Mode of action- and cause-specific drug retention of b/tsDMARDs in anti-SS-A antibody-positive rheumatoid arthritis: the ANSWER cohort study

Mode of action- and cause-specific drug retention of b/tsDMARDs in anti-SS-A antibody-positive rheumatoid arthritis: the ANSWER cohort study | 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 Article Mode of action- and cause-specific drug retention of b/tsDMARDs in anti-SS-A antibody-positive rheumatoid arthritis: the ANSWER cohort study Kazuma Nishisaka, Takaichi Okano, Takumi Imai, Masanori Tsubosaka, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7669680/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Mar, 2026 Read the published version in PLOS ONE → Version 1 posted You are reading this latest preprint version Abstract Background To investigate drug retention by mode of action (MOA) and cause in rheumatoid arthritis (RA) patients with or without anti-SS-A antibodies using a multicenter registry. Methods We retrospectively analyzed the ANSWER cohort in Japan. Patients with RA who started or switched biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) between 2011 and 2024 and had baseline anti-SS-A antibody testing were included. Propensity score matching balanced baseline characteristics. Kaplan–Meier and competing risk analyses were conducted, and hazard ratios (HRs) were estimated using Cox proportional hazards models. Results After matching, 507 treatment courses from 255 anti-SS-A antibody-positive and 1,014 from 628 antibody-negative patients were analyzed. Anti-SS-A antibody positivity was not associated with overall b/tsDMARD retention (HR 1.07, 95% CI 0.91–1.26, p = 0.382). In MOA-stratified analyses, positivity showed a trend toward increased discontinuation with IL-6 receptor inhibitors and CTLA4-Ig. In cause-specific analyses, discontinuation due to adverse events was significantly more frequent in antibody-positive patients (HR 1.72, 95% CI 1.23–2.42, p = 0.002). Among adverse event-related discontinuations, positivity was associated with higher risks with IL-6 receptor inhibitors (HR 2.39, 95% CI 1.21–4.69, p = 0.01) and TNF inhibitors (HR 1.87, 95% CI 1.11–3.14, p = 0.02), but not with CTLA4-Ig or JAK inhibitors. Conclusion Anti-SS-A antibody-positive RA patients had greater risk of discontinuation due to adverse events, particularly with IL-6 receptor inhibitors and TNF inhibitors. These findings underscore the importance of considering MOA and discontinuation causes when selecting therapies. Health sciences/Diseases Biological sciences/Immunology Health sciences/Medical research Health sciences/Rheumatology Rheumatoid arthritis Antirheumatic agents Interleukin-6 receptor inhibitors Tumor necrosis factor inhibitors Drug retention Anti-SS-A antibody Figures Figure 1 Figure 2 Figure 3 Background Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction and disability [ 1 – 5 ]. The advent of biologic and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) has markedly improved clinical outcomes in RA, providing additional therapeutic options for patients who do not respond adequately to conventional treatments [ 6 – 9 ]. However, the treatment response and drug retention rates for biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) vary among individuals. Anti-SS-A (Ro) antibody-positive RA constitutes a clinically important subgroup [ 10 – 12 ]. Approximately 20% of Japanese patients with RA are positive for anti-SS-A antibodies, with frequent overlap with Sjögren disease (SjD) [ 13 ]. Recent studies have indicated that anti-SS-A antibody-positive patients may be more difficult to treat than antibody-negative patients because of a reduced response to methotrexate monotherapy and less improvement in subjective symptoms [ 14 ]. However, the effect of anti-SS-A antibodies on the efficacy and retention of b/tsDMARDs, especially across different modes of action (MOA), has not been thoroughly investigated. Some reports suggest that tumor necrosis factor (TNF) inhibitors may be less effective in anti-SS-A antibody-positive RA [ 15 – 17 ], but limited data are available on retention and reasons for discontinuation of other b/tsDMARDs. To address this knowledge gap, we analyzed a large multicenter registry to compare drug retention among patients with RA with or without anti-SS-A antibodies, with a particular focus on MOA and reasons for discontinuation. Methods Study Design and Participants We conducted a retrospective observational study using data from the ANSWER cohort (Kansai Consortium for Well-being of Rheumatic Disease Patients), a multicenter registry in Japan. We included all patients with RA who initiated or switched to b/tsDMARDs between 2011 and 2024 and had anti-SS-A antibody testing at baseline. Patients could contribute multiple treatment courses if they initiated or switched to a different b/tsDMARD during the study period. For each treatment course, baseline was defined at the time of drug initiation or switching, and demographic and clinical data were collected at each baseline or within 90 days before. RA was diagnosed according to the 1987 ACR classification criteria [ 18 ] or the 2010 ACR/EULAR criteria [ 19 ]. Anti-SS-A antibody positivity was defined as a titer ≥ 10 U/mL by Enzyme-Linked Immunosorbent Assay (ELISA) or Chemiluminescent Enzyme Immunoassay (CLEIA) or ≥ 1 by double immunodiffusion (DID). To ensure data quality, the analysis was restricted to four facilities with a Clinical Disease Activity Index (CDAI) missing data rate below 30%. Follow-up was defined from the date of drug initiation to the earliest of 24 months, loss to follow-up, drug discontinuation (including switching to another agent), or death. Exposure and Outcomes The patients were divided into two groups based on the presence or absence of anti-SS-A antibodies. The primary outcome was the overall retention of all b/tsDMARDs. Secondary outcomes included drug retention stratified by (1) mode of action (MOA) of b/tsDMARDs and (2) reason for discontinuation (ineffectiveness, adverse events, and remission). The b/tsDMARDs analyzed included TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, ozoralizumab, and their biosimilars), interleukin-6 (IL-6) receptor inhibitors (tocilizumab and sarilumab), cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig: abatacept), and Janus kinase (JAK) inhibitors (baricitinib, tofacitinib, peficitinib, upadacitinib, and filgotinib). Statistical Analysis Overall drug retention, including all reasons for discontinuation, was visualized using the Kaplan–Meier method. A competing risks framework was used for the analysis stratified by reason for discontinuation, utilizing cumulative incidence functions. In this framework, alternative reasons for discontinuation are treated as competing events. Analyses were conducted at the treatment-course level, as patients could contribute multiple treatment courses. Hazard ratios (HRs) for drug discontinuation were estimated using Cox proportional hazards models, with robust variance estimates clustered by matching design and patient. To adjust for potential confounding factors, propensity score matching was conducted using the following covariates: age, sex, disease duration, glucocorticoid dosage (prednisolone equivalent), methotrexate (MTX) dosage, seropositivity (rheumatoid factor [RF], anti-citrullinated peptide antibody [ACPA]), CDAI, radiographic stage, functional class, MOA of b/tsDMARDs, and the number of prior b/tsDMARDs. Matching was performed using the nearest-neighbor method in a 1:2 ratio (one anti-SS-A antibody-positive case to two anti-SS-A antibody-negative cases). Post-matching covariate balance was assessed using standardized mean differences (SMD), with values below 0.2 considered acceptable. For variables with missing data, multiple imputations by chained equations (MICE) was used. A total of 100 imputed datasets were created and combined according to Rubin's rules using Within approach [ 20 ]. All statistical analyses were performed using R, version 4.4.3. Results Baseline Characteristics A total of 2,703 treatment courses from 1,452 patients were included in the analysis (Fig. 1 ). Among these, 507 treatment courses were from 255 anti-SS-A antibody-positive patients and 2,196 courses were from 1,197 antibody-negative patients (Table 1 and Supplementary Table 1). Before matching, notable differences were observed between the groups for variables such as age, sex, seropositivity (RF, ACPA), and prior b/tsDMARD exposure, with several covariates showing SMDs greater than 0.2. After propensity score matching, the matched dataset included 507 treatment courses from 255 anti-SS-A antibody-positive patients and 1,014 courses from 628 antibody-negative patients. The covariate balance was substantially improved, with SMDs for all variables reduced to below 0.2. Overall Drug Retention Rate of b/tsDMARDs Kaplan–Meier curves demonstrated a similar pattern of overall b/tsDMARD retention between the antibody-positive and -negative groups over the two-year period (Fig. 2 ). In Cox proportional hazards models, anti-SS-A antibody positivity was not associated with overall b/tsDMARD retention (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 0.91–1.26; p = 0.382). Drug Retention by Mode of Action Next, we analyzed the risk of drug discontinuation according to the MOA of b/tsDMARDs (Fig. 3 A). Among these, in terms of point estimates, anti-SS-A antibody positivity showed a trend toward an increased risk of discontinuation in IL-6 receptor inhibitor and CTLA4-Ig users, whereas the association between anti-SS-A antibody positivity and the risk of discontinuation appeared weaker in TNF inhibitor and JAK inhibitor users; none of these associations reached statistical significance (Table 2 A). These finding indicate that IL-6 receptor inhibitors or CTLA4-Ig might reduce the retention rates in anti-SS-A antibody-positive RA patients. Cause-Specific b/tsDMARDs Retention We examined the risk of b/tsDMARD discontinuation according to the reason for treatment termination. For each reason, the cumulative incidence functions of drug discontinuation in the antibody-positive and antibody-negative groups are presented in Fig. 3 B. Discontinuation due to adverse events was significantly more frequent in the anti-SS-A antibody-positive group (cause-specific HR: 1.72, 95% CI: 1.23–2.42, p = 0.002). In contrast, no significant differences were