Background: JAK inhibitors (JAKi) are the recommended target disease-modifying antirheumatic drugs (tDMARDs) by ACR/EULAR guideline in rheumatoid arthritis (RA) patients with poor response to conventional synthetic DMARDs (csDMARDs-IR) [1]. However, there are still some patients who do not respond well to monotherapy or intolernance due to adverse effects. Iguratimod (IGU) is widely used csDMARDs for RA in China, and its add-on effects have been demonstrated in biological DMARDs.

Objectives: To observe the efficacy and safety of IGU combined with JAKi compared with JAKi alone for 12/24 weeks in patients with csDMARDs-IR active rheumatoid arthritis.

Methods: The study was conducted in 16 Rheumatology sites in China (Chinese Clinical Trial Registry, ChiCTR2100048699), from June 2021 to February 2023. Patients who matched the 1987 ACR or 2010 ACR/EULAR RA criteria were recruited in the study. After other csDMARDs washed out screening for 4 weeks, the active patients (DAS28-ESR > 3.2) were randomized at 1:1 into two groups: the Tofacitinib monotherapy group (JAKi, 5mg po bid) and the Tofacitinib combined with IGU group (JAKi + IGU, Tofacitinib 5mg po bid & IGU 25mg po bid), with regular follow-up to 12 weeks. If the patient with Jaki monotherapy DAS28-ESR > 3.2, IGU (25mg po bid) would be added at 12 weeks (JAKi-Transfer group) (Figure 1A). In this study, the type and dose of combined glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were kept stable up to 12 weeks from the screening period, and only adjusted the dose after 12 weeks. The proportion of remission (REM) of DAS28-ESR achieved at week 12 and week 24, the ratio of ACR20, ACR50, ACR70, and the occurrence of adverse events (AE) were investigated. The corresponding statistical differences were compared by analysis of variance or chi-square test.

Results: A total of 123patients were screened and 111 patients (including 17 males) were enrolled in this study, with the average age of 50 years and randomly assigned to the JAKi group (n = 55) and the JAKi+IGU group (n = 56), the rates of combined GCs and NSAIDs in the JAKi and JAKi+IGU groups were 7.27% vs.10.71%, and 5.45% vs 1.78%, respectively. Efficacy analysis revealed that after 12 weeks of treatment, the proportion of patients achieving REM of DAS28-ESR was significantly higher in the JAKi+IGU group than in the JAKi group (42.86% vs. 23.64, p = 0.032) (Figure 1B). The difference in DAS28-ESR levels between the two groups also showed the same trend (2.96 ± 1.08 vs. 3.34 ± 0.96, p = 0.049) (Figure 1C). The proportion achieving ACR70 was significantly higher in the JAKi+IGU group than in the JAKi group (48.21% vs. 27.27%, p = 0.023), but without difference for ACR20/50 (Figure 1D). There was a trend toward a higher rate of AEs in the JAKi group than in the JAKi+IGU group during the follow-up without statistical difference (Figure 1E). A total of 16 AEs (14.41%) during 12-week follow-up, of which respiratory infections were mainly common.

86 (77.48%) participants completed the 24-week follow-up, including the JAKi group (n = 32), JAKi+IGU group (n = 39), JAKi-Transfer group (n = 15). 25 patients were lost because of unable to return on time due to the COVID-19 control policy, reduction or replacement of study drugs because of inaccessibility. As shown in Figure 1F, all the patients in the JAKi-Transfer group with DAS28-ESR >3.2 at 12 weeks, while the proportion of patients achieving REM after 12 weeks of combined IGU treatment was comparable to that of the JAKi+IGU group (60.00% vs. 64.10%, p > 0.05). The ratios of patients in the JAKi-Transfer group achieving ACR20, ACR50 and ACR70 showed the same trend after combined IGU treatment (Figure 1G).

Conclusion: The csDMARDs -IR RA patients could achieve rapid and deep remission the JAKi+IGU group than the JAKi group in 12 weeks, with better safety and tolerability. If JAKi monotherapy shows poor response in the beginning, the strategy of its combination with IGU could still achieve additional synergy efficacy.

REFERENCES: [1] Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79(6):685-699.

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Acknowledgements: This research was funded by the ECCM Program of Clinical Research Center of Shandong University (No. 2021SDUCRCB010), the Natural Science Foundation of Shandong Province (ZR2022MH177).

Disclosure of Interests: None declared.