Effective Second-Line b/tsDMARDs for Patients with Rheumatoid Arthritis Unresponsive to First-Line b/tsDMARDs from the FIRST Registry

Comparison of Efficacy of Second-Line b/tsDMARDs After Adjustment by PS-IPTW

Overall, 2973 patients with RA were initiated on the first-line b/tsDMARDs during the observation period (Fig. 1). The majority of patients received TNFi (61.4%), while only 3.5% of patients were treated with JAKi. Among these, 687 patients were started on second-line b/tsDMARDs because of an inadequate response to first-line therapy, and these cases were included in this study (TNFi, 246 patients; IL-6Ri, 195 patients; CTLA4Ig, 119 patients; JAKi, 127 patients) (Supplementary Table S3). Additionally, 295 patients received third-line b/tsDMARDs owing to the inefficacy of second-line therapy, and 292 patients received b/tsDMARDs as fourth-line therapy or beyond. The TNFi group had a high concomitant rate of MTX. The IL-6Ri group had high serum CRP levels and high ESRs. The CTLA4Ig group tended to include seropositive patients with long disease duration. Patients in the JAKi group had a short disease duration.

Fig. 1figure 1

Sankey diagram of RA patients treated with b/tsDMARDs from October 2013 to April 2023. Trends in the number of RA patients initiating b/tsDMARDs in the FIRST Registry from October 2013 to April 2023. RA rheumatoid arthritis, b/tsDMARDs biologic/targeted synthetic disease-modifying antirheumatic drugs, TNFi tumor necrosis factor inhibitor, IL-6Ri interleukin-6 receptor inhibitor, CTLA4Ig cytotoxic T lymphocyte-associated protein 4-immunoglobulin, JAKi Janus kinase inhibitor

The persistence rate at 24 weeks after introducing each b/tsDMARD was 79.3% for TNFi, 87.2% for IL-6Ri, 84.9% for CTLA4Ig, and 91.3% for JAKi (Supplementary Figure S1A). The most common reason for discontinuation within 24 weeks was ineffectiveness for all b/tsDMARDs (Supplementary Figure S1B). At 24 weeks after the introduction of b/tsDMARDs, CDAI scores, SDAI scores, HAQ-DI, EQ-5D, CRP, ESR, and matrix metalloproteinase 3 (MMP-3) levels all improved from the baseline in each group (Supplementary Figure S1C and Supplementary Table S4).

Due to significant differences in patient characteristics, direct comparisons among these four groups were not feasible. Therefore, PS-IPTW adjustment was employed to minimize selection bias. Table 1 presents the adjusted patient characteristics for all groups. No significant difference was observed in any patient characteristics, with standardized differences all below 0.1, indicating adequate variable balance.

Table 1 Patient characteristics in the second-line b/tsDMARDs groups after PS-IPTW adjustment

After PS-IPTW adjustment, the 24-week persistence rate differed among the four groups (Fig. 2A and Supplementary Table S5). The JAKi group had the highest persistence rate, significantly higher than the TNFi group. At 24 weeks after treatment initiation, the CDAI remission rate was significantly higher in the JAKi group than in each bDMARD group (Fig. 2B). Even in the sensitivity analysis using the data with missing values imputed through multiple imputation, the CDAI remission rate at week 24 was significantly higher in the JAKi group (JAKi vs. TNFi = 36.8% [47/126] vs. 21.3% [53/251] p = 0.001, JAKi vs. IL-6Ri = 36.8% [47/126] vs. 23.7% [45/188] p = 0.014, JAKi vs. CTLA4Ig = 36.8% [47/126] vs. 17.0% [20/118] p < 0.001). The CDAI-LDA achievement rate was also significantly higher in the JAKi group than in the TNFi group. According to the changes in CDAI scores after the introduction of b/tsDMARDs, the JAKi group had substantially lower CDAI scores at 4 weeks after treatment initiation than each bDMARD group and lower CDAI scores also at 24 weeks (Fig. 2C). The changes in disease activity and HAQ-DI scores from baseline to 24 weeks were most significant in the JAKi group (Supplementary Table S5). The ESR changed more greatly in the JAKi group than in the TNFi and CTLA4Ig groups, whereas the changes in ESR were greater in the IL-6Ri group than in the JAKi group.