observed in discontinuation due to ineffectiveness or remission (Table 2 B). These findings suggest that anti-SS-A antibody positivity is specifically associated with an increased risk of discontinuation owing to adverse events. MOA-Stratified Risks of Discontinuations due to Adverse Events In the analysis restricted to the outcome of discontinuations due to adverse events, anti-SS-A antibody-positive patients exhibited a significantly higher risk of discontinuation when treated with IL-6 receptor inhibitors (cause-specific HR: 2.39, 95% CI: 1.21–4.69, p = 0.012) or TNF inhibitors (HR: 1.87, 95% CI: 1.11–3.14, p = 0.019) than antibody-negative patients (Table 2 C, Fig. 3 C). In contrast, no significant difference in the adverse event-related discontinuation risk was observed for CTLA4-Ig or JAK inhibitors. Discussion This study is the first large multicenter investigation to comprehensively evaluate b/tsDMARD retention in anti-SS-A antibody-positive RA patients. The overall retention rate of b/tsDMARDs was similar between the antibody-positive and antibody-negative groups. In MOA-stratified analyses, anti-SS-A antibody positivity showed a trend toward increased discontinuation with IL-6 receptor inhibitors and CTLA4-Ig. Cause-specific analyses revealed that discontinuation due to adverse events was significantly more frequent in anti-SS-A antibody-positive patients, with an especially increased risk observed among those treated with IL-6 receptor inhibitors and TNF inhibitors. These findings highlight that treatment tolerability, rather than overall efficacy, may be a key determinant of drug survival in this subgroup. Previous reports have assessed the impact of anti-SS-A antibodies in patients receiving specific agents such as TNF inhibitors or abatacept [ 15 , 21 ]. However, few studies have systematically examined treatment retention across drug classes while distinguishing among various causes of discontinuation, including adverse events and ineffectiveness. The present study further demonstrated that the risk of discontinuation due to adverse events may differ by drug class in anti-SS-A antibody-positive patients, providing novel insights into treatment tolerability in this subset. Our analysis showed a trend toward an increased discontinuation risk among anti-SS-A antibody-positive patients treated with IL-6 receptor inhibitors. Previous studies have reported the favorable efficacy of IL-6 receptor inhibitors in this population [ 17 ]. In contrast, our analysis, which focused on reasons for discontinuation, demonstrated greater heterogeneity in treatment response and tolerability. These results suggest that anti-SS-A antibody-positive patients may be more susceptible to adverse effects of IL-6 receptor inhibitors despite their clinical efficacy. Cause-specific analysis revealed a significantly higher risk of discontinuation due to adverse events in the anti-SS-A antibody-positive group. This increased risk was especially apparent with the use of IL-6 receptor inhibitors and TNF inhibitors. Immune dysregulation and autoantibody production may contribute to the greater frequency of drug-related adverse events in this subgroup [ 16 ]. Previous studies have similarly reported that adverse events are a leading cause of TNF inhibitor discontinuation in RA patients [ 22 – 25 ]. Anti-SS-A antibody-positive RA often overlaps with Sjögren disease (SjD), which is characterized by sicca symptoms and extra-articular involvement [ 26 , 27 ]. These features may contribute to the increased susceptibility to adverse events and subsequent treatment discontinuation, particularly with IL-6 receptor inhibitors and TNF inhibitors. Conversely, we did not observe a significantly increased risk of adverse event-related discontinuation of CTLA4-Ig or JAK inhibitors. Previous studies have suggested favorable efficacy and retention of abatacept in anti-SS-A antibody-positive RA patients [ 21 ], and favorable tolerability of these agents in patients with autoimmune overlap [ 28 – 31 ]. The ROSE trial also demonstrated the clinical benefit and tolerability of CTLA4-Ig in RA patients with associated SjD, including those positive for anti-SS-A antibodies [ 32 – 34 ]. Our analysis did not detect an increased risk of discontinuation due to adverse events associated with JAK inhibitors in anti-SS-A antibody-positive patients. However, this finding should be interpreted with caution because few clinical studies have specifically addressed the safety and efficacy of JAK inhibitors in this subgroup. Most available evidence is derived from preclinical studies, which have shown that JAK inhibitors may modulate key pathogenic pathways, such as interferon signaling and autophagy, in both RA and SjD [ 35 ]. Further clinical research is needed to establish the safety profile of JAK inhibitors in anti-SS-A antibody-positive RA patients. From a clinical perspective, these findings suggest that anti-SS-A antibody status may be an important factor to consider when selecting b/tsDMARDs for RA patients. In antibody-positive patients, especially those with comorbidities that may increase susceptibility to adverse events (e.g., sicca symptoms or other extra-articular manifestations), the use of IL-6 receptor inhibitors or TNF inhibitors may require closer monitoring and careful risk–benefit assessment. Conversely, CTLA4-Ig or JAK inhibitors may represent reasonable alternatives in this subgroup, given the absence of a significantly increased risk of adverse event-related discontinuation in our study. Given that treatment decisions are individualized, incorporating serological profiles such as anti-SS-A antibody status into therapeutic planning may help optimize drug retention and minimize discontinuation due to adverse events. The strengths of this study include the use of a large multicenter registry, the simultaneous evaluation of both MOA-stratified and cause-specific drug retention, and the rigorous adjustment for confounders using propensity score matching and multiple imputation. However, as this was a retrospective observational study, residual confounding by unmeasured factors such as the severity of overlapping SjD, antibody titers, or infection risk factors could not be entirely excluded. The reasons for discontinuation were based on clinician assessment rather than standardized criteria. Therefore, the decision to stop or switch between b/tsDMARDs depends on the individual’s clinical judgment. Anti-SS-A antibody titers and SjD diagnoses were not uniformly recorded. The cohort was limited to facilities with adequate CDAI data, which may have affected the generalizability. Conclusion This multicenter study comprehensively evaluated MOA- and cause-specific b/tsDMARD retention in anti-SS-A antibody-positive RA patients. Overall retention rates were similar between antibody-positive and -negative groups. Discontinuation due to adverse events was significantly more common in antibody-positive patients. Among discontinuations due to adverse events, higher risks were observed with IL-6 receptor inhibitors and TNF inhibitors, but not with CTLA4-Ig or JAK inhibitors. These findings suggest that, in anti-SS-A antibody-positive RA, treatment tolerability rather than overall efficacy may be a key factor influencing drug survival, and that anti-SS-A antibody status may help inform therapeutic decision-making. Abbreviations Ab antibody ACPA anti-citrullinated peptide antibody bDMARDs biologic disease-modifying antirheumatic drugs b/tsDMARDs biologic and targeted synthetic disease-modifying antirheumatic drugs CDAI Clinical Disease Activity Index CI confidence interval CTLA4-Ig cytotoxic T lymphocyte-associated antigen 4-immunoglobulin DMARDs disease-modifying antirheumatic drugs HR hazard ratio IL6i interleukin-6 receptor inhibitors JAKi Janus kinase inhibitors MOA mode of action MTX methotrexate PSL prednisolone RA rheumatoid arthritis RF rheumatoid factor TNFi tumor necrosis factor inhibitors tsDMARDs targeted synthetic disease-modifying antirheumatic drugs. Declarations Ethics approval and consent to participate This multicenter observational study utilized data from the ANSWER cohort (Kansai Consortium for Well-being of Rheumatic Disease Patients) and was conducted in accordance with the Declaration of Helsinki and relevant national guidelines. The study protocol was reviewed and approved by the Ethics Review Committee of Osaka Metropolitan University (approval No. 2023-053; 25 July 2023). Written informed consent was obtained from patients currently under treatment. For patients who had already transferred to other hospitals or clinics, consent was obtained through an opt-out process via public postings on the participating hospitals’ websites. Consent for publication Not applicable. Competing interests TI has received speaking fees from Eisai Co., Ltd. KM has received speaking fees from AbbVie GK, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences K.K., Janssen Pharmaceutical K.K., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., and UCB Japan Co., Ltd. KT has received speaking fees from AYUMI Pharmaceutical Corporation. MH has received research grants and speaking fees from Asahi Kasei Corporation, Astellas Pharma Inc., AstraZeneca K.K., AYUMI Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and UCB Japan Co., Ltd. TK has received speaking fees from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Nippon Boehringer Ingelheim Co., Ltd. YS has received speaking fees from Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Eisai Co., Ltd., and AbbVie GK. YN has received speaking fees from AbbVie GK, Astellas Pharma Inc., Asahi Kasei Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., and Mitsubishi Tanabe Pharma Corporation. HY has received speaking fees from AbbVie GK, Asahi Kasei Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Gilead Sciences K.K., and Taiho Pharmaceutical Co., Ltd. KN has received speaking fees from Janssen Pharmaceutical K.K., Taisho Pharmaceutical Co., Ltd., UCB Japan Co., Ltd., AYUMI Pharmaceutical Corporation, Asahi Kasei Corporation, and Pfizer Japan Inc. YU has received speaking fees from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Eisai Co., Ltd., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., and Taisho Pharmaceutical Co., Ltd. SS has received speaking fees from AbbVie GK, Eli Lilly Japan K.K., UCB Japan Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., Pfizer