A 2025 systematic review and meta-analysis examined the comparative safety profiles of Janus kinase (JAK) inhibitors versus tumor necrosis factor (TNF) antagonists in patients with immune-mediated inflammatory diseases (IMIDs). The investigation encompassed 42 head-to-head trials (N= 813,881), involving participants with different types of IMIDs, including rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, and spondyloarthropathy. Hazard ratios and incidence rates were calculated for safety outcomes which included serious infections, malignant neoplasms, major cardiovascular events (MACEs), and venous thromboembolism (VTE) . The results revealed no significant differences in the risk of serious infections (incidence rate of 3.79 vs 3.03 per 100 person-years), malignant neoplasms (1.00 vs 0.94 per 100 person-years), or MACEs (0.72 vs 0.66 per 100 person-years) between users of JAK inhibitors and TNF antagonists. However, the study observed a slightly heightened risk of VTE associated with JAK inhibitors, reflected by a pooled hazard ratio of 1.26 compared to TNF antagonists. These findings, consistent across subgroups, highlight a low overall incidence of serious adverse events in this therapeutic area; however, they suggest a call for regulatory bodies to reconsider existing restrictions on JAK inhibitors. [1]
A 2023 meta-analysis evaluating cancer risk in patients treated with the JAK inhibitor tofacitinib included 22 articles describing 26 controlled studies, of which 22 were randomized controlled trials. When comparing tofacitinib with any control treatment, the relative risk (RR) for any cancer was 1.06 (95% confidence interval [CI] 0.86 to 1.31; p = 0.95), indicating no significant difference. In separate analyses comparing tofacitinib to either placebo or biological therapy, there was also no significant difference in overall cancer risk, with an RR of 1.04 (95% CI 0.44 to 2.48; p= 0.95) versus placebo and an RR of 1.06 (95% CI 0.86 to 1.31; p= 0.58) versus biological drugs. However, when tofacitinib was compared specifically with tumor necrosis factor (TNF) inhibitors, the overall cancer RR was 1.40 (95% CI 1.06 to 2.08; p= 0.02), indicating a modestly higher risk. This pattern was similar when examining all cancers except non-melanoma skin cancer (RR 1.47; 95% CI 1.05 to 2.06; p = 0.03). For non-melanoma skin cancer alone, no significant difference was observed (RR 1.30; 95% CI, 0.22–5.83; p= 0.88). In conclusion, the meta-analysis found no significant difference in overall cancer risk between tofacitinib and either placebo or biological drugs, while a slightly increased risk was observed compared with TNF inhibitors. The authors emphasized that further studies are required to more precisely define the cancer risk associated with tofacitinib therapy. [2]
A final meta-analysis, published in 2020, evaluated the risk of malignancy in patients with rheumatoid arthritis (RA) treated with non-TNF inhibitor biologics or tofacitinib. Out of 2,819 identified articles, 10 studies were included, encompassing over 40,587 patients with more than 87,622 patient-years of exposure to non-TNFi biologics and 2,221 patients with over 4,506 patient-years of exposure to tofacitinib. Pooled analyses showed no increased risk of overall cancer or specific cancer types in RA patients treated with rituximab (pooled RR 0.87; 95% CI 0.74 to 1.03), tocilizumab (pooled RR 0.92; 95% CI 0.79 to 1.06), or tofacitinib, compared with patients receiving csDMARDs or TNFi. In contrast, abatacept was associated with a slightly increased overall cancer risk (pooled RR = 1.13; 95% CI 1.02 to 1.24) and an increased risk of non-melanoma skin cancer (pooled RR 1.26; 95% CI 1.09 to 1.45) relative to csDMARDs or TNFi. Based on these findings, the authors concluded that among RA patients, a small but statistically significant increase in cancer risk was observed with abatacept exposure, while no increased risk was detected for rituximab, tocilizumab, or tofacitinib compared with csDMARDs or TNFi. [3]
A 2022 letter to the editor discussed findings from the ORAL Surveillance safety trial, which evaluated cardiovascular and cancer risks associated with tofacitinib in patients with RA. The authors noted that patients treated with tofacitinib had a higher incidence of cancer compared to those treated with TNF inhibitors, with a reported hazard ratio of 1.48 (95% CI 1.04 to 2.09). The trial was initially justified due to prior observations of increased cancer incidence, including lymphoma, in patients treated with tofacitinib. The letter highlighted that while the study reported overall cancer and non-melanoma skin cancer incidence, it did not provide lymphoma-specific rates, which are clinically relevant given that RA itself is associated with a 1.5- to 4-fold increased risk of lymphoma compared to the general population, primarily due to chronic inflammation and lymphocyte stimulation. The letter emphasized the importance of understanding lymphoma risk for treatment decisions, not only in RA but also in ulcerative colitis, where tofacitinib is commonly used. The letter concluded by advocating for greater transparency in informed consent and reporting of specific cancer outcomes, particularly lymphoma, in safety trials. In their reply to the letter, the ORAL Surveillance investigators clarified that all patients provided informed consent detailing the known risks of tofacitinib and TNF inhibitors, with updates following the dose reduction from 10 mg to 5 mg twice daily for safety reasons. They reported higher lymphoma incidence per 100 patient-years with tofacitinib (0.07 for 5 mg, 0.11 for 10 mg) compared with TNF inhibitors (0.02) and noted that differences in pathogenesis and patient characteristics limit extrapolation to ulcerative colitis. [4]
Additional evidence suggests that the risk of cancer with TNF inhibitors varies by the reporting study or review article. In a 2019 meta-analysis of 9 studies (N= 11,679 patients), the overall risk of new cancer or cancer recurrence with TNF inhibitors was 3.2/100 patient-years which was not significantly different compared to control therapies. A nationwide cohort study suggests that TNF inhibitors are associated with a lower risk of cancer compared to non-biologic disease-modifying anti-rheumatic drugs (nbDMARD) in a Korean population (incidence rate 6.5 vs 15.6 per 1000 patient-years). A 2021 systematic review specific to inflammatory disease patients found that among 28 included studies (N= 298,717 patients), the overall occurrence rate of cancer was 1.0%, but no significant association was found between TNF inhibitors and cancer in 10 of 11 studies. [5], [6], [7]