Fig. 2figure 2

Comparison of efficacy of second-line b/tsDMARDs after PS-IPTW adjustment. A Persistence rate at 24 weeks after b/tsDMARDs introduction (Kaplan–Meier curves). p values were calculated by log-rank test. B Rate of patients achieving CDAI remission (left) and CDAI-LDA (right) at 24 weeks after b/tsDMARDs. Pearson’s × 2 test was performed for JAKi and each bDMARD. The significance level was adjusted using the Bonferroni correction. C Change in CDAI after introduction of b/tsDMARDs with mean ± SD. Dunnett’s test was performed in comparison with bDMARDs using the reference of JAKi. b/tsDMARDs biologic/targeted synthetic disease-modifying antirheumatic drugs, PS-IPTW propensity score-based inverse probability of treatment weighting, TNFi tumor necrosis factor inhibitor, IL-6Ri interleukin-6 receptor inhibitor, CTLA4Ig cytotoxic T lymphocyte-associated protein 4-immunoglobulin, JAKi Janus kinase inhibitor, CDAI Clinical Disease Activity Index, LDA low disease activity

Next, we analyzed whether b/tsDMARDs used in first-line therapy affected the achievement of CDAI remission at 24 weeks after the introduction in each b/tsDMARD used in second-line therapy (Supplementary Table S6). Neither univariate nor multivariate analysis showed significant differences with the impact of the CDAI remission achievement in each first-line b/tsDMARD.

Comparison of the Safety of b/tsDMARDs Used in Second-Line Therapy

Adverse events leading to discontinuing second-line b/tsDMARDs within 24 weeks after its initiation are shown in Supplementary Figure S2. Severe skin rashes, such as injection site reactions, were more frequent in the TNFi group, while gastrointestinal symptoms were more frequent in the CTLA4Ig and JAKi groups. After adjustment by PS-IPTW, the overall incidence of adverse events was comparable among the four groups (Supplementary Table S7). Among adverse events, gastrointestinal symptoms were more frequent in the JAKi group than in the TNFi group. The profile of adverse events associated with b/tsDMARDs is shown in Supplementary Table S8.

Identification of JAKi Used as Second-Line b/tsDMARDs that is Most Associated with CDAI Remission at 24 Weeks

Next, multivariate analysis was performed to identify factors associated with CDAI remission at 24 weeks in patients with RA who started second-line therapy with JAKi (tofacitinib [TOF], 40 patients; baricitinib [BAR], 55 patients; upadacitinib [UPA], 32 patients) (Table 2). After adjusting for baseline factors (age, sex, disease duration, CDAI, HAQ-DI, and use of MTX), the introduction of UPA was significantly more associated with CDAI remission at 24 weeks than TOF (odds ratio: 5.71, 95%CI: 1.62–20.14, p = 0.007).

Table 2 JAKi as a second-line option that is most associated with CDAI remission at 24 weeks

We also examined whether first-line b/tsDMARDs were associated with CDAI remission at 24 weeks in each JAKi used as second-line b/tsDMARDs (Supplementary Table S9). Neither univariate nor multivariate analysis showed significant differences with the impact of the CDAI remission achievement at 24 weeks in each first-line b/tsDMARD.

Comparison of Efficacy Between UPA and Non-UPA JAKi Used as Second-Line b/tsDMARDs After Adjustment by PS-IPTW

As UPA might be more optimal for second-line b/tsDMARDs than non-UPA JAKi (TOF and BAR), efficacy was evaluated at 24 weeks in patients with RA who started second-line therapy with UPA group (n = 32) and non-UPA JAKi group (n = 95). The UPA group had a longer disease duration and a higher percentage of patients concomitantly using GC than the non-UPA JAKi group. The concomitant rate of MTX was higher in the non-UPA JAKi group (Table 3 left).

