Meta-Analysis Finds Comparable Safety Profiles for JAK Inhibitors and TNF Antagonists in Immune Mediated Inflammatory Diseases

JAK inhibitors served as an important treatment option, offering rapid and targeted immunomodulation in IMIDs. However, regulatory agencies modified the label for JAK inhibitors based on the ORAL Surveillance trial. The trial focused on older high risk patients with rheumatoid arthritis, limiting the applicability of the trial findings to broader population.

Given the lack of generalizability of the trial, the researchers conducted a systematic review and meta-analysis of head to head comparative effectiveness studies of JAK inhibitors and TNF antagonist for serious infections, malignant neoplasms, major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) to provide a comprehensive safety assessment across IMIDs.

For the study, researchers searched the Ovid Medline, Ovid EMBASE and Web of Science databases from inception to June, 2025.

The study included head-to-head comparative studies of adults (>18 years) with IMIDs (rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, and spondyloarthropathy) treated with either JAK inhibitors or TNF antagonists. Only studies with sample sizes of >500 were included. Randomized clinical trials and comparative observational studies were considered. The review followed PRISMA guidelines.

The primary outcome was risk of serious infections (requiring hospitalization, intravenous antibiotics, or therapy cessation or causing death), malignant neoplasms (excluding non-melanoma skin cancer), MACE (myocardial infarction, stroke or cardiovascular mortality), and Venous thromboembolism (pulmonary embolism or deep venous thrombosis).

42 head to head comparative effectiveness studies (41 published and 1 unpublished), including 813881 patients (128705 treated with JAK inhibitors compared with 685176 treated with TNF antagonists) were involved in the review following a detailed literature review.

The key findings from the study include:

1. Risk of serious infections: Among 226,788 patients (30869 treated with JAK inhibitors vs 195919 treated with TNF antagonists) from 18 cohorts, 9,369 experienced serious infections. The incidence rate was 3.79 (95% CI, 2.85–5.05) per 100 person-years for JAK inhibitors and 3.03 (95% CI, 2.32–3.95) for TNF antagonists. No statistically significant difference was found (pooled HR, 1.05; 95% CI, 0.97–1.13), with low heterogeneity (I² = 20.4%)
2. Risk of malignant neoplasm: Out of 185530 patients (33681 treated with JAK inhibitors vs 151849 treated with TNF antagonists) from 17 cohorts, 3467 patients had malignant neoplasms. The incidence rate of malignant neoplasm was 1.00 (95%CI, 0.77-1.31) per 100 person-years with JAK inhibitors vs 0.94 (95%CI, 0.72-1.22) with TNF antagonists. No statistically significant difference was found (pooled HR,1.02 [95%CI,0.90-1.16]), with low heterogeneity (I² =6.0%).
3. Risk of MACE: Out of 361516 patients (80983 treated with JAK inhibitors vs 280533 treated with TNF antagonist) from 29 cohorts, 5522 with MACE were included in the study. The incidence rate of MACEs was 0.72 (95% CI, 0.56-0.92) per 100 person-years with JAK inhibitors vs 0.66 (95% CI,0.49-0.89) with TNF antagonists. No statistically significant difference was found (pooled HR, 0.91 [95% CI, 0.80-1.04]), with moderate heterogeneity (I² = 48.8%).
4. Risk of VTE: Out of 231967 patients (40140 treated with JAK inhibitors vs 191827 treated with TNF antagonists) from 16 cohorts, 1940 patients with VTE were included. The incidence rate was 0.57 (95% CI, 0.40-0.82) per 100 person-years with JAK inhibitors vs 0.52 (95% CI, 0.37-0.73) with TNF antagonists. There was a significantly higher risk of VTE with JAK inhibitors compared with TNF antagonists (pooled HR, 1.26 [95%CI,1.03-1.54]), with moderate heterogeneity (I² = 29.8%). It is noteworthy that in patients with with rheumatoid arthritis
   there was a 31% higher risk of VTE with JAK inhibitors vs TNF antagonists.

This comprehensive study provides a strong evidence that JAK inhibitors do not pose a significantly higher risk of serious infections, malignant neoplasms, or MACE compared to TNF antagonists in the treatment of immune-mediated inflammatory diseases (IMIDs).

However, a modestly increased risk of venous thromboembolism (VTE) was observed with JAK inhibitors, particularly in patients with rheumatoid arthritis.

These findings suggest that while JAK inhibitors remain a valuable treatment option offering rapid immunomodulation, careful patient selection and VTE risk assessment are warranted, especially in higher-risk subgroups. The findings also call for revisiting the strict regulatory guidelines for the use of these agents.

Reference: Solitano V, Ahuja D, Lee HH, Gaikwad R, Yeh KH, Facciorusso A, Singh AG, Ma C, Ananthakrishnan AN, Yuan Y, Singh N, Jairath V, Singh S. Comparative Safety of JAK Inhibitors vs TNF Antagonists in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Sep 2;8(9):e2531204. doi: 10.1001/jamanetworkopen.2025.31204. PMID: 40928778; PMCID: PMC12423869.