Add-on Iguratimod or Tacrolimus in Methotrexate Inadequate Rheumatoid Arthritis: Efficacy, Safety and Propensity Score-Matched Analysis

Add-on Iguratimod or Tacrolimus in Methotrexate Inadequate Rheumatoid Arthritis: Efficacy, Safety and Propensity Score-Matched Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Add-on Iguratimod or Tacrolimus in Methotrexate Inadequate Rheumatoid Arthritis: Efficacy, Safety and Propensity Score-Matched Analysis Yuji Kishimoto, Kazuki Nakazawa, Manami Uemura, Koji Kuranobu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8026013/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Dec, 2025 Read the published version in BMC Rheumatology → Version 1 posted 11 You are reading this latest preprint version Abstract Background To evaluate the efficacy and safety of combination therapy with iguratimod (IGU) versus tacrolimus (TAC) plus methotrexate (MTX) in patients with rheumatoid arthritis (RA) who failed to achieve remission with MTX monotherapy. Methods This retrospective, single-centre study included RA patients treated with IGU + MTX (n = 56) and TAC + MTX (n = 52). Propensity score matching generated two balanced cohorts (n = 30 per group). The primary endpoint was the Simplified Disease Activity Index (SDAI) remission rate at week 52. Secondary outcomes included disease activity parameters, drug retention rates, and safety profiles over 52 weeks. Results Both regimens substantially improved disease activity from baseline. In the matched analysis, SDAI remission rates at week 52 were similar between IGU and TAC (43.3% vs 46.7%, p = 1.00), as were drug retention rates (70.0% vs 76.7%, p = 0.62). The TAC group showed numerically larger reductions in SDAI, Clinical Disease Activity Index, and C-reactive protein, though these differences were not statistically significant. Treatment discontinuations due to adverse events were infrequent, and both combinations were well tolerated. Conclusions Combination therapies with IGU + MTX and TAC + MTX are both effective and safe treatment options for RA patients who failed to achieve remission with MTX monotherapy. These findings support the use of conventional synthetic disease-modifying anti-rheumatic drug combinations as valuable alternatives for MTX-inadequate responders, particularly those with low disease activity, safety concerns, or economic constraints. iguratimod tacrolimus methotrexate rheumatoid arthritis remission Figures Figure 1 Figure 2 Figure 3 Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive joint destruction. Current treatment guidelines recommend a treat-to-target strategy, which focuses on achieving clinical remission through structured disease activity assessment and therapeutic adjustments [ 1 ]. Methotrexate (MTX) is the most frequently used first-line disease-modifying anti-rheumatic drug (DMARD) [ 2 , 3 ], but only 30%–50% of patients achieve clinical remission with MTX monotherapy [ 4 ]. Although biological DMARDs (bDMARDs) and Janus kinase (JAK) inhibitors are effective for MTX-inadequate responders (MTX-IRs), clinicians often hesitate to initiate these therapies in high-risk patients or those with economic constraints [ 5 , 6 ], particularly when disease activity is partially controlled (i.e., achieving low disease activity (LDA) but not remission) in real-world practice. Combination therapy with conventional synthetic DMARDs (csDMARDs) is a valuable therapeutic alternative in such patients [ 3 ]. Among the various csDMARD combination therapies, triple therapy with MTX plus hydroxychloroquine and salazosulfapyridine has been extensively investigated [ 7 ]. However, this regimen is not feasible in Japan because hydroxychloroquine is not locally approved for the treatment of RA. In response, alternative combination approaches have been developed, including triple combination treatment with MTX plus salazosulfapyridine and bucillamine [ 8 ], as well as dual csDMARD therapy with MTX plus either iguratimod (IGU) [ 9 ] or tacrolimus (TAC) [ 10 ]. In Japan, MTX was initially approved for the treatment of RA at a maximum dose of 8 mg/week, which was subsequently increased to 16 mg/week following clinical evidence demonstrating enhanced efficacy at higher dosages. However, most clinical investigations evaluating MTX plus either IGU or TAC in Japan were conducted during the time when the approved maximum dose was only 8 mg/week [ 9 – 11 ]. After the change in dosing, research on the efficacy and safety profiles of these combination therapies has been limited. Furthermore, comparative studies between different csDMARD combinations for MTX-IRs are extremely scarce [ 12 ], and to the best of our knowledge, IGU + MTX has not been compared to TAC + MTX. This evidence gap significantly hinders optimal treatment selection for MTX-IR patients. This study investigated the efficacy and safety profiles of IGU and TAC in combination with MTX (at doses up to 16 mg/week) among RA patients who did not achieve remission with MTX monotherapy. Additionally, the groups were compared after propensity score matching to minimize selection bias and potential confounding factors. This information can be valuable for guiding optimal treatment selection for such patients in current clinical practice. Methods Study design and patients This retrospective, single-center study collected the clinical and laboratory data of RA patients who did not achieve remission with MTX monotherapy and underwent combination therapy with IGU + MTX or TAC + MTX from 2018 to 2024. Non-remission with MTX monotherapy was defined as failure to achieve clinical remission, defined by Simplified Disease Activity Index (SDAI) ≤ 3.3 [ 13 ], despite treatment with the maximum tolerated individual dose of MTX (up to 16mg/week) for a minimum duration of 3 months. Efficacy and safety were analyzed within each group separately, followed by a comparative analysis of the two groups after propensity score matching. This study included patients diagnosed with RA based on the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria [ 14 ], while excluding those who received any csDMARDs other than MTX at the time of IGU or TAC initiation and those with prior exposure to bDMARDs or JAK inhibitors. Concomitant use of glucocorticoids at baseline was permitted. MTX plus IGU or TAC combination therapy Patients received either IGU (25 mg or 50 mg/day) or TAC (1.5–3.0 mg/day) in combination with MTX (6–16 mg/week), within the approved dosage range in Japan, with each patient receiving the maximum tolerated individual dose. Dose assignments were determined by rheumatologists based on individual patient characteristics. Glucocorticoid doses could be tapered when treatment efficacy was observed. Patients were observed for 52 weeks starting from the initiation of combination treatment. Clinical efficacy assessment The primary outcome was the proportion of patients achieving the SDAI remission at 52 weeks in each treatment group. The secondary outcomes were as follows: 1) remission rates assessed by the Clinical Disease Activity Index (CDAI ≤ 2.8), Boolean criteria, and Boolean 2.0 criteria [ 15 ]; 2) the proportion of patients achieving LDA (SDAI ≤ 11 and CDAI ≤ 10); and 3) longitudinal changes in disease activity measures and their components. The following parameters were evaluated at baseline, and at weeks 12, 24, 36, and 52, also assessing changes from baseline to week 52: SDAI and CDAI scores; Health Assessment Questionnaire-Disability Index (HAQ-DI); SDAI components including tender and swollen joint count using 28 joints (TJC28 and SJC28), patient global assessment (PGA), and physician global assessment (PhGA); laboratory markers including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3); and glucocorticoid dose. To account for missing data, analyses were performed using the last observation carried forward method. Safety assessment Adverse events (AEs) were identified through a retrospective review of medical records throughout the 52-week observation period. All AEs documented during treatment were reviewed, regardless of potential causal relationship to the study drugs. The severity of each AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Only grade 2 or higher AEs were extracted and analyzed. Events leading to the discontinuation of combination therapy were also recorded. Any treatment modifications or decisions to discontinue therapy were made according to the discretion of the treating physicians, based on the clinical severity of the observed AEs. Drug retention analysis The drug retention rates for both groups were analyzed as a comprehensive outcome measure. Drug discontinuation was classified into three categories: lack of efficacy, AEs, and other reasons. The overall discontinuation rate was also analyzed by combining all reasons for discontinuation. Discontinuation due to lack of efficacy was defined as cases requiring either the addition of another csDMARD or the initiation of bDMARDs/JAK inhibitors. Retention rates were estimated via Kaplan–Meier analysis. After propensity score matching, the retention rates between the IGU and TAC groups were compared using the log-rank test. Propensity score matching To calculate propensity scores, a multivariable logistic regression model was created to model the likelihood of receiving IGU versus TAC treatment, incorporating the following key variables: age, sex, body mass index, disease duration, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, CRP, methotrexate dose, glucocorticoid dose, comorbidities estimated by the Rheumatoid Disease Comorbidity Index (RDCI) [ 16 ], HAQ-DI, and CDAI. Patients in each group were matched one-to-one based on these propensity scores, using a caliper width of 0.2 of the standard deviation of the logit of the propensity score. Balance between the groups was assessed using standardized mean differences, with values < 0.1 indicating adequate balance [ 17 ]. After propensity score matching, the IGU and TAC groups were reduced from 56 and 52 patients, respectively, to 30 patients in each group. Other statistical analysis Patient characteristics are expressed as the median with interquartile range (IQR) or n (%) for continuous and categorical variables, respectively. For intra-group comparisons over time (baseline, 12, 24, 36, and 52 weeks), we used the Friedman test followed by the Wilcoxon signed-rank test with Bonferroni correction for post-hoc analyses. After propensity score matching, between-group comparisons were performed using the Mann-Whitney U-test and Fisher’s exact test for continuous and categorical variables, respectively. Drug retention rates were compared between the groups using the log-rank test. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R software (the R Foundation for Statistical Computing) [ 18 ], with P < 0.05 indicating statistical significance. Results Patient characteristics Table 1 shows the baseline characteristics of the patients before and after propensity score matching. Before propensity score matching, there were 56 patients in the IGU group and 52 in the TAC group. Demographic characteristics (age, sex, disease duration) and comorbidity index were comparable between groups. However, disease activity measures were higher in the TAC group; for example, the median SDAI score was 11.8 [9.0–16.0] vs 7.4 [5.9–10.6] in the IGU group ( p < 0.01), and other indices such as CDAI, DAS28-CRP, SJC28, PhGA, HAQ-DI, and CRP levels were consistently higher in the TAC group. To adjust for these differences, propensity score matching was performed. After matching, 30 patients remained in each group, and most baseline characteristics were balanced with standardized mean differences less than 0.1, confirming successful matching and enabling meaningful comparison of treatment outcomes. Table 1 Patient characteristics in the IGU and TAC groups before and after propensity score matching Before propensity score matching After propensity score matching Variables IGU, n = 56 TAC, n = 52 P value IGU, n = 30 TAC, n = 30 P value SMD Age (years) 67(59–74) 63(59–73) 0.59 67(55–74) 66(59–76) 0.68 0.03 Sex, n (% female) 41(73.2) 39(75.0) 1.00 23(76.7) 24(80.0) 1.00 0.08 Disease duration (months) 20(8–32) 26(9–128) 0.13 24(8–68) 12(7–66) 0.47 0.04 RDCI 1(0–2) 1(0–2) 0.96 1(0–2) 1(0–2) 0.77 0.09 MTX use, n (%) 56(100) 52(100) NA 30(100) 30(100) NA < 0.01 MTX dose, mg/w 10(8–12) 10(8–12) 0.32 10(8–12) 10(8–12) 0.78 0.06 Glucocorticoid use, n (%) 20(35.7) 21(40.4) 0.69 14(46.7) 12(40.0) 0.80 0.13 Glucocorticoid dose, mg/day 0(0–2.0) 0(0–2.5) 0.44 0(0–2.9) 0(0–3.6) 0.76 < 0.01 TJC28 1(0–2) 1(0–1) 0.70 1(0–2) 1(0–1) 0.61 0.04 SJC28 2(1–3) 3(1–5) 0.01 2(1–4) 2(1–4) 0.42 0.01 PGA, 0–10 scale 2.8(1.6–4.1) 4.5(2.1–5.7) 0.07 3.1(1.8–4.9) 4.5(1.9–5.7) 0.54 0.12 PhGA, 0–10 scale 1.9(1.0–2.6) 3.0(1.8–4.5) < 0.01 2.0(1.2–3.0) 2.6(1.5–4.0) 0.24 0.13 SDAI 7.4(5.9–10.6) 11.8(9.0–16.0) < 0.01 8.4(6.0–12.7) 10.9(7.8–15.0) 0.24 0.08 CDAI 6.8(5.5–10.0) 11.1(8.7–14.4) < 0.01 8.0(5.7–12.1) 10.1(7.1–13.9) 0.29 0.07 DAS28-CRP 2.5(2.1–3.0) 3.0(2.5–3.6) < 0.01 2.8(2.3–3.4) 2.9(2.4–3.4) 0.57 0.08 HAQ-DI 0.19(0–0.53) 0.31(0.12–0.75) 0.03 0.25(0–0.75) 0.44(0.12–0.75) 0.46 0.11 CRP (mg/dL) 0.30(0.15–0.54) 0.53(0.25–1.21) 0.01 0.36(0.17–0.53) 0.44(0.21–0.94) 0.30 0.09 ESR (mm/hour) 17(12–34) 24(13–41) 0.55 26(14–34) 23(16–45) 0.73 0.08 MMP-3 (ng/mL) 78.6(60.7–111.0) 111.4(62.6–240.9) 0.09 91.1(63.4–111.1) 111.4(57.0–196.7) 0.51 0.01 Rheumatoid factor positive, n (%) 45(80.4) 41(78.8) 1.00 23(76.7) 21(70.0) 0.77 0.15 Rheumatoid factor (U/mL) 38(18–71) 53(18–135) 0.42 37(12–56) 35(8–60) 0.95 0.05 Anti-CCP antibody positive, n (%) 41(73.2) 42(80.8) 0.37 23(76.7) 22(73.3) 1.00 0.08 Anti-CCP antibody (U/mL) 115(3–278) 70(9–312) 0.88 144(9–242) 60(4–413) 0.89 0.09 Data are median (IQR) or number (%) of patients IGU, iguratimod; TAC, tacrolimus; SMD, standardized mean difference; RDCI, rheumatoid disease comorbidity index; MTX, methotrexate; TJC28, tender joint count using 28 joints; SJC28, swollen joint count using 28 joints; PGA, patient's global assessment; PhGA, physician global assessment; SDAI, Simplified Disease Activity Index, CDAI, Clinical Disease Activity Index; DAS, Disease Activity Score; CRP, C-reactive protein; HAQ-DI, Health Assessment Questionnaire-Disability Index; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; CCP, cyclic citrullinated peptide Efficacy and drug retention in the IGU group In the IGU group, the median final dose was 50 mg/day (IQR: 25–50 mg). The SDAI remission rate increased from 0% at baseline to 39.3% at week 12, then to 41.1% at week 24 and remained stable thereafter. The composite rate of remission and LDA (SDAI ≤ 11) improved from 78.6% at baseline to 91.1% at week 12, and reached 85.7% by week 52. Correspondingly, the median SDAI score decreased significantly from 7.4 (5.9–10.6) at baseline to 4.4 (1.5–8.0) at week 12, with sustained improvement throughout the study period ( p < 0.05 for all time points compared to baseline) (Fig. 1 -A). Regarding the other outcome measures, including CDAI, TJC28, SJC28, PhGA, and MMP-3, all improved significantly throughout the observation period, whereas HAQ-DI, PGA, CRP, and ESR showed numerical improvements that were not statistically significant (Supplementary Table 1). Glucocorticoid dose decreased from 0 (0–2) mg/day at baseline to 0 (0–0) mg/day at week 52 ( p < 0.01). Figure 1 -B shows the drug retention rate by reason for discontinuation. At 52 weeks, the drug retention rate was 78.6% overall, while the rates were 90.1%, 94.6%, and 92.3% for lack of efficacy, AEs, and other reasons, respectively. Efficacy and drug retention in the TAC group In the TAC group, the median final dose was 2.0 mg/day (IQR: 1.5–3.0 mg). The SDAI remission rate increased from 0% at baseline to 40.4% at week 12, decreased slightly to 33.7% at week 24 and 34.6% at week 36, then returned to 40.4% at week 52. The composite rate of remission and LDA was 44.2% at baseline, 82.7% at week 12 and 84.6% at week 52. The median SDAI score decreased significantly from 11.8 (9.0–16.0) at baseline to 4.1 (2.3–8.1) at week 12 and remained significantly lower thereafter ( p < 0.05 for all time points compared to baseline) (Fig. 2 -A). Other outcomes, including CDAI, TJC28, SJC28, PhGA, and CRP, all improved significantly throughout the observation period, whereas ESR showed significant improvement after week 24, HAQ-DI after week 36 and MMP-3 at week 52 (Supplementary Table 2). Glucocorticoid dose decreased significantly from 0 (0–2.5) mg/day at baseline to 0 (0–0) mg/day at week 52 ( p < 0.01). Figure 2 -B illustrates the drug retention rate by reasons; overall retention at week 52 was 73.1%, with rates of 83.6%, 96.0%, and 88.7% for lack of efficacy, AEs, and other reasons, respectively. Safety outcomes During the 52-week observation period, 51 AEs of CTCAE grade ≥ 2 were identified (IGU group: 31 events; TAC group: 20 events). The AEs were diverse with no specific pattern between groups (Supplementary Table 3). The most frequently reported AEs were upper respiratory infection (10 cases), anemia (9 cases), oral mucositis (6 cases: 5 grade 2, 1 grade 3), and shingles (4 cases). No grade 4 or 5 AEs occurred in either group. Five grade 3 AEs were reported, all assessed as unrelated to study drugs by treating physicians. Treatment discontinuation due to AEs occurred in 5 patients: 3 in the IGU group (increased creatinine, urticaria, and increased aminotransferase) and 2 in the TAC group (increased creatinine, malaise). All AEs resolved completely without any lasting effects. Comparison of efficacy and drug retention after propensity score matching The primary outcome, SDAI remission rate at week 52, showed no significant difference between the IGU and TAC groups (43.3% vs 46.7%, p = 1.00). Similarly, other clinical remission criteria, including CDAI remission, Boolean, and Boolean 2.0, were also equivalent between groups (Fig. 3 -A). Longitudinal changes in SDAI scores decreased significantly from baseline in both groups at weeks 12, 24, 36, and 52, with no significant between-group differences at any time point (Fig. 3 -B). Other disease activity measures and their components (i.e., TJC28, SJC28, PGA, and PhGA) and laboratory parameters also showed no significant between-group differences throughout the study period (Supplementary Table 2). Secondary analyses revealed numerical trends favoring the TAC group in several measures, though without statistical significance (Table 2 ). The TAC group had numerically greater median changes from baseline in SDAI score (5.2 [4.1–10.2] vs 3.7 [0.1–5.9], p = 0.09), CDAI score (5.2 [3.4–10.1] vs 3.7 [0.2–6.1], p = 0.14), and CRP reduction (0.18 [0.03–0.69] vs 0.09 [-0.17–0.30], p = 0.08) compared to the IGU group. Table 2 Effectiveness of IGU and TAC groups at 52-week after propensity score matching IGU, n = 30 TAC, n = 30 P value number (%) at week 52 SDAI LDA 24(80.0) 29(90.0) 0.47 CDAI LDA 24(80.0) 29(90.0) 0.47 changes from baseline to week 52 SDAI 3.7(0.1–5.9) 5.2(4.1–10.2) 0.09 CDAI 3.7(0.2–6.1) 5.2(3.4–10.1) 0.14 HAQ-DI 0(0–0.25) 0.12(0–0.44) 0.59 CRP (mg/dL) 0.09(-0.17–0.30) 0.18(0.03–0.69) 0.08 ESR (mm/hr) 3(-3–8) 6(0–11) 0.16 MMP-3 (ng/mL) 26.3(-2.9–51.2) 30.8(-0.5–82.2) 0.61 GC dose (mg/day) 0(-0.5–6.0) 0(-1.5–10.0) 0.97 Data are median (IQR) or number (%) IGU, iguratimod; TAC, tacrolimus; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; HAQ-DI, Health Assessment Questionnaire-Disability Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; GC, glucocorticoid Drug retention rates were also comparable between groups. Kaplan–Meier analysis showed no significant difference in 52-week retention rates between the IGU and TAC groups (70.0% vs 76.7%; log-rank test, p = 0.62) (Fig. 3 -C). Discussion This retrospective study evaluated the effectiveness and safety of combination therapies with MTX plus either IGU or TAC in patients with RA who failed to achieve remission with MTX monotherapy at doses up to 16 mg/week. Both regimens demonstrated substantial clinical improvements, with SDAI remission rates increasing from 0% at baseline to approximately 40% at week 52, accompanied by significant improvements in SDAI scores and multiple disease activity parameters. Both therapies demonstrated favorable safety profiles, with low discontinuation rates due to adverse events (5.4% for IGU, 4.0% for TAC). After propensity score matching to adjust for baseline differences, SDAI remission rates at week 52 were comparable between the IGU and TAC groups (43.3% vs 46.7%, p = 1.00), as were drug retention rates (70.0% vs 76.7%, p = 0.62). While the TAC group showed numerical trends toward greater improvements in SDAI, CDAI, and CRP, these differences did not reach statistical significance. One important characteristic of this study is that it included a substantial proportion of patients with LDA at baseline (n = 67/108, 62.0%). While numerous clinical studies of MTX-IR populations focus on patients with moderate or high disease activity, data on those with LDA remain scarce. Although LDA is recognized as an acceptable alternative treatment goal, accumulating evidence indicates that long-term outcomes are inferior compared with remission. In the ERAS and ERAN cohorts, patients who achieved remission showed significantly better HAQ scores, quality of life, and radiographic outcomes over 5 years compared with those who remained in LDA, with differences exceeding the minimal clinically important difference [ 19 ]. Similarly, in the ESPOIR cohort, sustained remission was associated with markedly less 10-year radiographic progression and better functional outcomes compared with sustained LDA [ 20 ]. These findings underscore that remission, rather than LDA, should remain the primary therapeutic target in RA. This study addresses an important evidence gap regarding optimal treatment strategies for patients with LDA in real-world clinical practice. Our findings regarding the effectiveness of IGU + MTX are generally consistent with previous reports. Ishiguro et al. demonstrated that IGU + MTX significantly improved disease activity in Japanese patients with MTX-IR patients [ 9 ], showing a higher ACR20 response rate at week 24 compared with placebo (69.5% vs 30.7%). Interestingly, the DAS28 remission rate at week 24 was notably higher in our study (78.6%) than in their report (27.4%). This discrepancy likely reflects differences in baseline disease activity: our cohort had a lower median DAS28-CRP at baseline (2.5 [IQR: 2.1–3.0]) compared with Ishiguro’s population (mean 4.87 ± 0.89). In addition, the higher MTX doses employed in our study may have also contributed to these favorable outcomes. While Ishiguro et al. used MTX