Japan Inc., Asahi Kasei Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. JS has received research grants from Asahi Kasei Corporation, AbbVie GK, and Chugai Pharmaceutical Co., Ltd., and personal fees from Asahi Kasei Corporation, AbbVie GK, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Eisai Co., Ltd., Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation. All other authors have declared no conflicts of interests. Authors’ information (optional) The authors are clinicians and researchers affiliated with the participating departments listed under “Authors and affiliations.” Kazuma Nishisaka is a graduate student and Takaichi Okano is a lecturer in the Department of Rheumatology and Clinical Immunology at Kobe University Graduate School of Medicine. Funding The study reported in this publication uses ANSWER Cohort supported by grants from 12 pharmaceutical companies (AbbVie GK, Asahi Kasei, Ayumi, Chugai, Eisai, Eli Lilly Japan K.K., Janssen K.K., Ono, Sanofi K.K., Taisho, Teijin Healthcare, and UCB Japan). This study was conducted as an investigator-initiated study. These companies have no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Author Contribution KN performed the data analysis, interpreted the results, and drafted the manuscript. TO supervised the study and provided critical revision of the manuscript. All authors contributed to the data collection, reviewed the manuscript for important intellectual content, and approved the final version. Acknowledgement We thank all the medical staff at the participating institutions of the ANSWER cohort for their support and for providing the data used in this study. Data Availability The datasets generated and/or analyzed during the current study are not publicly available. Patients did not provide consent for raw data sharing during data collection. All aggregated data relevant to the study are provided in this article and its additional file(s). Further information is available from the corresponding author on reasonable request and subject to institutional approvals. References Wu, S. et al. Macrophage polarization regulates the pathogenesis and progression of autoimmune diseases. Autoimmun. Rev. 24 (7), 103820. 10.1016/j.autrev.2025.103820 (2025). Epub 2025 Apr 21. Laraib, I., Qasim, S., Uttra, A. M. & Ahmed, S. R. 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Efficacy and safety of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis: ROSE trial—an open-label, one-year, prospective study—interim analysis of 32 patients for 24 weeks. Mod. Rheumatol. 25 (2), 187–193. 10.3109/14397595.2014.951144 (2015). Epub 2014 Sep 11. Barrera, M. J. et al. Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjögren's syndrome. Rheumatol. (Oxford) . 60 (4), 1951–1962. 10.1093/rheumatology/keaa670 (2021). Tables Table 1. Baseline characteristics of treatment courses before and after propensity score matching. Before Matching After Matching Variable Overall anti-SS-A antibody Difference Overall anti-SS-A antibody Difference Negative Positive Negative Positive N = 2,703 N = 2,196 N = 507 N = 1,521 N = 1,014 N = 507 Age (years) 59 ± 16 60 ± 16 55 ± 15 0.34 55 ± 16 55 ± 16 55 ± 15 0.00 Sex 0.57 0.06 Male 475 (18%) 459 (21%) 16 (3.2%) 59 (3.9%) 43 (4.2%) 16 (3.2%) Female 2,228 (82%) 1,737 (79%) 491 (97%) 1,462 (96%) 971 (96%) 491 (97%) Disease Duration (months) 113 ± 118 112 ± 122 117 ± 103 -0.05 112 ± 108 110 ± 110 117 ± 103 -0.07 PSL (mg/day) 2.0 ± 5.9 2.0 ± 6.3 2.1 ± 3.9 -0.01 2.1 ± 6.9 2.1 ± 8.0 2.1 ± 3.9 0.00 MTX (mg/week) 3.7 ± 5.0 3.7 ± 4.8 3.8 ± 5.8 -0.03 4.0 ± 5.3 4.0 ± 5.0 3.8 ± 5.8 0.04 RF positive 1,941 (73%) 1,525 (71%) 416 (85%) -0.35 1,285 (84%) 852 (84%) 433 (85%) -0.04 ACPA positive 1,947 (77%) 1,551 (75%) 396 (86%) -0.30 1,305 (86%) 867 (86%) 438 (86%) -0.03 b/tsDMARDs Line 2 ± 2 2 ± 2 2 ± 2 -0.16 2 ± 2 2 ± 2 2 ± 2 -0.05 CDAI 17 ± 11 17 ± 11 17 ± 12 -0.01 16 ± 11 16 ± 11 17 ± 11 -0.02 Stage -0.10 -0.03 1 827 (37%) 693 (38%) 134 (30%) 527 (35%) 369 (36%) 158 (31%) 2 584 (26%) 462 (25%) 122 (28%) 375 (25%) 237 (23%) 138 (27%) 3 323 (14%) 238 (13%) 85 (19%) 241 (16%) 145 (14%) 96 (19%) 4 529 (23%) 430 (24%) 99 (23%) 378 (25%) 263 (26%) 115 (23%) Class 0.12 -0.01 1 650 (28%) 520 (28%) 130 (29%) 495 (33%) 342 (34%) 153 (30%) 2 1,181 (51%) 930 (50%) 251 (56%) 773 (51%) 494 (49%) 279 (55%) 3 434 (19%) 376 (20%) 58 (13%) 237 (16%) 168 (17%) 69 (14%) 4 33 (1.4%) 27 (1.5%) 6 (1.3%) 16 (1.1%) 10 (1.0%) 6 (1.2%) b/tsDMARDs 0.07 0.05 TNFi 1,327 (49%) 1,090 (50%) 237 (47%) 735 (48%) 498 (49%) 237 (47%) IL6i 620 (23%) 495 (23%) 125 (25%) 360 (24%) 235 (23%) 125 (25%) CTLA4-Ig 368 (14%) 300 (14%) 68 (13%) 194 (13%) 126 (12%) 68 (13%) JAKi 388 (14%) 311 (14%) 77 (15%) 232 (15%) 155 (15%) 77 (15%) Values are presented as mean ± standard deviation (SD) for continuous variables, and n (%) for categorical variables. “Difference” indicates the standardized mean difference (SMD) between anti-SS-A antibody-positive and -negative groups. “Before matching” and “After matching” refer to the datasets prior to and following propensity score matching, respectively. Baseline was defined at the initiation or switching of each biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Propensity scores were calculated using the following covariates: age, sex, disease duration, glucocorticoid dosage, methotrexate dosage, seropositivity (RF, ACPA), CDAI, radiographic stage, functional class, mode of action (MOA) of b/tsDMARDs, and the number of prior b/tsDMARDs. For presentation, Table 1 displays one representative dataset from the 100 multiply imputed datasets. Similar trends were observed across the other imputed datasets, with all post-matching SMDs < 0.20. Abbreviations : ACPA, anti-citrullinated peptide antibody; b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs; CDAI, Clinical Disease Activity Index; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen 4-immunoglobulin; DMARDs, disease-modifying antirheumatic drugs; IL6i, interleukin-6 receptor inhibitors; JAKi, Janus kinase inhibitors; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor; TNFi, tumor necrosis factor inhibitors. Table 2. Hazard ratios for b/tsDMARD discontinuation in RA patients with or without anti-SS-A antibodies. Table 2A. Discontinuation risk by mode of action. MOA HR 95% CI p value TNFi 0.86 [0.68–1.10] 0.226 IL6i 1.38 [1.00–1.91] 0.053 CTLA4-Ig 1.40 [0.92–2.11] 0.114 JAKi 1.13 [0.74–1.72] 0.562 Table 2B. Cause-specific discontinuation risk. Cause cause-specific HR 95% CI p value Adverse Events 1.72 [1.23–2.42] 0.002 Ineffectiveness 0.96 [0.77–1.19] 0.692 Remission 0.69 [0.30–1.57] 0.382 Table 2C. Discontinuation risk due to adverse events by mode of action. MOA cause-specific HR 95% CI p value TNFi 1.87 [1.11–3.14] 0.019 IL6i 2.39 [1.21–4.69] 0.012 CTLA4-Ig 1.19 [0.44–3.25] 0.731 JAKi 1.15 [0.49–2.73] 0.745 Hazard ratios (HR), 95% confidence intervals (CI), and p-values for drug discontinuation are shown for rheumatoid arthritis (RA) patients with or without anti-SS-A antibodies, analyzed after propensity score matching. Analyses were performed using Cox proportional hazards models. (2A) Discontinuation risk stratified by mode of action (MOA) of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). (2B) Cause-specific discontinuation risk (adverse events, ineffectiveness, and remission). (2C) Discontinuation risk due to adverse events stratified by MOA. Abbreviations : b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs; CI, confidence interval; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen 4-immunoglobulin; DMARDs, disease-modifying antirheumatic drugs; HR, hazard ratio; IL6i, interleukin-6 receptor inhibitors; JAKi, Janus kinase inhibitors; MOA, mode of action; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitors. Additional Declarations No competing interests reported. Supplementary Files TableSupp1.docx Additional file 1 (DOCX): Table S1 - Baseline characteristics of patients before and after propensity score matching. Description: Continuous variables are summarized as mean ± standard deviation (SD) and categorical variables as n (%). “Difference” indicates the standardized mean difference (SMD) between anti-SS-A–positive and –negative groups. “Before” and “After matching” denote datasets prior to and following propensity score matching, respectively. The table shows one representative dataset from the 100 multiply imputed datasets; similar trends were observed across the other imputed datasets, with all post-matching SMDs < 0.20. Abbreviations: ACPA, anti-citrullinated peptide antibody; b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs; CDAI, Clinical Disease Activity Index; DMARDs, disease-modifying antirheumatic drugs; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor. Cite Share Download PDF Status: Published Journal Publication published 17 Mar, 2026 Read the published version in PLOS ONE → Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":23953,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eStudy flow diagram.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe flow chart shows the selection of treatment courses and patients included in the analysis. Of the initial 3,378 treatment courses from 1,747 patients in the ANSWER cohort, 675 courses (295 patients) were excluded due to missing Clinical Disease Activity Index (CDAI) data, lack of follow-up, or discontinuation before treatment initiation. The eligible dataset before propensity score matching included 2,703 courses from 1,452 patients. After propensity score matching, the matched analysis dataset comprised 1,521 courses from 883 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e CDAI, Clinical Disease Activity Index.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-7669680/v1/2bae202c4b810bb4cbe7b629.png"},{"id":93946727,"identity":"55379868-c3a8-4a54-87bb-43c3188e9f61","added_by":"auto","created_at":"2025-10-20 14:24:18","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":29662,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier curves of overall b/tsDMARD retention in RA patients with or without anti-SS-A antibodies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKaplan–Meier curves show the overall retention of biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) over 24 months in rheumatoid arthritis (RA) patients according to anti-SS-A antibody status. Overall retention rates were similar between antibody-positive and -negative patients. Analyses were performed after propensity score matching. The number at risk is shown below the plot.