Infectious Risk Similar Between cDMARDs and TNFis With Concomitant Methotrexate for RA

methotrexate syringe
Researchers investigated the risk for infection between leflunomide vs TNFi and tacrolimus vs TFNi among patients with rheumatoid arthritis treated with concomitant methotrexate.

There was no difference in the risk for serious infection between leflunomide and tumor necrosis factor inhibitors (TNFis) and tacrolimus and TNFis in patients with rheumatoid arthritis (RA) treated with concomitant methotrexate, according to study results published in Seminars in Arthritis & Rheumatology.

A cohort of patients with RA taking methotrexate and initiating TNFis, leflunomide, or tacrolimus was selected from the Korean National Health Insurance Service database.

The primary outcome was a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were the individual components of the composite endpoint. Data analyses included propensity score fine stratification and weighting and Cox proportional hazard models comparing leflunomide vs TNFi, and tacrolimus vs TNFi.

The researchers identified 72,516 patients treated with methotrexate, including 3336 initiating TNFis, 11,122 initiating leflunomide, and 5136 initiating tacrolimus. Two propensity score-weighted study cohorts were constructed: 10,992 leflunomide-initiators vs 1623 TNFi-initiators, and 5126 tacrolimus-initiators vs 2521 TNFi-initiators.

Overall, the incidence rate of herpes zoster infection (3.70-4.27) was significantly higher than serious bacterial infection (1.12-1.36) and opportunistic infection (0.11-0.27). The incidence rate of serious infection per 100 person-years was 5.76 and 5.59 for patients initiating leflunomide and TNFis, respectively (hazard ratio [HR], 1.03; 95% CI, 0.87-1.22) and 4.91 and 5.83 for patients initiating tacrolimus and TNFi, respectively (HR, 0.91; 95% CI, 0.77-1.08). The secondary outcomes for the individual types of infections showed similar results.

Limitations of the study included the retrospective study design, the potential for confounding due to a lack of information on RA activity, and a small number of patients treated with TNFis.

The study authors concluded, “In summary, we found a 3 [to] 4 times higher [incidence rate] of herpes zoster infections compared to serious bacterial infections among patients [with RA] treated with leflunomide, tacrolimus or TNFis under concomitant [methotrexate]. We did not find significant difference in the risk of any serious infections between add-on leflunomide or tacrolimus [vs] TNFis after methotrexate failure. Thus, the same degree of vigilance for serious bacterial, opportunistic, and herpes zoster infections is required for intensive cDMARD combination as for TNFi treatment.”


Shin A, Lee JH, You-Jung H, Lee YJ, Lee EB, Kang EH. Infectious risk of add-on leflunomide or tacrolimus versus TNF inhibitors among patients with rheumatoid arthritis receiving background methotrexate: a population-based cohort study. Semin Arthritis Rheum. Published online April 28, 2022. doi:10.1016/j.semarthrit.2022.152019