doses of 6 or 8 mg/week, our study had a median dose of 10 mg/week (IQR: 8–12 mg), reflecting current dosing practices in Japan. IGU exerts immunomodulatory effects by regulating T- and B-cell function and suppressing pro-inflammatory cytokine production via cyclooxygenase-2 and nuclear factor-kappa B pathway suppression [ 21 ]. These mechanisms are distinct from those of MTX [ 22 ], suggesting potential synergistic effects when used in combination. Although it seems reasonable to hypothesize that higher MTX doses in combination with IGU would enhance therapeutic efficacy, direct evidence supporting this dose-response relationship remains limited, warranting further investigation. TAC suppresses T-cell activation through inhibition of the calcineurin pathway, thereby blocking interleukin-2 production [ 23 ]—a mechanism distinct from that of MTX, providing a rationale for combination therapy. Our results align with previous evidence demonstrating the efficacy of TAC + MTX in MTX-IR patients. Kitahama et al. conducted a large-scale cohort study with propensity score matching, demonstrating that TAC + MTX significantly reduced DAS28 scores versus MTX monotherapy, with an adjusted mean difference of − 0.273 over 6 months [ 24 ]. Similarly, a retrospective analysis by Morita et al. reported that low-dose TAC + MTX resulted in significant clinical improvement, with 72% of patients achieving a moderate or good EULAR response and over half achieving clinical remission according to DAS28-CRP criteria at 6 months [ 25 ]. Despite variations in dosing regimens and baseline patient characteristics among studies, these findings consistently indicate that combination therapy with TAC + MTX is effective and well-tolerated for MTX-IR patients. Our study contributes to this growing body of evidence by evaluating long-term clinical outcomes over a 52-week period under contemporary treatment standards in Japan, where higher MTX doses up to 16 mg/week are now routinely employed. Direct comparisons of csDMARD combination therapies for MTX-IR patients remain scarce. A recent retrospective analysis by Nozaki et al. compared IGU + MTX versus salazosulfapyridine + MTX in Japanese MTX-IR patients [ 12 ]. After propensity score matching, IGU + MTX was associated with a significantly higher 24-month drug retention rate (67.8% vs 38.5%, p < 0.05) and superior clinical responses, underscoring the importance of selecting appropriate combination partners for MTX. To our knowledge, no previous studies have directly compared IGU + MTX with TAC + MTX in MTX-IR patients. In the present study, both regimens demonstrated comparable efficacy and safety, with similar SDAI remission rates and drug retention at 52 weeks. Notably, TAC + MTX showed numerically greater improvements in SDAI, CDAI, and CRP reduction, though these differences did not reach statistical significance. Beyond clinical efficacy and safety, several practical factors can influence treatment selection in real-world practice. Although treatment cost was not evaluated in our study, it represents an important determinant in therapeutic decision-making [ 26 ]. Based on current Japanese drug pricing as of 2025, the estimated monthly cost is approximately 35 USD for IGU (50 mg/day) versus 230 USD for TAC (3 mg/day), representing a nearly sevenfold difference. In addition, patient-specific clinical factors warrant careful consideration: TAC requires close monitoring in patients with renal dysfunction or diabetes mellitus [ 27 ], whereas IGU is contraindicated for concomitant use with warfarin and should be used with caution in patients with hepatic impairment [ 28 ]. Considering efficacy, safety, and economic aspects together, the selection of csDMARDs in clinical practice should be guided by a comprehensive assessment that includes cost-effectiveness, patient preferences, and comorbidities. Ultimately, shared decision-making between clinicians and patients remains essential in determining the optimal csDMARD combination strategy for MTX-IR patients. Several limitations should be acknowledged when interpreting our findings. First, the retrospective, non-randomized design introduces potential selection and information bias, despite the use of propensity score matching to minimize baseline imbalances. Second, reliance on propensity score methods may not fully adjust for unmeasured confounding. However, sensitivity analyses using inverse probability of treatment weighting yielded results consistent with the primary propensity score matching analysis, showing no statistically significant differences between the IGU and TAC groups across major efficacy endpoints (data not shown). This consistency supports the overall robustness of our conclusions. Third, the single-center setting and the relatively small matched sample (n = 30 per group) limit the statistical power and constrain generalizability beyond similar practice settings. The numerical trends favoring TAC in SDAI, CDAI, and CRP reduction, though not statistically significant, may reflect type II error and warrant investigation in larger studies. Finally, because radiographic assessments were not performed, we were unable to evaluate structural joint damage progression, an important long-term outcome in RA management. Conclusions In conclusion, combination therapies with IGU + MTX and TAC + MTX are both effective and well-tolerated treatment options for patients with RA who failed to achieve remission with MTX monotherapy. This study addresses an important evidence gap regarding these combinations under current higher MTX dosing standards in Japan. Both combinations represent valuable therapeutic alternatives that may be considered before escalation to bDMARDs or JAK inhibitors, particularly in patients with low disease activity who may not warrant escalation to advanced therapies, as well as those with safety concerns or economic constraints. When selecting between these csDMARD combinations, clinicians should consider efficacy and safety profiles alongside treatment costs, patient preferences, and comorbidities through shared decision-making. These findings warrant further validation through larger multicenter studies that incorporate radiographic assessments and evaluate long-term structural outcomes. Abbreviations ACR: American College of Rheumatology AE: Adverse event bDMARDs: Biological disease-modifying antirheumatic drugs CDAI: Clinical Disease Activity Index CRP: C-reactive protein csDMARDs: Conventional synthetic disease-modifying antirheumatic drugs DAS28: Disease Activity Score in 28 joints DAS28-CRP: Disease Activity Score in 28 joints based on C-reactive protein ESR: Erythrocyte sedimentation rate EULAR: European Alliance of Associations for Rheumatology EZR: Easy R (R-based statistical software) HAQ: Health Assessment Questionnaire HAQ-DI: Health Assessment Questionnaire Disability Index IGU: Iguratimod IQR: Interquartile range JAK: Janus kinase LDA: Low disease activity MMP-3: Matrix metalloproteinase-3 MTX: Methotrexate MTX-IRs: Methotrexate inadequate responders PGA: Patient Global Assessment PhGA: Physician Global Assessment RA: Rheumatoid arthritis RDCI: Rheumatic Disease Comorbidity Index SDAI: Simplified Disease Activity Index SJC28: Swollen joint count (28 joints) TAC: Tacrolimus TJC28: Tender joint count (28 joints) Declarations Acknowledgments and Funding Information During the preparation of this work, the authors used Claude (Claude 4.5 Sonnet, by Anthropic) to improve readability and to proofread the English text. After using this tool, the authors carefully reviewed and edited the content as needed and take full responsibility for the final version of manuscript. The authors also thank Enago (www.enago.jp) for their English language review. The authors declare that they have no conflicts of interest. No funding was received for this study. Ethics approval and consent to participate This study was approved by the Institutional Review Board of Tottori Red Cross Hospital (Approval No. 262) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available doe to privacy and ethical restrictions, but are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding None. Authors’ contributions All authors contributed to the study design and data analysis. They interpreted the results, reviewed the manuscript critically, and approved the final version for publication. All authors take full responsibility for the integrity of the work. References Smolen JS, Breedveld FC, Burmester GR, et al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75:3–15. https://doi.org/10.1136/annrheumdis-2015-207524 Smolen JS, Landewé RBM, Bergstra SA, et al (2023) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 82:3–18. https://doi.org/10.1136/ard-2022-223356 Harigai M, Kaneko Y, Tanaka E, et al (2025) 2024 Update of the Japan College of Rheumatology Clinical Practice Guidelines for the Management of Rheumatoid Arthritis: Secondary publication. 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Arthritis Res Ther 25:207. https://doi.org/10.1186/s13075-023-03176-7 Long Z, Zeng L, He Q, et al (2023) Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases. Front Immunol 14:1150661. https://doi.org/10.3389/fimmu.2023.1150661 Cronstein BN, Aune TM (2020) Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 16:145–154. https://doi.org/10.1038/s41584-020-0373-9 Dutta S, Ahmad Y (2011) The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther Adv Musculoskelet Dis 3:283–291. https://doi.org/10.1177/1759720X11419038 Kitahama M, Nakajima A, Inoue E, et al (2013) Efficacy of adjunct tacrolimus treatment in patients with rheumatoid arthritis with inadequate responses to methotrexate. Mod Rheumatol 23:788–93. https://doi.org/10.1007/s10165-012-0745-3 Morita Y, Sasae Y, Sakuta T, et al (2008) Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study. Mod Rheumatol 18:379–84. https://doi.org/10.1007/s10165-008-0071-y Singh JA, Tornberg H, Goodman SM (2021) Pop a pill or give myself a shot? Patient perspectives of disease-modifying anti-rheumatic drug choice for rheumatoid arthritis. Joint Bone Spine 88:105053. https://doi.org/10.1016/j.jbspin.2020.07.002 Takeuchi T, Kawai S, Yamamoto K, et al (2014) Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis. Mod Rheumatol 24:8–16. https://doi.org/10.3109/14397595.2013.854074 Shibata K, Yoshimura A, Ikeuchi S, Ishii M (2021) Effectiveness of drug safety measures for reducing the incidence of adverse drug reactions: Post-hoc analysis of data from all-case surveillance of iguratimod using generalized estimating equations. PloS One 16:e0253513. https://doi.org/10.1371/journal.pone.0253513 Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1.docx SupplementaryTable2.docx SupplementaryTable3.docx Cite Share Download PDF Status: Published Journal Publication published 30 Dec, 2025 Read the published version in BMC Rheumatology → Version 1 posted Editorial decision: Revision requested 15 Dec, 2025 Reviews received at journal 13 Dec, 2025 Reviewers agreed at journal 10 Dec, 2025 Reviews received at journal 09 Dec, 2025 Reviewers agreed at journal 08 Dec, 2025 Reviewers agreed at journal 27 Nov, 2025 Reviewers invited by journal 11 Nov, 2025 Editor invited by journal 07 Nov, 2025 Editor assigned by journal 06 Nov, 2025 Submission checks completed at journal 06 Nov, 2025 First submitted to journal 04 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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The line graph shows median values with interquartile ranges. (B) Kaplan–Meier curves showing drug retention rates, stratified by the reasons for discontinuation (i.e., lack of efficacy, adverse events, and other reasons). IGU, iguratimod; SDAI, Simplified Disease Activity Index.