Comparative Risk of Infections Between JAK Inhibitors Versus TNF Inhibitors Among Patients With Rheumatoid Arthritis

A Cohort Study

Se Rim Choi; Anna Shin; You-Jung Ha; Yun Jong Lee; Eun Bong Lee; Eun Ha Kang


Arthritis Res Ther. 2023;25(129) 

In This Article

Abstract and Introduction


Background: To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea.

Methods: Using 2009–2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users.

Results: We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00–2.80) for HZ, 1.04 (0.71–1.52) for SBI, and 0.25 (0.09–0.73) for OI.

Conclusions: This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.


Rheumatoid arthritis (RA) is a systemic inflammatory disease in which synovial joints are the primary target of autoimmunity.[1] However, chronic inflammation causes not only the joint failure but also a wide spectrum of comorbidities.[2] Therefore, international guidelines endorse the treat-to-target strategy to achieve remission or low disease activity.[3,4] With the introduction of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs and tsDMARDs, respectively), clinical outcome of RA refractory to conventional DMARDs (cDMARDs) has dramatically improved.[5] In particular, Janus kinase inhibitors (JAKis) of the tsDMARD class have shown impressive efficacy against RA.[6] According to the international guidelines, the b/tsDMARDs are used as monotherapy or in combination with DMARDs including methotrexate (MTX) to treat moderate-to-severe RA[3,4]

Infection is one of the most common treatment-emergent adverse events in RA patients due to disease-associated immune alteration and/or treatment-related immune suppression. Overall, there is a twofold risk of serious infections among RA patients compared to the non-RA population.[7] Also, there has been a particular concern for infection among RA patients treated with high efficacy DMARDs including bDMARDs or JAKis.[8–10] The incidence rate (IR) of serious infections in randomized controlled trials (RCTs) investigating tofacitinib, a JAKi, was similar to that in RCTs evaluating bDMARDs including TNF inhibitors (TNFis) in patients with RA.[10] However, unlike bacterial infections, the risk of herpes zoster (HZ) with tofacitinib was significantly higher than that with TNFis.[11,12] In particular, higher susceptibility to developing HZ in Asian patients has been suggested.[12]

Despite such backgrounds, population-based studies have been few in the real-world setting that directly compared the risk of infections of JAKis versus bDMARDs users among RA patients of Asian ancestry.[13] To meet this end, we compared the risk of HZ, serious bacterial infections (SBI), and opportunistic infections (OI) among RA patients treated with JAKis versus TNFis using the nationally representative Korea National Health Insurance Service (KNHIS) database.