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e Ab, antibody; b/tsDMARD, biologic and targeted synthetic disease-modifying antirheumatic drug; CI, confidence interval; HR, hazard ratio; RA, rheumatoid arthritis.\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-7669680/v1/feb754b9bceb12982cda1c32.png"},{"id":93947801,"identity":"19cb372e-181e-4d7d-9fa4-c7fbcf47a01c","added_by":"auto","created_at":"2025-10-20 14:32:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69682,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier and cumulative incidence curves of b/tsDMARD retention and discontinuation in RA patients with or without anti-SS-A antibodies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Kaplan–Meier curves of biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) retention by mode of action (MOA: TNF inhibitors [TNFi], IL-6 receptor inhibitors [IL6i], CTLA4-Ig, and JAK inhibitors [JAKi]) in rheumatoid arthritis (RA) patients with or without anti-SS-A antibodies. Anti-SS-A antibody-positive patients tended to show lower retention with IL6i and CTLA4-Ig, while retention appeared similar with TNFi or JAKi. \u003cstrong\u003e(B)\u003c/strong\u003eCumulative incidence function curves of b/tsDMARD discontinuation due to adverse events, ineffectiveness, or remission in RA patients with or without anti-SS-A antibodies. Anti-SS-A antibody-positive patients showed a higher cumulative incidence of discontinuation due to adverse events, while no clear differences were observed for ineffectiveness or remission. \u003cstrong\u003e(C)\u003c/strong\u003e Cumulative incidence function curves of b/tsDMARD discontinuation due to adverse events by MOA (TNFi, IL6i, CTLA4-Ig, JAKi) according to anti-SS-A antibody status. Anti-SS-A antibody positivity was associated with a higher risk of discontinuation due to adverse events with IL6i and TNFi, while no clear differences were observed with CTLA4-Ig or JAKi. The number at risk and the number of events are shown below each plot.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e Ab, antibody; b/tsDMARD, biologic and targeted synthetic disease-modifying antirheumatic drug; CI, confidence interval; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen 4-immunoglobulin; IL6i, interleukin-6 receptor inhibitors; JAKi, Janus kinase inhibitors; MOA, mode of action; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitors.\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-7669680/v1/482f840cacd8beed7623e6f1.png"},{"id":104983108,"identity":"d1c115e2-1e91-462b-bbdc-675bf6747db4","added_by":"auto","created_at":"2026-03-19 13:47:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1534526,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7669680/v1/d78abfe9-7155-459a-9e94-533df1b1ecbc.pdf"},{"id":93946730,"identity":"970878a2-a8d0-41ef-9a61-19c73e55b93b","added_by":"auto","created_at":"2025-10-20 14:24:18","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21317,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1 (DOCX): Table S1 - Baseline characteristics of patients before and after propensity score matching.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDescription:\u003c/em\u003e Continuous variables are summarized as mean ± standard deviation (SD) and categorical variables as n (%). “Difference” indicates the standardized mean difference (SMD) between anti-SS-A–positive and –negative groups. “Before” and “After matching” denote datasets prior to and following propensity score matching, respectively. The table shows one representative dataset from the 100 multiply imputed datasets; similar trends were observed across the other imputed datasets, with all post-matching SMDs \u0026lt; 0.20. Abbreviations: ACPA, anti-citrullinated peptide antibody; b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs; CDAI, Clinical Disease Activity Index; DMARDs, disease-modifying antirheumatic drugs; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor.\u003c/p\u003e","description":"","filename":"TableSupp1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7669680/v1/dbb37f54768d76a46e95354f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mode of action- and cause-specific drug retention of b/tsDMARDs in anti-SS-A antibody-positive rheumatoid arthritis: the ANSWER cohort study","fulltext":[{"header":"Background","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by progressive joint destruction and disability [\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The advent of biologic and targeted synthetic disease-modifying antirheumatic drugs (bDMARDs and tsDMARDs) has markedly improved clinical outcomes in RA, providing additional therapeutic options for patients who do not respond adequately to conventional treatments [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the treatment response and drug retention rates for biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) vary among individuals.\u003c/p\u003e\u003cp\u003eAnti-SS-A (Ro) antibody-positive RA constitutes a clinically important subgroup [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Approximately 20% of Japanese patients with RA are positive for anti-SS-A antibodies, with frequent overlap with Sj\u0026ouml;gren disease (SjD) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recent studies have indicated that anti-SS-A antibody-positive patients may be more difficult to treat than antibody-negative patients because of a reduced response to methotrexate monotherapy and less improvement in subjective symptoms [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the effect of anti-SS-A antibodies on the efficacy and retention of b/tsDMARDs, especially across different modes of action (MOA), has not been thoroughly investigated. Some reports suggest that tumor necrosis factor (TNF) inhibitors may be less effective in anti-SS-A antibody-positive RA [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], but limited data are available on retention and reasons for discontinuation of other b/tsDMARDs. To address this knowledge gap, we analyzed a large multicenter registry to compare drug retention among patients with RA with or without anti-SS-A antibodies, with a particular focus on MOA and reasons for discontinuation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Participants\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective observational study using data from the ANSWER cohort (Kansai Consortium for Well-being of Rheumatic Disease Patients), a multicenter registry in Japan. We included all patients with RA who initiated or switched to b/tsDMARDs between 2011 and 2024 and had anti-SS-A antibody testing at baseline. Patients could contribute multiple treatment courses if they initiated or switched to a different b/tsDMARD during the study period. For each treatment course, baseline was defined at the time of drug initiation or switching, and demographic and clinical data were collected at each baseline or within 90 days before. RA was diagnosed according to the 1987 ACR classification criteria [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] or the 2010 ACR/EULAR criteria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Anti-SS-A antibody positivity was defined as a titer\u0026thinsp;\u0026ge;\u0026thinsp;10 U/mL by Enzyme-Linked Immunosorbent Assay (ELISA) or Chemiluminescent Enzyme Immunoassay (CLEIA) or \u0026ge;\u0026thinsp;1 by double immunodiffusion (DID). To ensure data quality, the analysis was restricted to four facilities with a Clinical Disease Activity Index (CDAI) missing data rate below 30%. Follow-up was defined from the date of drug initiation to the earliest of 24 months, loss to follow-up, drug discontinuation (including switching to another agent), or death.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eExposure and Outcomes\u003c/h3\u003e\n\u003cp\u003eThe patients were divided into two groups based on the presence or absence of anti-SS-A antibodies. The primary outcome was the overall retention of all b/tsDMARDs. Secondary outcomes included drug retention stratified by (1) mode of action (MOA) of b/tsDMARDs and (2) reason for discontinuation (ineffectiveness, adverse events, and remission). The b/tsDMARDs analyzed included TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, ozoralizumab, and their biosimilars), interleukin-6 (IL-6) receptor inhibitors (tocilizumab and sarilumab), cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig: abatacept), and Janus kinase (JAK) inhibitors (baricitinib, tofacitinib, peficitinib, upadacitinib, and filgotinib).\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eOverall drug retention, including all reasons for discontinuation, was visualized using the Kaplan\u0026ndash;Meier method. A competing risks framework was used for the analysis stratified by reason for discontinuation, utilizing cumulative incidence functions. In this framework, alternative reasons for discontinuation are treated as competing events. Analyses were conducted at the treatment-course level, as patients could contribute multiple treatment courses. Hazard ratios (HRs) for drug discontinuation were estimated using Cox proportional hazards models, with robust variance estimates clustered by matching design and patient. To adjust for potential confounding factors, propensity score matching was conducted using the following covariates: age, sex, disease duration, glucocorticoid dosage (prednisolone equivalent), methotrexate (MTX) dosage, seropositivity (rheumatoid factor [RF], anti-citrullinated peptide antibody [ACPA]), CDAI, radiographic stage, functional class, MOA of b/tsDMARDs, and the number of prior b/tsDMARDs. Matching was performed using the nearest-neighbor method in a 1:2 ratio (one anti-SS-A antibody-positive case to two anti-SS-A antibody-negative cases). Post-matching covariate balance was assessed using standardized mean differences (SMD), with values below 0.2 considered acceptable. For variables with missing data, multiple imputations by chained equations (MICE) was used. A total of 100 imputed datasets were created and combined according to Rubin's rules using Within approach [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. All statistical analyses were performed using R, version 4.4.3.