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/73b0d599ef5883d0a4e3d884.png"},{"id":96557034,"identity":"80edda3f-4614-4bf3-9074-76578b420b7b","added_by":"auto","created_at":"2025-11-23 11:51:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":979475,"visible":true,"origin":"","legend":"\u003cp\u003eClinical outcomes in the TAC group (overall population, n=52) over 52 weeks\u003c/p\u003e\n\u003cp\u003e(A) Distribution of SDAI disease activity categories (bars, left y-axis) and median SDAI scores (line, right y-axis) over time. The line graph shows median values with interquartile ranges. (B) Kaplan–Meier curves showing drug retention rates, stratified by the reasons for discontinuation (i.e., lack of efficacy, adverse events, and other reasons). TAC, tacrolimus; SDAI, Simplified Disease Activity Index.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/220155f24d01d564a7070d02.png"},{"id":96557035,"identity":"1703cc03-e48d-41d9-86c6-b182331075f4","added_by":"auto","created_at":"2025-11-23 11:51:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":778028,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of treatment outcomes between the IGU and TAC groups after propensity score matching\u003c/p\u003e\n\u003cp\u003e(A) SDAI remission rates and other clinical remission criteria at 52 weeks. Bar graphs show the percentage of patients achieving remission according to each criterion in the IGU and TAC group.(B) Longitudinal changes in median SDAI scores over 52 weeks. The line graphs show median values with interquartile ranges for both treatment groups. (C) Kaplan–Meier curves comparing the drug retention rates between the IGU and TAC groups. IGU, iguratimod; TAC, tacrolimus; SDAI, Simplified Disease Activity Index; LDA, low disease activity.\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/875e3af0404e2e57fa6ab786.png"},{"id":99545422,"identity":"a2735a3c-f2c9-48ce-a9a3-f68daaf4d19a","added_by":"auto","created_at":"2026-01-05 16:07:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3580603,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/4d1eb63f-64f5-40f6-9365-92527c6c6359.pdf"},{"id":96557039,"identity":"6106d5ec-a739-430b-9a74-36e5e8e78246","added_by":"auto","created_at":"2025-11-23 11:51:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23524,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/44eaf19dc9a83f79422c2f35.docx"},{"id":96557032,"identity":"7d3fc82e-c1ac-42a3-b416-a322b5b53ce3","added_by":"auto","created_at":"2025-11-23 11:51:28","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":28639,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/1dd0758560e919515b5f3095.docx"},{"id":96557045,"identity":"44dbaf25-a879-4c7c-b9bd-bdcd2132f288","added_by":"auto","created_at":"2025-11-23 11:51:29","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21688,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8026013/v1/4b8486cf4715d2d6e145929b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Add-on Iguratimod or Tacrolimus in Methotrexate Inadequate Rheumatoid Arthritis: Efficacy, Safety and Propensity Score-Matched Analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive joint destruction. Current treatment guidelines recommend a treat-to-target strategy, which focuses on achieving clinical remission through structured disease activity assessment and therapeutic adjustments [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Methotrexate (MTX) is the most frequently used first-line disease-modifying anti-rheumatic drug (DMARD) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], but only 30%\u0026ndash;50% of patients achieve clinical remission with MTX monotherapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although biological DMARDs (bDMARDs) and Janus kinase (JAK) inhibitors are effective for MTX-inadequate responders (MTX-IRs), clinicians often hesitate to initiate these therapies in high-risk patients or those with economic constraints [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], particularly when disease activity is partially controlled (i.e., achieving low disease activity (LDA) but not remission) in real-world practice. Combination therapy with conventional synthetic DMARDs (csDMARDs) is a valuable therapeutic alternative in such patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong the various csDMARD combination therapies, triple therapy with MTX plus hydroxychloroquine and salazosulfapyridine has been extensively investigated [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, this regimen is not feasible in Japan because hydroxychloroquine is not locally approved for the treatment of RA. In response, alternative combination approaches have been developed, including triple combination treatment with MTX plus salazosulfapyridine and bucillamine [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], as well as dual csDMARD therapy with MTX plus either iguratimod (IGU) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] or tacrolimus (TAC) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn Japan, MTX was initially approved for the treatment of RA at a maximum dose of 8 mg/week, which was subsequently increased to 16 mg/week following clinical evidence demonstrating enhanced efficacy at higher dosages. However, most clinical investigations evaluating MTX plus either IGU or TAC in Japan were conducted during the time when the approved maximum dose was only 8 mg/week [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. After the change in dosing, research on the efficacy and safety profiles of these combination therapies has been limited. Furthermore, comparative studies between different csDMARD combinations for MTX-IRs are extremely scarce [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], and to the best of our knowledge, IGU\u0026thinsp;+\u0026thinsp;MTX has not been compared to TAC\u0026thinsp;+\u0026thinsp;MTX. This evidence gap significantly hinders optimal treatment selection for MTX-IR patients.\u003c/p\u003e\u003cp\u003eThis study investigated the efficacy and safety profiles of IGU and TAC in combination with MTX (at doses up to 16 mg/week) among RA patients who did not achieve remission with MTX monotherapy. Additionally, the groups were compared after propensity score matching to minimize selection bias and potential confounding factors. This information can be valuable for guiding optimal treatment selection for such patients in current clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy design and patients\u003c/p\u003e\u003cp\u003eThis retrospective, single-center study collected the clinical and laboratory data of RA patients who did not achieve remission with MTX monotherapy and underwent combination therapy with IGU\u0026thinsp;+\u0026thinsp;MTX or TAC\u0026thinsp;+\u0026thinsp;MTX from 2018 to 2024. Non-remission with MTX monotherapy was defined as failure to achieve clinical remission, defined by Simplified Disease Activity Index (SDAI)\u0026thinsp;\u0026le;\u0026thinsp;3.3 [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], despite treatment with the maximum tolerated individual dose of MTX (up to 16mg/week) for a minimum duration of 3 months. Efficacy and safety were analyzed within each group separately, followed by a comparative analysis of the two groups after propensity score matching. This study included patients diagnosed with RA based on the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], while excluding those who received any csDMARDs other than MTX at the time of IGU or TAC initiation and those with prior exposure to bDMARDs or JAK inhibitors. Concomitant use of glucocorticoids at baseline was permitted.\u003c/p\u003e\u003cp\u003eMTX plus IGU or TAC combination therapy\u003c/p\u003e\u003cp\u003ePatients received either IGU (25 mg or 50 mg/day) or TAC (1.5\u0026ndash;3.0 mg/day) in combination with MTX (6\u0026ndash;16 mg/week), within the approved dosage range in Japan, with each patient receiving the maximum tolerated individual dose. Dose assignments were determined by rheumatologists based on individual patient characteristics. Glucocorticoid doses could be tapered when treatment efficacy was observed. Patients were observed for 52 weeks starting from the initiation of combination treatment.\u003c/p\u003e\u003cp\u003eClinical efficacy assessment\u003c/p\u003e\u003cp\u003eThe primary outcome was the proportion of patients achieving the SDAI remission at 52 weeks in each treatment group. The secondary outcomes were as follows: 1) remission rates assessed by the Clinical Disease Activity Index (CDAI\u0026thinsp;\u0026le;\u0026thinsp;2.8), Boolean criteria, and Boolean 2.0 criteria [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]; 2) the proportion of patients achieving LDA (SDAI\u0026thinsp;\u0026le;\u0026thinsp;11 and CDAI\u0026thinsp;\u0026le;\u0026thinsp;10); and 3) longitudinal changes in disease activity measures and their components.\u003c/p\u003e\u003cp\u003eThe following parameters were evaluated at baseline, and at weeks 12, 24, 36, and 52, also assessing changes from baseline to week 52: SDAI and CDAI scores; Health Assessment Questionnaire-Disability Index (HAQ-DI); SDAI components including tender and swollen joint count using 28 joints (TJC28 and SJC28), patient global assessment (PGA), and physician global assessment (PhGA); laboratory markers including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3); and glucocorticoid dose. To account for missing data, analyses were performed using the last observation carried forward method.\u003c/p\u003e\u003cp\u003eSafety assessment\u003c/p\u003e\u003cp\u003eAdverse events (AEs) were identified through a retrospective review of medical records throughout the 52-week observation period. All AEs documented during treatment were reviewed, regardless of potential causal relationship to the study drugs. The severity of each AE was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Only grade 2 or higher AEs were extracted and analyzed. Events leading to the discontinuation of combination therapy were also recorded. Any treatment modifications or decisions to discontinue therapy were made according to the discretion of the treating physicians, based on the clinical severity of the observed AEs.\u003c/p\u003e\u003cp\u003eDrug retention analysis\u003c/p\u003e\u003cp\u003eThe drug retention rates for both groups were analyzed as a comprehensive outcome measure. Drug discontinuation was classified into three categories: lack of efficacy, AEs, and other reasons. The overall discontinuation rate was also analyzed by combining all reasons for discontinuation. Discontinuation due to lack of efficacy was defined as cases requiring either the addition of another csDMARD or the initiation of bDMARDs/JAK inhibitors. Retention rates were estimated via Kaplan\u0026ndash;Meier analysis. After propensity score matching, the retention rates between the IGU and TAC groups were compared using the log-rank test.