Table 3 Patient characteristics in the UPA and non-UPA JAKi groups as second-line b/tsDMARDs

The 24-week persistence rate was 93.8% in the UPA group and 90.5% in the non-UPA JAKi group (Supplementary Figure S3A). The reasons for discontinuation within 24 weeks included ineffectiveness and adverse events (Supplementary Figure S3B). The CDAI score at 24 weeks after the introduction of JAKi was 5.7 ± 7.3 in the UPA group and 8.1 ± 8.1 in the non-UPA JAKi group, showing improvement at 24 weeks in both groups (Supplementary Figure S3C). Supplementary Figure S3D shows the changes in disease activity in both groups. Although 1–3% of patients were in remission at baseline, tapering the GC dose was difficult with first-line b/tsDMARDs, and these patients switched to second-line b/tsDMARDs. The CDAI remission rate at 24 weeks was 46.9% in the UPA group and 25.3% in the non-UPA JAKi group. At 24 weeks after treatment initiation, the values of HAQ-DI, EQ-5D, CRP, ESR, and MMP-3 improved in both groups (Supplementary Table S10).

Table 3 (right) shows the patient characteristics in both groups after PS-IPTW adjustment. No significant difference was observed in any patient characteristics with standardized differences being less than 0.1 for all patient characteristics, showing an appropriate variable balance.

The persistence rate after PS-IPTW adjustment was 93.5% in the UPA group and 88.8% in the non-UPA JAKi group, showing no significant difference (Fig. 3A and Supplementary Table S11). Although the achievement rate of CDAI-LDA at 24 weeks was comparable between the two groups, the CDAI remission rate was significantly higher in the UPA group (UPA vs. non-UPA JAKi: 49.6% vs. 25.3%, p = 0.012) (Fig. 3B). Owing to the small sample size in the subgroup analysis of JAKi, statistical power was calculated using a post hoc analysis. For the primary endpoint, the CDAI remission rate at 24 weeks after adjustment for PS-IPTW, the remission rate in the UPA group (30 patients) was 49.9%, whereas that in the non-UPA JAKi group (96 patients) was 25.4%. With an α error set at 0.05, the effect size was calculated to be 0.45, and the statistical power was determined to be 0.80. Additionally, owing to differences in disease duration and GC use between the UPA and non-UPA JAKi groups prior to PS-IPTW adjustment, a sensitivity analysis was performed using multivariate analysis to assess the influence of UPA use on CDAI remission at 24 weeks, adjusting for disease duration and GC use. UPA use remained associated with CDAI remission at 24 weeks even after adjusting for these factors (UPA use: odds ratio 3.30, 95% CI 1.32–8.24, p = 0.010). The CDAI score at 24 weeks after the introduction of JAKi was significantly lower in the UPA group than in the non-UPA JAKi group (UPA vs. non-UPA JAKi: 5.7 ± 6.7 vs. 8.0 ± 7.8, p = 0.048) (Fig. 3C). Regarding changes in disease activity and laboratory test results from baseline to 24 weeks, CDAI and SDAI scores greatly improved in the UPA group. Still, no statistically significant difference was observed. These findings suggested that UPA might be more effective as second-line b/tsDMARDs for patients with RA.

Fig. 3figure 3

Comparison of efficacy between UPA and non-UPA JAKi as second-line b/tsDMARDs after PS-IPTW adjustment. A Persistence rate at 24 weeks after JAKi introduction (Kaplan–Meier curves). p values were calculated by log-rank test. B Rate of patients achieving CDAI remission (left) and CDAI-LDA (right) at 24 weeks after JAKi. Pearson’s × 2 test was performed for UPA and non-UPA JAKi groups. C Change in CDAI after introduction of JAKi with mean ± SD. p values were calculated by Student’s t test. b/tsDMARDs biologic/targeted synthetic disease-modifying antirheumatic drugs, PS-IPTW propensity score-based inverse probability of treatment weighting, UPA upadacitinib, JAKi Janus kinase inhibitor, CDAI Clinical Disease Activity Index, LDA low disease activity

Comparison of the Safety of UPA and Non-UPA JAKi Used as Second-Line b/tsDMARDs

Significantly few adverse events led to discontinuation within 24 weeks after the JAKi was introduced as second-line b/tsDMARDs (Supplementary Figure S3B). Thus, both groups’ adverse events within 24 weeks were recorded (Supplementary Figure S4). Adverse events, particularly infections and herpes zoster, were more frequent in the UPA group. After PS-IPTW adjustment, we observed no significant difference in the incidence of adverse events between the two groups (Supplementary Table S12). The profile of the adverse events associated with JAKi is presented in Supplementary Table S13.

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