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eBaseline Characteristics\u003c/h2\u003e\u003cp\u003eA total of 2,703 treatment courses from 1,452 patients were included in the analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among these, 507 treatment courses were from 255 anti-SS-A antibody-positive patients and 2,196 courses were from 1,197 antibody-negative patients (Table\u0026nbsp;1 and Supplementary Table\u0026nbsp;1). Before matching, notable differences were observed between the groups for variables such as age, sex, seropositivity (RF, ACPA), and prior b/tsDMARD exposure, with several covariates showing SMDs greater than 0.2. After propensity score matching, the matched dataset included 507 treatment courses from 255 anti-SS-A antibody-positive patients and 1,014 courses from 628 antibody-negative patients. The covariate balance was substantially improved, with SMDs for all variables reduced to below 0.2.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eOverall Drug Retention Rate of b/tsDMARDs\u003c/h2\u003e\u003cp\u003eKaplan\u0026ndash;Meier curves demonstrated a similar pattern of overall b/tsDMARD retention between the antibody-positive and -negative groups over the two-year period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In Cox proportional hazards models, anti-SS-A antibody positivity was not associated with overall b/tsDMARD retention (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 0.91\u0026ndash;1.26; p\u0026thinsp;=\u0026thinsp;0.382).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDrug Retention by Mode of Action\u003c/h3\u003e\n\u003cp\u003eNext, we analyzed the risk of drug discontinuation according to the MOA of b/tsDMARDs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Among these, in terms of point estimates, anti-SS-A antibody positivity showed a trend toward an increased risk of discontinuation in IL-6 receptor inhibitor and CTLA4-Ig users, whereas the association between anti-SS-A antibody positivity and the risk of discontinuation appeared weaker in TNF inhibitor and JAK inhibitor users; none of these associations reached statistical significance (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). These finding indicate that IL-6 receptor inhibitors or CTLA4-Ig might reduce the retention rates in anti-SS-A antibody-positive RA patients.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eCause-Specific b/tsDMARDs Retention\u003c/h3\u003e\n\u003cp\u003eWe examined the risk of b/tsDMARD discontinuation according to the reason for treatment termination. For each reason, the cumulative incidence functions of drug discontinuation in the antibody-positive and antibody-negative groups are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. Discontinuation due to adverse events was significantly more frequent in the anti-SS-A antibody-positive group (cause-specific HR: 1.72, 95% CI: 1.23\u0026ndash;2.42, p\u0026thinsp;=\u0026thinsp;0.002). In contrast, no significant differences were observed in discontinuation due to ineffectiveness or remission (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). These findings suggest that anti-SS-A antibody positivity is specifically associated with an increased risk of discontinuation owing to adverse events.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eMOA-Stratified Risks of Discontinuations due to Adverse Events\u003c/h2\u003e\u003cp\u003eIn the analysis restricted to the outcome of discontinuations due to adverse events, anti-SS-A antibody-positive patients exhibited a significantly higher risk of discontinuation when treated with IL-6 receptor inhibitors (cause-specific HR: 2.39, 95% CI: 1.21\u0026ndash;4.69, p\u0026thinsp;=\u0026thinsp;0.012) or TNF inhibitors (HR: 1.87, 95% CI: 1.11\u0026ndash;3.14, p\u0026thinsp;=\u0026thinsp;0.019) than antibody-negative patients (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e2\u003c/span\u003eC, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). In contrast, no significant difference in the adverse event-related discontinuation risk was observed for CTLA4-Ig or JAK inhibitors.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the first large multicenter investigation to comprehensively evaluate b/tsDMARD retention in anti-SS-A antibody-positive RA patients. The overall retention rate of b/tsDMARDs was similar between the antibody-positive and antibody-negative groups. In MOA-stratified analyses, anti-SS-A antibody positivity showed a trend toward increased discontinuation with IL-6 receptor inhibitors and CTLA4-Ig. Cause-specific analyses revealed that discontinuation due to adverse events was significantly more frequent in anti-SS-A antibody-positive patients, with an especially increased risk observed among those treated with IL-6 receptor inhibitors and TNF inhibitors. These findings highlight that treatment tolerability, rather than overall efficacy, may be a key determinant of drug survival in this subgroup.\u003c/p\u003e\u003cp\u003ePrevious reports have assessed the impact of anti-SS-A antibodies in patients receiving specific agents such as TNF inhibitors or abatacept [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, few studies have systematically examined treatment retention across drug classes while distinguishing among various causes of discontinuation, including adverse events and ineffectiveness. The present study further demonstrated that the risk of discontinuation due to adverse events may differ by drug class in anti-SS-A antibody-positive patients, providing novel insights into treatment tolerability in this subset.\u003c/p\u003e\u003cp\u003eOur analysis showed a trend toward an increased discontinuation risk among anti-SS-A antibody-positive patients treated with IL-6 receptor inhibitors. Previous studies have reported the favorable efficacy of IL-6 receptor inhibitors in this population [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In contrast, our analysis, which focused on reasons for discontinuation, demonstrated greater heterogeneity in treatment response and tolerability. These results suggest that anti-SS-A antibody-positive patients may be more susceptible to adverse effects of IL-6 receptor inhibitors despite their clinical efficacy.\u003c/p\u003e\u003cp\u003eCause-specific analysis revealed a significantly higher risk of discontinuation due to adverse events in the anti-SS-A antibody-positive group. This increased risk was especially apparent with the use of IL-6 receptor inhibitors and TNF inhibitors. Immune dysregulation and autoantibody production may contribute to the greater frequency of drug-related adverse events in this subgroup [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Previous studies have similarly reported that adverse events are a leading cause of TNF inhibitor discontinuation in RA patients [\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Anti-SS-A antibody-positive RA often overlaps with Sj\u0026ouml;gren disease (SjD), which is characterized by sicca symptoms and extra-articular involvement [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. These features may contribute to the increased susceptibility to adverse events and subsequent treatment discontinuation, particularly with IL-6 receptor inhibitors and TNF inhibitors.\u003c/p\u003e\u003cp\u003eConversely, we did not observe a significantly increased risk of adverse event-related discontinuation of CTLA4-Ig or JAK inhibitors. Previous studies have suggested favorable efficacy and retention of abatacept in anti-SS-A antibody-positive RA patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], and favorable tolerability of these agents in patients with autoimmune overlap [\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. The ROSE trial also demonstrated the clinical benefit and tolerability of CTLA4-Ig in RA patients with associated SjD, including those positive for anti-SS-A antibodies [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Our analysis did not detect an increased risk of discontinuation due to adverse events associated with JAK inhibitors in anti-SS-A antibody-positive patients. However, this finding should be interpreted with caution because few clinical studies have specifically addressed the safety and efficacy of JAK inhibitors in this subgroup. Most available evidence is derived from preclinical studies, which have shown that JAK inhibitors may modulate key pathogenic pathways, such as interferon signaling and autophagy, in both RA and SjD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Further clinical research is needed to establish the safety profile of JAK inhibitors in anti-SS-A antibody-positive RA patients.\u003c/p\u003e\u003cp\u003eFrom a clinical perspective, these findings suggest that anti-SS-A antibody status may be an important factor to consider when selecting b/tsDMARDs for RA patients. In antibody-positive patients, especially those with comorbidities that may increase susceptibility to adverse events (e.g., sicca symptoms or other extra-articular manifestations), the use of IL-6 receptor inhibitors or TNF inhibitors may require closer monitoring and careful risk\u0026ndash;benefit assessment. Conversely, CTLA4-Ig or JAK inhibitors may represent reasonable alternatives in this subgroup, given the absence of a significantly increased risk of adverse event-related discontinuation in our study. Given that treatment decisions are individualized, incorporating serological profiles such as anti-SS-A antibody status into therapeutic planning may help optimize drug retention and minimize discontinuation due to adverse events.\u003c/p\u003e\u003cp\u003eThe strengths of this study include the use of a large multicenter registry, the simultaneous evaluation of both MOA-stratified and cause-specific drug retention, and the rigorous adjustment for confounders using propensity score matching and multiple imputation. However, as this was a retrospective observational study, residual confounding by unmeasured factors such as the severity of overlapping SjD, antibody titers, or infection risk factors could not be entirely excluded. The reasons for discontinuation were based on clinician assessment rather than standardized criteria. Therefore, the decision to stop or switch between b/tsDMARDs depends on the individual\u0026rsquo;s clinical judgment. Anti-SS-A antibody titers and SjD diagnoses were not uniformly recorded. The cohort was limited to facilities with adequate CDAI data, which may have affected the generalizability.