\u003c/p\u003e\u003cp\u003ePropensity score matching\u003c/p\u003e\u003cp\u003eTo calculate propensity scores, a multivariable logistic regression model was created to model the likelihood of receiving IGU versus TAC treatment, incorporating the following key variables: age, sex, body mass index, disease duration, rheumatoid factor titer, anti-cyclic citrullinated peptide antibody titer, CRP, methotrexate dose, glucocorticoid dose, comorbidities estimated by the Rheumatoid Disease Comorbidity Index (RDCI) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], HAQ-DI, and CDAI. Patients in each group were matched one-to-one based on these propensity scores, using a caliper width of 0.2 of the standard deviation of the logit of the propensity score. Balance between the groups was assessed using standardized mean differences, with values\u0026thinsp;\u0026lt;\u0026thinsp;0.1 indicating adequate balance [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. After propensity score matching, the IGU and TAC groups were reduced from 56 and 52 patients, respectively, to 30 patients in each group.\u003c/p\u003e\u003cp\u003eOther statistical analysis\u003c/p\u003e\u003cp\u003ePatient characteristics are expressed as the median with interquartile range (IQR) or n (%) for continuous and categorical variables, respectively. For intra-group comparisons over time (baseline, 12, 24, 36, and 52 weeks), we used the Friedman test followed by the Wilcoxon signed-rank test with Bonferroni correction for post-hoc analyses. After propensity score matching, between-group comparisons were performed using the Mann-Whitney U-test and Fisher\u0026rsquo;s exact test for continuous and categorical variables, respectively. Drug retention rates were compared between the groups using the log-rank test. All statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R software (the R Foundation for Statistical Computing) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicating statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePatient characteristics\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the baseline characteristics of the patients before and after propensity score matching. Before propensity score matching, there were 56 patients in the IGU group and 52 in the TAC group. Demographic characteristics (age, sex, disease duration) and comorbidity index were comparable between groups. However, disease activity measures were higher in the TAC group; for example, the median SDAI score was 11.8 [9.0\u0026ndash;16.0] vs 7.4 [5.9\u0026ndash;10.6] in the IGU group (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and other indices such as CDAI, DAS28-CRP, SJC28, PhGA, HAQ-DI, and CRP levels were consistently higher in the TAC group. To adjust for these differences, propensity score matching was performed. After matching, 30 patients remained in each group, and most baseline characteristics were balanced with standardized mean differences less than 0.1, confirming successful matching and enabling meaningful comparison of treatment outcomes.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics in the IGU and TAC groups before and after propensity score matching\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eBefore propensity score matching\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e\u003cp\u003eAfter propensity score matching\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIGU, n\u0026thinsp;=\u0026thinsp;56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTAC, n\u0026thinsp;=\u0026thinsp;52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIGU, n\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTAC, n\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSMD\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67(59\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e63(59\u0026ndash;73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e67(55\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e66(59\u0026ndash;76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, n (% female)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41(73.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39(75.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23(76.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24(80.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease duration (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20(8\u0026ndash;32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26(9\u0026ndash;128)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e24(8\u0026ndash;68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12(7\u0026ndash;66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRDCI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTX use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56(100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52(100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30(100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30(100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTX dose, mg/w\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10(8\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10(8\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10(8\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10(8\u0026ndash;12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucocorticoid use, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20(35.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21(40.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14(46.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12(40.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucocorticoid dose, mg/day\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0(0\u0026ndash;2.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0\u0026ndash;2.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0(0\u0026ndash;2.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0(0\u0026ndash;3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTJC28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1(0\u0026ndash;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1(0\u0026ndash;2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1(0\u0026ndash;1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSJC28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2(1\u0026ndash;3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(1\u0026ndash;5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2(1\u0026ndash;4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2(1\u0026ndash;4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePGA, 0\u0026ndash;10 scale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.8(1.6\u0026ndash;4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.5(2.1\u0026ndash;5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.1(1.8\u0026ndash;4.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.5(1.9\u0026ndash;5.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhGA, 0\u0026ndash;10 scale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.9(1.0\u0026ndash;2.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.0(1.8\u0026ndash;4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.0(1.2\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.6(1.5\u0026ndash;4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.4(5.9\u0026ndash;10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.8(9.0\u0026ndash;16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8.4(6.0\u0026ndash;12.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10.9(7.8\u0026ndash;15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.8(5.5\u0026ndash;10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.1(8.7\u0026ndash;14.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8.0(5.7\u0026ndash;12.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10.1(7.1\u0026ndash;13.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDAS28-CRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.5(2.1\u0026ndash;3.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.0(2.5\u0026ndash;3.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.8(2.3\u0026ndash;3.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.9(2.4\u0026ndash;3.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHAQ-DI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.19(0\u0026ndash;0.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.31(0.12\u0026ndash;0.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.25(0\u0026ndash;0.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.44(0.12\u0026ndash;0.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.30(0.15\u0026ndash;0.54)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.53(0.25\u0026ndash;1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.36(0.17\u0026ndash;0.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.44(0.21\u0026ndash;0.94)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eESR (mm/hour)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17(12\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24(13\u0026ndash;41)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e26(14\u0026ndash;34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e23(16\u0026ndash;45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMMP-3 (ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e78.6(60.7\u0026ndash;111.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e111.4(62.6\u0026ndash;240.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e91.1(63.4\u0026ndash;111.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e111.4(57.0\u0026ndash;196.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRheumatoid factor positive, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45(80.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41(78.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23(76.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e21(70.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRheumatoid factor (U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38(18\u0026ndash;71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53(18\u0026ndash;135)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e37(12\u0026ndash;56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e35(8\u0026ndash;60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-CCP antibody positive, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41(73.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42(80.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23(76.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e22(73.