/jamanetworkopen.2025.31204
