JAK Inhibitors in Ankylosing Spondylitis Linked to Higher Mortality and GI Bleeding Risk Compared to TNF Inhibitors

A head-to-head comparison of Janus kinase inhibitors (JAKi) versus tumor necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS) revealed distinct safety trade-offs, according to a large retrospective cohort study using real-world data presented at ACR Convergence.

While JAKi use was linked to greater mortality and gastrointestinal bleeding, TNFi users showed higher rates of malignancy.

“To compare safety outcomes in patients with ankylosing spondylitis (AS) initiating Janus kinase inhibitors (JAKi) versus tumor necrosis factor inhibitors (TNFi),” the authors wrote, a retrospective cohort analysis was conducted using the TriNetX Global Collaborative Network.

The study included 598 AS patients—299 initiating JAKi and 299 initiating TNFi—matched by propensity scores for age, sex, race, and comorbidities (including diabetes, hypertension, psoriasis, inflammatory bowel disease, uveitis, and hyperlipidemia). Patients were followed for up to three years to assess major safety outcomes including all-cause mortality, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancy, infections, gastrointestinal bleeding, and neuropsychiatric events. Kaplan–Meier analysis was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).

Key Findings:

• Mortality:

  • Higher in JAKi group (4.3% vs. 3.3%)

  • HR 4.94; 95% CI: 1.59–15.37

• Gastrointestinal bleeding:

  • Reported in 3.4% of JAKi users vs. 0% in TNFi users (p=0.002)

• Malignancy:

  • Occurred only in TNFi group (3.4% vs. 0%, p=0.001)

• Infections:

  • Herpes zoster occurred more in JAKi group (6.0% vs. 5.0%), with a non-significant trend (HR 1.90; 95% CI: 0.95–3.83)

  • No significant differences in pneumonia, sepsis, or other serious infections

• Neuropsychiatric events:

  • Anxiety and insomnia occurred less often in JAKi group (14.3% vs. 24.1%) but without statistical significance

• No differences in MACE, VTE, dermatologic events, or hepatitis

“Compared with TNFi, JAKi therapy in AS was associated with increased mortality and gastrointestinal bleeding, but lower short-term malignancy incidence. Infection-related outcomes were similar, aside from a potential herpes zoster risk,” the authors concluded. “These findings highlight distinct safety trade-offs, underscoring the need for individualized treatment choices in AS.”

Reference:

Chen H. Comparative 3-year Safety Outcomes in Patients with Ankylosing Spondylitis Initiating JAK Inhibitor or TNF Inhibitor Therapy [abstract]. Arthritis Rheumatol. 2025; 77 (suppl 9). https://acrabstracts.org/abstract/comparative-3-year-safety-outcomes-in-patients-with-ankylosing-spondylitis-initiating-jak-inhibitor-or-tnf-inhibitor-therapy

Accessed October 17, 2025.