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-CCP antibody (U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e115(3\u0026ndash;278)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70(9\u0026ndash;312)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e144(9\u0026ndash;242)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e60(4\u0026ndash;413)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eData are median (IQR) or number (%) of patients\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eIGU, iguratimod; TAC, tacrolimus; SMD, standardized mean difference; RDCI, rheumatoid disease comorbidity index; MTX, methotrexate; TJC28, tender joint count using 28 joints; SJC28, swollen joint count using 28 joints; PGA, patient's global assessment; PhGA, physician global assessment; SDAI, Simplified Disease Activity Index, CDAI, Clinical Disease Activity Index; DAS, Disease Activity Score; CRP, C-reactive protein; HAQ-DI, Health Assessment Questionnaire-Disability Index; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; CCP, cyclic citrullinated peptide\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eEfficacy and drug retention in the IGU group\u003c/p\u003e\u003cp\u003eIn the IGU group, the median final dose was 50 mg/day (IQR: 25\u0026ndash;50 mg). The SDAI remission rate increased from 0% at baseline to 39.3% at week 12, then to 41.1% at week 24 and remained stable thereafter. The composite rate of remission and LDA (SDAI\u0026thinsp;\u0026le;\u0026thinsp;11) improved from 78.6% at baseline to 91.1% at week 12, and reached 85.7% by week 52. Correspondingly, the median SDAI score decreased significantly from 7.4 (5.9\u0026ndash;10.6) at baseline to 4.4 (1.5\u0026ndash;8.0) at week 12, with sustained improvement throughout the study period (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all time points compared to baseline) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-A).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRegarding the other outcome measures, including CDAI, TJC28, SJC28, PhGA, and MMP-3, all improved significantly throughout the observation period, whereas HAQ-DI, PGA, CRP, and ESR showed numerical improvements that were not statistically significant (Supplementary Table\u0026nbsp;1). Glucocorticoid dose decreased from 0 (0\u0026ndash;2) mg/day at baseline to 0 (0\u0026ndash;0) mg/day at week 52 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e-B shows the drug retention rate by reason for discontinuation. At 52 weeks, the drug retention rate was 78.6% overall, while the rates were 90.1%, 94.6%, and 92.3% for lack of efficacy, AEs, and other reasons, respectively.\u003c/p\u003e\u003cp\u003eEfficacy and drug retention in the TAC group\u003c/p\u003e\u003cp\u003eIn the TAC group, the median final dose was 2.0 mg/day (IQR: 1.5\u0026ndash;3.0 mg). The SDAI remission rate increased from 0% at baseline to 40.4% at week 12, decreased slightly to 33.7% at week 24 and 34.6% at week 36, then returned to 40.4% at week 52. The composite rate of remission and LDA was 44.2% at baseline, 82.7% at week 12 and 84.6% at week 52. The median SDAI score decreased significantly from 11.8 (9.0\u0026ndash;16.0) at baseline to 4.1 (2.3\u0026ndash;8.1) at week 12 and remained significantly lower thereafter (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for all time points compared to baseline) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-A).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOther outcomes, including CDAI, TJC28, SJC28, PhGA, and CRP, all improved significantly throughout the observation period, whereas ESR showed significant improvement after week 24, HAQ-DI after week 36 and MMP-3 at week 52 (Supplementary Table\u0026nbsp;2). Glucocorticoid dose decreased significantly from 0 (0\u0026ndash;2.5) mg/day at baseline to 0 (0\u0026ndash;0) mg/day at week 52 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e-B illustrates the drug retention rate by reasons; overall retention at week 52 was 73.1%, with rates of 83.6%, 96.0%, and 88.7% for lack of efficacy, AEs, and other reasons, respectively.\u003c/p\u003e\u003cp\u003eSafety outcomes\u003c/p\u003e\u003cp\u003eDuring the 52-week observation period, 51 AEs of CTCAE grade\u0026thinsp;\u0026ge;\u0026thinsp;2 were identified (IGU group: 31 events; TAC group: 20 events). The AEs were diverse with no specific pattern between groups (Supplementary Table\u0026nbsp;3). The most frequently reported AEs were upper respiratory infection (10 cases), anemia (9 cases), oral mucositis (6 cases: 5 grade 2, 1 grade 3), and shingles (4 cases). No grade 4 or 5 AEs occurred in either group. Five grade 3 AEs were reported, all assessed as unrelated to study drugs by treating physicians. Treatment discontinuation due to AEs occurred in 5 patients: 3 in the IGU group (increased creatinine, urticaria, and increased aminotransferase) and 2 in the TAC group (increased creatinine, malaise). All AEs resolved completely without any lasting effects.\u003c/p\u003e\u003cp\u003eComparison of efficacy and drug retention after propensity score matching\u003c/p\u003e\u003cp\u003eThe primary outcome, SDAI remission rate at week 52, showed no significant difference between the IGU and TAC groups (43.3% vs 46.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00). Similarly, other clinical remission criteria, including CDAI remission, Boolean, and Boolean 2.0, were also equivalent between groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-A). Longitudinal changes in SDAI scores decreased significantly from baseline in both groups at weeks 12, 24, 36, and 52, with no significant between-group differences at any time point (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-B). Other disease activity measures and their components (i.e., TJC28, SJC28, PGA, and PhGA) and laboratory parameters also showed no significant between-group differences throughout the study period (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSecondary analyses revealed numerical trends favoring the TAC group in several measures, though without statistical significance (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The TAC group had numerically greater median changes from baseline in SDAI score (5.2 [4.1\u0026ndash;10.2] vs 3.7 [0.1\u0026ndash;5.9], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.09), CDAI score (5.2 [3.4\u0026ndash;10.1] vs 3.7 [0.2\u0026ndash;6.1], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.14), and CRP reduction (0.18 [0.03\u0026ndash;0.69] vs 0.09 [-0.17\u0026ndash;0.30], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.08) compared to the IGU group.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEffectiveness of IGU and TAC groups at 52-week after propensity score matching\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIGU, n\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTAC, n\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enumber (%) at week 52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSDAI LDA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24(80.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29(90.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCDAI LDA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24(80.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29(90.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003echanges from baseline to week 52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.7(0.1\u0026ndash;5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.2(4.1\u0026ndash;10.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCDAI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.7(0.2\u0026ndash;6.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.2(3.4\u0026ndash;10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHAQ-DI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(0\u0026ndash;0.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.12(0\u0026ndash;0.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCRP (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.09(-0.17\u0026ndash;0.30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.18(0.03\u0026ndash;0.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eESR (mm/hr)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3(-3\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6(0\u0026ndash;11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMMP-3 (ng/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.3(-2.9\u0026ndash;51.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30.8(-0.5\u0026ndash;82.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGC dose (mg/day)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0(-0.5\u0026ndash;6.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0(-1.5\u0026ndash;10.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eData are median (IQR) or number (%)\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eIGU, iguratimod; TAC, tacrolimus; SDAI, Simplified Disease Activity Index; CDAI, Clinical Disease Activity Index; HAQ-DI, Health Assessment Questionnaire-Disability Index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MMP-3, matrix metalloproteinase-3; GC, glucocorticoid\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eDrug retention rates were also comparable between groups. Kaplan\u0026ndash;Meier analysis showed no significant difference in 52-week retention rates between the IGU and TAC groups (70.0% vs 76.7%; log-rank test, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.62) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e-C).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective study evaluated the effectiveness and safety of combination therapies with MTX plus either IGU or TAC in patients with RA who failed to achieve remission with MTX monotherapy at doses up to 16 mg/week. Both regimens demonstrated substantial clinical improvements, with SDAI remission rates increasing from 0% at baseline to approximately 40% at week 52, accompanied by significant improvements in SDAI scores and multiple disease activity parameters. Both therapies demonstrated favorable safety profiles, with low discontinuation rates due to adverse events (5.4% for IGU, 4.0% for TAC). After propensity score matching to adjust for baseline differences, SDAI remission rates at week 52 were comparable between the IGU and TAC groups (43.3% vs 46.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00), as were drug retention rates (70.0% vs 76.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.62). While the TAC group showed numerical trends toward greater improvements in SDAI, CDAI, and CRP, these differences did not reach statistical significance.\u003c/p\u003e\u003cp\u003eOne important characteristic of this study is that it included a substantial proportion of patients with LDA at baseline (n\u0026thinsp;=\u0026thinsp;67/108, 62.0%). While numerous clinical studies of MTX-IR populations focus on patients with moderate or high disease activity, data on those with LDA remain scarce. Although LDA is recognized as an acceptable alternative treatment goal, accumulating evidence indicates that long-term outcomes are inferior compared with remission. In the ERAS and ERAN cohorts, patients who achieved remission showed significantly better HAQ scores, quality of life, and radiographic outcomes over 5 years compared with those who remained in LDA, with differences exceeding the minimal clinically important difference [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, in the ESPOIR cohort, sustained remission was associated with markedly less 10-year radiographic progression and better functional outcomes compared with sustained LDA [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These findings underscore that remission, rather than LDA, should remain the primary therapeutic target in RA. This study addresses an important evidence gap regarding optimal treatment strategies for patients with LDA in real-world clinical practice.