Comparison between Janus kinase inhibitor monotherapy and combination therapy with methotrexate in patients with rheumatoid arthritis: insight from the National Database of Rheumatic Diseases in Japan (NinJa) registry

Abstract Background: Janus kinase inhibitors (JAKi) are effective for rheumatoid arthritis (RA) and can be used as monotherapy; however, the clinical benefit of concomitant methotrexate (MTX) and the optimal MTX dose in JAKi-treated patients remain unclear in real-world settings. In this study, we aimed to clarify the roles of MTX by comparing the patient profiles between JAKi monotherapy (Mono) and combination with MTX (Combi) using the National Database of Rheumatic Diseases in Japan (NinJa). Methods: Using the 2022 version of the NinJa database, we analyzed RA patients treated with JAKi. Patients were classified into Mono and Combi groups. Clinical characteristics, disease activity, remission rates, and hospitalization due to serious adverse events (SAEs) were compared. Multivariable logistic regression and propensity score (PS)-matched analyses were performed to adjust for confounding factors. Associations between MTX dose and disease activity were examined using correlation and multiple regression analyses. Results: Among the enrolled patients (n = 1315), 554 (42.1%) received Combi therapy. Patients in the Combi group were younger, had shorter disease duration, and showed lower DAS28 (ESR) and HAQ scores than those in the Mono group. DAS28 (ESR)–defined remission was achieved more frequently in the Combi group (50.0% vs. 38.1%, p < 0.001). Multivariable logistic regression demonstrated that MTX use was independently associated with clinical remission (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.06–2.04). In PS-matched analyses, Combi therapy remained associated with lower DAS28 (ESR) values and higher remission rates. MTX dose was not associated with disease activity among patients receiving Combi therapy. Hospitalization due to SAEs occurred in 11.0% of JAKi-treated patients and was not independently associated with MTX use, whereas glucocorticoid use was a significant risk factor for several SAEs. Conclusions: In real-world clinical practice, Combi therapy with JAKi and MTX was associated with higher remission rates without increasing the risk of SAEs. However, MTX dose did not influence disease activity, suggesting that low-dose MTX may be sufficient when used in combination with JAKi. Although further studies are warranted to evaluate long-term outcomes, Combi therapy appears to be a favorable and well-tolerated option for RA management.