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis multicenter study comprehensively evaluated MOA- and cause-specific b/tsDMARD retention in anti-SS-A antibody-positive RA patients. Overall retention rates were similar between antibody-positive and -negative groups. Discontinuation due to adverse events was significantly more common in antibody-positive patients. Among discontinuations due to adverse events, higher risks were observed with IL-6 receptor inhibitors and TNF inhibitors, but not with CTLA4-Ig or JAK inhibitors. These findings suggest that, in anti-SS-A antibody-positive RA, treatment tolerability rather than overall efficacy may be a key factor influencing drug survival, and that anti-SS-A antibody status may help inform therapeutic decision-making.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAb\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eantibody\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eACPA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eanti-citrullinated peptide antibody\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ebDMARDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebiologic disease-modifying antirheumatic drugs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eb/tsDMARDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ebiologic and targeted synthetic disease-modifying antirheumatic drugs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCDAI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eClinical Disease Activity Index\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003econfidence interval\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCTLA4-Ig\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecytotoxic T lymphocyte-associated antigen 4-immunoglobulin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDMARDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003edisease-modifying antirheumatic drugs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ehazard ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIL6i\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003einterleukin-6 receptor inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eJAKi\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eJanus kinase inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMOA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emode of action\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMTX\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003emethotrexate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePSL\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eprednisolone\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erheumatoid arthritis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRF\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003erheumatoid factor\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eTNFi\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etumor necrosis factor inhibitors\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003etsDMARDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003etargeted synthetic disease-modifying antirheumatic drugs.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter observational study utilized data from the ANSWER cohort (Kansai Consortium for Well-being of Rheumatic Disease Patients) and was conducted in accordance with the Declaration of Helsinki and relevant national guidelines. The study protocol was reviewed and approved by the Ethics Review Committee of Osaka Metropolitan University (approval No. 2023-053; 25 July 2023). Written informed consent was obtained from patients currently under treatment. For patients who had already transferred to other hospitals or clinics, consent was obtained through an opt-out process via public postings on the participating hospitals\u0026rsquo; websites.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch3\u003eCompeting interests\u003c/h3\u003e\n\u003cp\u003eTI has received speaking fees from Eisai Co., Ltd. KM has received speaking fees from AbbVie GK, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences K.K., Janssen Pharmaceutical K.K., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., and UCB Japan Co., Ltd. KT has received speaking fees from AYUMI Pharmaceutical Corporation. MH has received research grants and speaking fees from Asahi Kasei Corporation, Astellas Pharma Inc., AstraZeneca K.K., AYUMI Pharmaceutical Corporation, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Gilead Sciences K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and UCB Japan Co., Ltd. TK has received speaking fees from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., and Nippon Boehringer Ingelheim Co., Ltd. YS has received speaking fees from Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Eisai Co., Ltd., and AbbVie GK. YN has received speaking fees from AbbVie GK, Astellas Pharma Inc., Asahi Kasei Corporation, Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., and Mitsubishi Tanabe Pharma Corporation. HY has received speaking fees from AbbVie GK, Asahi Kasei Corporation, Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Gilead Sciences K.K., and Taiho Pharmaceutical Co., Ltd. KN has received speaking fees from Janssen Pharmaceutical K.K., Taisho Pharmaceutical Co., Ltd., UCB Japan Co., Ltd., AYUMI Pharmaceutical Corporation, Asahi Kasei Corporation, and Pfizer Japan Inc. YU has received speaking fees from Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Eisai Co., Ltd., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., and Taisho Pharmaceutical Co., Ltd. SS has received speaking fees from AbbVie GK, Eli Lilly Japan K.K., UCB Japan Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., Pfizer Japan Inc., Asahi Kasei Corporation, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Corporation. JS has received research grants from Asahi Kasei Corporation, AbbVie GK, and Chugai Pharmaceutical Co., Ltd., and personal fees from Asahi Kasei Corporation, AbbVie GK, Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Pfizer Japan Inc., Eisai Co., Ltd., Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation. All other authors have declared no conflicts of interests.\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026rsquo; information (optional)\u003c/h2\u003e\n\u003cp\u003eThe authors are clinicians and researchers affiliated with the participating departments listed under \u0026ldquo;Authors and affiliations.\u0026rdquo; Kazuma Nishisaka is a graduate student and Takaichi Okano is a lecturer in the Department of Rheumatology and Clinical Immunology at Kobe University Graduate School of Medicine.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThe study reported in this publication uses ANSWER Cohort supported by grants from 12 pharmaceutical companies (AbbVie GK, Asahi Kasei, Ayumi, Chugai, Eisai, Eli Lilly Japan K.K., Janssen K.K., Ono, Sanofi K.K., Taisho, Teijin Healthcare, and UCB Japan). This study was conducted as an investigator-initiated study. These companies have no role in the study design, data collection, data analysis, data interpretation, or writing of the report.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eKN performed the data analysis, interpreted the results, and drafted the manuscript. TO supervised the study and provided critical revision of the manuscript. All authors contributed to the data collection, reviewed the manuscript for important intellectual content, and approved the final version.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u003c/h2\u003e\n\u003cp\u003eWe thank all the medical staff at the participating institutions of the ANSWER cohort for their support and for providing the data used in this study.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available. Patients did not provide consent for raw data sharing during data collection. All aggregated data relevant to the study are provided in this article and its additional file(s). Further information is available from the corresponding author on reasonable request and subject to institutional approvals.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWu, S. et al. Macrophage polarization regulates the pathogenesis and progression of autoimmune diseases. \u003cem\u003eAutoimmun. Rev.\u003c/em\u003e \u003cb\u003e24\u003c/b\u003e (7), 103820. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.autrev.2025.103820\u003c/span\u003e\u003cspan address=\"10.1016/j.autrev.2025.103820\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025). Epub 2025 Apr 21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLaraib, I., Qasim, S., Uttra, A. M. \u0026amp; Ahmed, S. R. 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Avoiding pitfalls when combining multiple imputation and propensity scores. \u003cem\u003eStat. Med.\u003c/em\u003e \u003cb\u003e38\u003c/b\u003e (26), 5120\u0026ndash;5132. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/sim.8355\u003c/span\u003e\u003cspan address=\"10.1002/sim.8355\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019). Epub 2019 Sep 11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEndo, Y. et al. Significance of anti-Ro/SSA antibodies in the response and retention of abatacept in patients with rheumatoid arthritis: a multicentre cohort study. \u003cem\u003eScand. J. Rheumatol.\u003c/em\u003e \u003cb\u003e50\u003c/b\u003e (1), 15\u0026ndash;19 (2021). Epub 2020 Sep 3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-Lagunar, M. H. et al. 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Drug tolerability and reasons for discontinuation of seven biologics in elderly patients with rheumatoid arthritis: the ANSWER cohort study. \u003cem\u003ePLoS One\u003c/em\u003e. \u003cb\u003e14\u003c/b\u003e (5), e0216624. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0216624\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0216624\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRisser, L. M. et al. Janus kinase inhibitors show a longer drug survival than biologics in a real-world cohort of patients with rheumatoid arthritis: a retrospective analysis from the RHADAR database. \u003cem\u003eRheumatol. Int.\u003c/em\u003e \u003cb\u003e45\u003c/b\u003e (5), 100. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00296-025-05859-7\u003c/span\u003e\u003cspan address=\"10.1007/s00296-025-05859-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e\u0026Ouml;st\u0026ouml;r, A. et al. Achievement of treatment targets and maintenance of response with upadacitinib in patients with moderate-to-severe rheumatoid arthritis in real-world practice: 1-year outcomes from the UPHOLD observational study. \u003cem\u003eArthritis Res. Ther.\u003c/em\u003e \u003cb\u003e27\u003c/b\u003e (1), 84. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13075-025-03528-5\u003c/span\u003e\u003cspan address=\"10.1186/s13075-025-03528-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaldi, C. et al. Real-world effectiveness and retention rate of upadacitinib in patients with rheumatoid arthritis: results from a multicentre study. \u003cem\u003eClin. Exp. Med.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e (1), 50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10238-025-01578-2\u003c/span\u003e\u003cspan address=\"10.1007/s10238-025-01578-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2025).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsuboi, H. et al. 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Rheumatol.\u003c/em\u003e \u003cb\u003e26\u003c/b\u003e (6), 891\u0026ndash;899. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3109/14397595.2016.1158773\u003c/span\u003e\u003cspan address=\"10.3109/14397595.2016.1158773\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2016). Epub 2016 Jul 26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsuboi, H. et al. Efficacy and safety of abatacept for patients with Sj\u0026ouml;gren's syndrome associated with rheumatoid arthritis: ROSE trial\u0026mdash;an open-label, one-year, prospective study\u0026mdash;interim analysis of 32 patients for 24 weeks. \u003cem\u003eMod. Rheumatol.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e (2), 187\u0026ndash;193. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3109/14397595.2014.951144\u003c/span\u003e\u003cspan address=\"10.3109/14397595.2014.951144\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015). Epub 2014 Sep 11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBarrera, M. J. et al. Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sj\u0026ouml;gren's syndrome. \u003cem\u003eRheumatol. (Oxford)\u003c/em\u003e. \u003cb\u003e60\u003c/b\u003e (4), 1951\u0026ndash;1962. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/rheumatology/keaa670\u003c/span\u003e\u003cspan address=\"10.1093/rheumatology/keaa670\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2021).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline characteristics of treatment courses\u003c/strong\u003e \u003cstrong\u003ebefore and after propensity score matching.\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"701\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 294px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore Matching\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 292px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAfter Matching\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 116px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eanti-SS-A antibody\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eanti-SS-A antibody\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" valign=\"bottom\" style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNegative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePositive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eN = 2,703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eN = 2,196\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eN = 507\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eN = 1,521\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eN = 1,014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003eN = 507\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e59 \u0026plusmn; 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e60 \u0026plusmn; 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e55 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e55 \u0026plusmn; 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e55 \u0026plusmn; 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e55 \u0026plusmn; 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e475 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e459 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e16 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e59 (3.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e43 (4.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e16 (3.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2,228 (82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,737 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e491 (97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,462 (96%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e971 (96%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e491 (97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eDisease Duration\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e113 \u0026plusmn; 118\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e112 \u0026plusmn; 122\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e117 \u0026plusmn; 103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e112 \u0026plusmn; 108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e110 \u0026plusmn; 110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e117 \u0026plusmn; 103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003ePSL (mg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2.0 \u0026plusmn; 5.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2.0 \u0026plusmn; 6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2.1 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2.1 \u0026plusmn; 6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2.1 \u0026plusmn; 8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2.1 \u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eMTX (mg/week)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e3.7 \u0026plusmn; 5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e3.7 \u0026plusmn; 4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e3.8 \u0026plusmn; 5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e4.0 \u0026plusmn; 5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e4.0 \u0026plusmn; 5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e3.8 \u0026plusmn; 5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eRF positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,941 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,525 (71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e416 (85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,285 (84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e852 (84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e433 (85%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eACPA positive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,947 (77%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,551 (75%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e396 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,305 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e867 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e438 (86%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eb/tsDMARDs Line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e2 \u0026plusmn; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eCDAI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e16 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e16 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17 \u0026plusmn; 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eStage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e-0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e827 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e693 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e134 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e527 (35%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e369 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e158 (31%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e584 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e462 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e122 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e375 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e237 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e138 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e323 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e238 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e85 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e241 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e145 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e96 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e529 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e430 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e99 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e378 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e263 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e115 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eClass\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e-0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e650 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e520 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e130 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e495 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e342 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e153 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,181 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e930 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e251 (56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e773 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e494 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e279 (55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e434 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e376 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e58 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e237 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e168 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e69 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e33 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e27 (1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e6 (1.