\u003c/p\u003e\u003cp\u003eOur findings regarding the effectiveness of IGU\u0026thinsp;+\u0026thinsp;MTX are generally consistent with previous reports. Ishiguro et al. demonstrated that IGU\u0026thinsp;+\u0026thinsp;MTX significantly improved disease activity in Japanese patients with MTX-IR patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], showing a higher ACR20 response rate at week 24 compared with placebo (69.5% vs 30.7%). Interestingly, the DAS28 remission rate at week 24 was notably higher in our study (78.6%) than in their report (27.4%). This discrepancy likely reflects differences in baseline disease activity: our cohort had a lower median DAS28-CRP at baseline (2.5 [IQR: 2.1\u0026ndash;3.0]) compared with Ishiguro\u0026rsquo;s population (mean 4.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.89). In addition, the higher MTX doses employed in our study may have also contributed to these favorable outcomes. While Ishiguro et al. used MTX doses of 6 or 8 mg/week, our study had a median dose of 10 mg/week (IQR: 8\u0026ndash;12 mg), reflecting current dosing practices in Japan. IGU exerts immunomodulatory effects by regulating T- and B-cell function and suppressing pro-inflammatory cytokine production via cyclooxygenase-2 and nuclear factor-kappa B pathway suppression [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These mechanisms are distinct from those of MTX [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], suggesting potential synergistic effects when used in combination. Although it seems reasonable to hypothesize that higher MTX doses in combination with IGU would enhance therapeutic efficacy, direct evidence supporting this dose-response relationship remains limited, warranting further investigation.\u003c/p\u003e\u003cp\u003eTAC suppresses T-cell activation through inhibition of the calcineurin pathway, thereby blocking interleukin-2 production [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u0026mdash;a mechanism distinct from that of MTX, providing a rationale for combination therapy. Our results align with previous evidence demonstrating the efficacy of TAC\u0026thinsp;+\u0026thinsp;MTX in MTX-IR patients. Kitahama et al. conducted a large-scale cohort study with propensity score matching, demonstrating that TAC\u0026thinsp;+\u0026thinsp;MTX significantly reduced DAS28 scores versus MTX monotherapy, with an adjusted mean difference of \u0026minus;\u0026thinsp;0.273 over 6 months [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, a retrospective analysis by Morita et al. reported that low-dose TAC\u0026thinsp;+\u0026thinsp;MTX resulted in significant clinical improvement, with 72% of patients achieving a moderate or good EULAR response and over half achieving clinical remission according to DAS28-CRP criteria at 6 months [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Despite variations in dosing regimens and baseline patient characteristics among studies, these findings consistently indicate that combination therapy with TAC\u0026thinsp;+\u0026thinsp;MTX is effective and well-tolerated for MTX-IR patients. Our study contributes to this growing body of evidence by evaluating long-term clinical outcomes over a 52-week period under contemporary treatment standards in Japan, where higher MTX doses up to 16 mg/week are now routinely employed.\u003c/p\u003e\u003cp\u003eDirect comparisons of csDMARD combination therapies for MTX-IR patients remain scarce. A recent retrospective analysis by Nozaki et al. compared IGU\u0026thinsp;+\u0026thinsp;MTX versus salazosulfapyridine\u0026thinsp;+\u0026thinsp;MTX in Japanese MTX-IR patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. After propensity score matching, IGU\u0026thinsp;+\u0026thinsp;MTX was associated with a significantly higher 24-month drug retention rate (67.8% vs 38.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and superior clinical responses, underscoring the importance of selecting appropriate combination partners for MTX. To our knowledge, no previous studies have directly compared IGU\u0026thinsp;+\u0026thinsp;MTX with TAC\u0026thinsp;+\u0026thinsp;MTX in MTX-IR patients. In the present study, both regimens demonstrated comparable efficacy and safety, with similar SDAI remission rates and drug retention at 52 weeks. Notably, TAC\u0026thinsp;+\u0026thinsp;MTX showed numerically greater improvements in SDAI, CDAI, and CRP reduction, though these differences did not reach statistical significance.\u003c/p\u003e\u003cp\u003eBeyond clinical efficacy and safety, several practical factors can influence treatment selection in real-world practice. Although treatment cost was not evaluated in our study, it represents an important determinant in therapeutic decision-making [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Based on current Japanese drug pricing as of 2025, the estimated monthly cost is approximately 35 USD for IGU (50 mg/day) versus 230 USD for TAC (3 mg/day), representing a nearly sevenfold difference. In addition, patient-specific clinical factors warrant careful consideration: TAC requires close monitoring in patients with renal dysfunction or diabetes mellitus [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], whereas IGU is contraindicated for concomitant use with warfarin and should be used with caution in patients with hepatic impairment [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Considering efficacy, safety, and economic aspects together, the selection of csDMARDs in clinical practice should be guided by a comprehensive assessment that includes cost-effectiveness, patient preferences, and comorbidities. Ultimately, shared decision-making between clinicians and patients remains essential in determining the optimal csDMARD combination strategy for MTX-IR patients.\u003c/p\u003e\u003cp\u003eSeveral limitations should be acknowledged when interpreting our findings. First, the retrospective, non-randomized design introduces potential selection and information bias, despite the use of propensity score matching to minimize baseline imbalances. Second, reliance on propensity score methods may not fully adjust for unmeasured confounding. However, sensitivity analyses using inverse probability of treatment weighting yielded results consistent with the primary propensity score matching analysis, showing no statistically significant differences between the IGU and TAC groups across major efficacy endpoints (data not shown). This consistency supports the overall robustness of our conclusions. Third, the single-center setting and the relatively small matched sample (n\u0026thinsp;=\u0026thinsp;30 per group) limit the statistical power and constrain generalizability beyond similar practice settings. The numerical trends favoring TAC in SDAI, CDAI, and CRP reduction, though not statistically significant, may reflect type II error and warrant investigation in larger studies. Finally, because radiographic assessments were not performed, we were unable to evaluate structural joint damage progression, an important long-term outcome in RA management.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, combination therapies with IGU\u0026thinsp;+\u0026thinsp;MTX and TAC\u0026thinsp;+\u0026thinsp;MTX are both effective and well-tolerated treatment options for patients with RA who failed to achieve remission with MTX monotherapy. This study addresses an important evidence gap regarding these combinations under current higher MTX dosing standards in Japan. Both combinations represent valuable therapeutic alternatives that may be considered before escalation to bDMARDs or JAK inhibitors, particularly in patients with low disease activity who may not warrant escalation to advanced therapies, as well as those with safety concerns or economic constraints. When selecting between these csDMARD combinations, clinicians should consider efficacy and safety profiles alongside treatment costs, patient preferences, and comorbidities through shared decision-making. These findings warrant further validation through larger multicenter studies that incorporate radiographic assessments and evaluate long-term structural outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACR: American College of Rheumatology\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;AE: Adverse event\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;bDMARDs: Biological disease-modifying antirheumatic drugs\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CDAI: Clinical Disease Activity Index\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CRP: C-reactive protein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;csDMARDs: Conventional synthetic disease-modifying antirheumatic drugs\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DAS28: Disease Activity Score in 28 joints\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;DAS28-CRP: Disease Activity Score in 28 joints based on C-reactive protein\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ESR: Erythrocyte sedimentation rate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;EULAR: European Alliance of Associations for Rheumatology\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;EZR: Easy R (R-based statistical software)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HAQ: Health Assessment Questionnaire\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HAQ-DI: Health Assessment Questionnaire Disability Index\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IGU: Iguratimod\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;IQR: Interquartile range\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;JAK: Janus kinase\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;LDA: Low disease activity\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MMP-3: Matrix metalloproteinase-3\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MTX: Methotrexate\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MTX-IRs: Methotrexate inadequate responders\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PGA: Patient Global Assessment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;PhGA: Physician Global Assessment\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;RA: Rheumatoid arthritis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;RDCI: Rheumatic Disease Comorbidity Index\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SDAI: Simplified Disease Activity Index\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;SJC28: Swollen joint count (28 joints)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TAC: Tacrolimus\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TJC28: Tender joint count (28 joints)\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments and Funding Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the authors used Claude (Claude 4.5 Sonnet, by Anthropic) to improve readability and to proofread the English text. After using this tool, the authors carefully reviewed and edited the content as needed and take full responsibility for the final version of manuscript. The authors also thank Enago (www.enago.jp) for their English language review.\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicts of interest. No funding was received for this study.\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of Tottori Red Cross Hospital (Approval No. 262) and conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent.\u003c/p\u003e\n\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available doe to privacy and ethical restrictions, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study design and data analysis. They interpreted the results, reviewed the manuscript critically, and approved the final version for publication. All authors take full responsibility for the integrity of the work.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSmolen JS, Breedveld FC, Burmester GR, et al (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75:3\u0026ndash;15. https://doi.org/10.1136/annrheumdis-2015-207524\u003c/li\u003e\n\u003cli\u003eSmolen JS, Landew\u0026eacute; RBM, Bergstra SA, et al (2023) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 82:3\u0026ndash;18. https://doi.org/10.1136/ard-2022-223356\u003c/li\u003e\n\u003cli\u003eHarigai M, Kaneko Y, Tanaka E, et al (2025) 2024 Update of the Japan College of Rheumatology Clinical Practice Guidelines for the Management of Rheumatoid Arthritis: Secondary publication. Mod Rheumatol 35:387\u0026ndash;401. https://doi.org/10.1093/mr/roaf006\u003c/li\u003e\n\u003cli\u003eChatzidionysiou K, Sfikakis PP (2019) Low rates of remission with methotrexate monotherapy in rheumatoid arthritis: review of randomised controlled trials could point towards a paradigm shift. RMD Open 5:e000993. https://doi.org/10.1136/rmdopen-2019-000993\u003c/li\u003e\n\u003cli\u003eHarigai M, Sugihara T (2025) Management of Late-Onset Rheumatoid Arthritis with Treat-to-Target Strategy. Drugs Aging 42:413\u0026ndash;433. https://doi.org/10.1007/s40266-025-01195-4\u003c/li\u003e\n\u003cli\u003eThomas K, Lazarini A, Kaltsonoudis E, et al (2021) Incidence, risk factors and validation of the RABBIT score for serious infections in a cohort of 1557 patients with rheumatoid arthritis. Rheumatol Oxf Engl 60:2223\u0026ndash;2230. https://doi.org/10.1093/rheumatology/keaa557\u003c/li\u003e\n\u003cli\u003evan Vollenhoven RF, Geborek P, Forslind K, et al (2012) Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet Lond Engl 379:1712\u0026ndash;1720. https://doi.org/10.1016/S0140-6736(12)60027-0\u003c/li\u003e\n\u003cli\u003eMatsuno H, Okada M, Sakai Y, et al (2016) The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis. Mod Rheumatol 26:51\u0026ndash;6. https://doi.org/10.3109/14397595.2015.1059984\u003c/li\u003e\n\u003cli\u003eIshiguro N, Yamamoto K, Katayama K, et al (2013) Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial. Mod Rheumatol 23:430\u0026ndash;9. https://doi.org/10.1007/s10165-012-0724-8\u003c/li\u003e\n\u003cli\u003eKawai S, Takeuchi T, Yamamoto K, et al (2011) Efficacy and safety of additional use of tacrolimus in patients with early rheumatoid arthritis with inadequate response to DMARDs--a multicenter, double-blind, parallel-group trial. Mod Rheumatol 21:458\u0026ndash;68. https://doi.org/10.1007/s10165-011-0425-8\u003c/li\u003e\n\u003cli\u003eHara M, Ishiguro N, Katayama K, et al (2014) Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: an open-label extension of a randomized, double-blind, placebo-controlled trial. Mod Rheumatol 24:410\u0026ndash;8. https://doi.org/10.3109/14397595.2013.843756\u003c/li\u003e\n\u003cli\u003eNozaki Y, Oribe M, Tomita D, et al (2023) Iguratimod versus salazosulfapyridine in rheumatoid arthritis patients with an inadequate response to methotrexate: Adjusted with propensity score matching. Mod Rheumatol 33:472\u0026ndash;480. https://doi.org/10.1093/mr/roac060\u003c/li\u003e\n\u003cli\u003eFelson DT, Smolen JS, Wells G, et al (2011) American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 70:404\u0026ndash;13. https://doi.org/10.1136/ard.2011.149765\u003c/li\u003e\n\u003cli\u003eAletaha D, Neogi T, Silman AJ, et al (2010) 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 62:2569\u0026ndash;81. https://doi.org/10.1002/art.27584\u003c/li\u003e\n\u003cli\u003eStudenic P, Aletaha D, de Wit M, et al (2023) American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision. Ann Rheum Dis 82:74\u0026ndash;80. https://doi.org/10.1136/ard-2022-223413\u003c/li\u003e\n\u003cli\u003eEngland BR, Sayles H, Mikuls TR, et al (2015) Validation of the rheumatic disease comorbidity index. Arthritis Care Res Hoboken 67:865\u0026ndash;72. https://doi.org/10.1002/acr.22456\u003c/li\u003e\n\u003cli\u003eAustin PC (2011) An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivar Behav Res 46:399\u0026ndash;424. https://doi.org/10.1080/00273171.2011.568786\u003c/li\u003e\n\u003cli\u003eKanda Y (2013) Investigation of the freely available easy-to-use software \u0026ldquo;EZR\u0026rdquo; for medical statistics. Bone Marrow Transplant 48:452\u0026ndash;458. https://doi.org/10.1038/bmt.2012.244\u003c/li\u003e\n\u003cli\u003eNikiphorou E, Norton SJ, Carpenter L, et al (2019) Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network. Rheumatol Oxf. https://doi.org/10.1093/rheumatology/kez461\u003c/li\u003e\n\u003cli\u003eRuyssen-Witrand A, Guernec G, Dupont J, et al (2023) Ten-year radiographic and functional outcomes in rheumatoid arthritis patients in remission compared to patients in low disease activity. Arthritis Res Ther 25:207. https://doi.org/10.1186/s13075-023-03176-7\u003c/li\u003e\n\u003cli\u003eLong Z, Zeng L, He Q, et al (2023) Research progress on the clinical application and mechanism of iguratimod in the treatment of autoimmune diseases and rheumatic diseases. Front Immunol 14:1150661. https://doi.org/10.3389/fimmu.2023.1150661\u003c/li\u003e\n\u003cli\u003eCronstein BN, Aune TM (2020) Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 16:145\u0026ndash;154. https://doi.org/10.1038/s41584-020-0373-9\u003c/li\u003e\n\u003cli\u003eDutta S, Ahmad Y (2011) The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther Adv Musculoskelet Dis 3:283\u0026ndash;291. https://doi.org/10.1177/1759720X11419038\u003c/li\u003e\n\u003cli\u003eKitahama M, Nakajima A, Inoue E, et al (2013) Efficacy of adjunct tacrolimus treatment in patients with rheumatoid arthritis with inadequate responses to methotrexate. Mod Rheumatol 23:788\u0026ndash;93. https://doi.org/10.1007/s10165-012-0745-3\u003c/li\u003e\n\u003cli\u003eMorita Y, Sasae Y, Sakuta T, et al (2008) Efficacy of low-dose tacrolimus added to methotrexate in patients with rheumatoid arthritis in Japan: a retrospective study. Mod Rheumatol 18:379\u0026ndash;84. https://doi.org/10.1007/s10165-008-0071-y\u003c/li\u003e\n\u003cli\u003eSingh JA, Tornberg H, Goodman SM (2021) Pop a pill or give myself a shot? Patient perspectives of disease-modifying anti-rheumatic drug choice for rheumatoid arthritis. Joint Bone Spine 88:105053. https://doi.org/10.1016/j.jbspin.2020.07.002\u003c/li\u003e\n\u003cli\u003eTakeuchi T, Kawai S, Yamamoto K, et al (2014) Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis. Mod Rheumatol 24:8\u0026ndash;16. https://doi.org/10.3109/14397595.2013.854074\u003c/li\u003e\n\u003cli\u003eShibata K, Yoshimura A, Ikeuchi S, Ishii M (2021) Effectiveness of drug safety measures for reducing the incidence of adverse drug reactions: Post-hoc analysis of data from all-case surveillance of iguratimod using generalized estimating equations. PloS One 16:e0253513. https://doi.org/10.1371/journal.pone.0253513\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"iguratimod, tacrolimus, methotrexate, rheumatoid arthritis, remission","lastPublishedDoi":"10.21203/rs.3.rs-8026013/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8026013/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTo evaluate the efficacy and safety of combination therapy with iguratimod (IGU) versus tacrolimus (TAC) plus methotrexate (MTX) in patients with rheumatoid arthritis (RA) who failed to achieve remission with MTX monotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis retrospective, single-centre study included RA patients treated with IGU\u0026thinsp;+\u0026thinsp;MTX (n\u0026thinsp;=\u0026thinsp;56) and TAC\u0026thinsp;+\u0026thinsp;MTX (n\u0026thinsp;=\u0026thinsp;52). Propensity score matching generated two balanced cohorts (n\u0026thinsp;=\u0026thinsp;30 per group). The primary endpoint was the Simplified Disease Activity Index (SDAI) remission rate at week 52. Secondary outcomes included disease activity parameters, drug retention rates, and safety profiles over 52 weeks.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBoth regimens substantially improved disease activity from baseline. In the matched analysis, SDAI remission rates at week 52 were similar between IGU and TAC (43.3% vs 46.7%, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;1.00), as were drug retention rates (70.0% vs 76.7%, \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.62). The TAC group showed numerically larger reductions in SDAI, Clinical Disease Activity Index, and C-reactive protein, though these differences were not statistically significant. Treatment discontinuations due to adverse events were infrequent, and both combinations were well tolerated.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCombination therapies with IGU\u0026thinsp;+\u0026thinsp;MTX and TAC\u0026thinsp;+\u0026thinsp;MTX are both effective and safe treatment options for RA patients who failed to achieve remission with MTX monotherapy. These findings support the use of conventional synthetic disease-modifying anti-rheumatic drug combinations as valuable alternatives for MTX-inadequate responders, particularly those with low disease activity, safety concerns, or economic constraints.\u003c/p\u003e","manuscriptTitle":"Add-on Iguratimod or Tacrolimus in Methotrexate Inadequate Rheumatoid Arthritis: Efficacy, Safety and Propensity Score-Matched Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-23 11:51:10","doi":"10.21203/rs.3.rs-8026013/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-15T17:59:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-13T08:36:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"43896853586953278057037416938253257423","date":"2025-12-10T08:05:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-09T07:51:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110446168417140873328364083844220324824","date":"2025-12-08T07:04:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198349565773663748677815219128727341263","date":"2025-11-27T12:37:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-12T03:04:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-07T17:32:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-06T10:59:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-06T10:56:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Rheumatology","date":"2025-11-04T07:45:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2dc1e4a-488d-46e3-bc38-9366138e6b07","owner":[],"postedDate":"November 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T16:03:45+00:00","versionOfRecord":{"articleIdentity":"rs-8026013","link":"https://doi.org/10.1186/s41927-025-00611-x","journal":{"identity":"bmc-rheumatology","isVorOnly":false,"title":"BMC Rheumatology"},"publishedOn":"2025-12-30 15:57:00","publishedOnDateReadable":"December 30th, 2025"},"versionCreatedAt":"2025-11-23 11:51:10","video":"","vorDoi":"10.1186/s41927-025-00611-x","vorDoiUrl":"https://doi.org/10.1186/s41927-025-00611-x","workflowStages":[]},"version":"v1","identity":"rs-8026013","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8026013","identity":"rs-8026013","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}