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e16 (1.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10 (1.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (1.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003eb/tsDMARDs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; TNFi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,327 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1,090 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e237 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e735 (48%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e498 (49%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e237 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; IL6i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e620 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e495 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e125 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e360 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e235 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e125 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; CTLA4-Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e368 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e300 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e68 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e194 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e126 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e68 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 116px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; JAKi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e388 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e311 (14%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e77 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e232 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e155 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e77 (15%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eValues are presented as mean \u0026plusmn; standard deviation (SD) for continuous variables, and n (%) for categorical variables. \u0026ldquo;Difference\u0026rdquo; indicates the standardized mean difference (SMD) between anti-SS-A antibody-positive and -negative groups. \u0026ldquo;Before matching\u0026rdquo; and \u0026ldquo;After matching\u0026rdquo; refer to the datasets prior to and following propensity score matching, respectively. Baseline was defined at the initiation or switching of each biologic and targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). Propensity scores were calculated using the following covariates: age, sex, disease duration, glucocorticoid dosage, methotrexate dosage, seropositivity (RF, ACPA), CDAI, radiographic stage, functional class, mode of action (MOA) of b/tsDMARDs, and the number of prior b/tsDMARDs. For presentation, Table 1 displays one representative dataset from the 100 multiply imputed datasets. Similar trends were observed across the other imputed datasets, with all post-matching SMDs \u0026lt; 0.20.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: ACPA, anti-citrullinated peptide antibody;\u0026nbsp;b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs;\u0026nbsp;CDAI, Clinical Disease Activity Index; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen 4-immunoglobulin; DMARDs, disease-modifying antirheumatic drugs; IL6i, interleukin-6 receptor inhibitors; JAKi, Janus kinase inhibitors; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor; TNFi, tumor necrosis factor inhibitors.\u003cbr\u003e\u003cstrong\u003eTable 2. Hazard ratios for b/tsDMARD discontinuation in RA patients with or without anti-SS-A antibodies.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2A. Discontinuation risk by mode of action.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMOA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eTNFi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.68\u0026ndash;1.10]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eIL6i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[1.00\u0026ndash;1.91]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.053\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eCTLA4-Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.92\u0026ndash;2.11]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.114\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eJAKi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.74\u0026ndash;1.72]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.562\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2B. Cause-specific discontinuation risk.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCause\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecause-specific HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eAdverse Events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[1.23\u0026ndash;2.42]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eIneffectiveness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.77\u0026ndash;1.19]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eRemission\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.30\u0026ndash;1.57]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2C. Discontinuation risk due to adverse events by mode of action.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMOA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecause-specific HR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eTNFi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[1.11\u0026ndash;3.14]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eIL6i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e2.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[1.21\u0026ndash;4.69]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eCTLA4-Ig\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.44\u0026ndash;3.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.731\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003eJAKi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e1.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e[0.49\u0026ndash;2.73]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 142px;\"\u003e\n \u003cp\u003e0.745\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eHazard ratios (HR), 95% confidence intervals (CI), and p-values for drug discontinuation are shown for rheumatoid arthritis (RA) patients with or without anti-SS-A antibodies, analyzed after propensity score matching. Analyses were performed using Cox proportional hazards models. \u003cstrong\u003e(2A)\u003c/strong\u003e Discontinuation risk stratified by mode of action (MOA) of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). \u003cstrong\u003e(2B)\u003c/strong\u003e Cause-specific discontinuation risk (adverse events, ineffectiveness, and remission). \u003cstrong\u003e(2C)\u003c/strong\u003e Discontinuation risk due to adverse events stratified by MOA.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: b/tsDMARDs, biologic and targeted synthetic disease-modifying antirheumatic drugs; CI, confidence interval; CTLA4-Ig, cytotoxic T lymphocyte-associated antigen 4-immunoglobulin; DMARDs, disease-modifying antirheumatic drugs; HR, hazard ratio; IL6i, interleukin-6 receptor inhibitors; JAKi, Janus kinase inhibitors; MOA, mode of action; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitors.\u003c/p\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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rheumatoid arthritis, Antirheumatic agents, Interleukin-6 receptor inhibitors, Tumor necrosis factor inhibitors, Drug retention, Anti-SS-A antibody","lastPublishedDoi":"10.21203/rs.3.rs-7669680/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7669680/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eTo investigate drug retention by mode of action (MOA) and cause in rheumatoid arthritis (RA) patients with or without anti-SS-A antibodies using a multicenter registry.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively analyzed the ANSWER cohort in Japan. Patients with RA who started or switched biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) between 2011 and 2024 and had baseline anti-SS-A antibody testing were included. Propensity score matching balanced baseline characteristics. Kaplan\u0026ndash;Meier and competing risk analyses were conducted, and hazard ratios (HRs) were estimated using Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAfter matching, 507 treatment courses from 255 anti-SS-A antibody-positive and 1,014 from 628 antibody-negative patients were analyzed. Anti-SS-A antibody positivity was not associated with overall b/tsDMARD retention (HR 1.07, 95% CI 0.91\u0026ndash;1.26, p\u0026thinsp;=\u0026thinsp;0.382). In MOA-stratified analyses, positivity showed a trend toward increased discontinuation with IL-6 receptor inhibitors and CTLA4-Ig. In cause-specific analyses, discontinuation due to adverse events was significantly more frequent in antibody-positive patients (HR 1.72, 95% CI 1.23\u0026ndash;2.42, p\u0026thinsp;=\u0026thinsp;0.002). Among adverse event-related discontinuations, positivity was associated with higher risks with IL-6 receptor inhibitors (HR 2.39, 95% CI 1.21\u0026ndash;4.69, p\u0026thinsp;=\u0026thinsp;0.01) and TNF inhibitors (HR 1.87, 95% CI 1.11\u0026ndash;3.14, p\u0026thinsp;=\u0026thinsp;0.02), but not with CTLA4-Ig or JAK inhibitors.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eAnti-SS-A antibody-positive RA patients had greater risk of discontinuation due to adverse events, particularly with IL-6 receptor inhibitors and TNF inhibitors. These findings underscore the importance of considering MOA and discontinuation causes when selecting therapies.\u003c/p\u003e","manuscriptTitle":"Mode of action- and cause-specific drug retention of b/tsDMARDs in anti-SS-A antibody-positive rheumatoid arthritis: the ANSWER cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 14:24:13","doi":"10.21203/rs.3.rs-7669680/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"050f1607-7df9-44cc-a0c0-e41b5f04e9a0","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":56529994,"name":"Health sciences/Diseases"},{"id":56529995,"name":"Biological sciences/Immunology"},{"id":56529996,"name":"Health sciences/Medical research"},{"id":56529997,"name":"Health sciences/Rheumatology"}],"tags":[],"updatedAt":"2026-03-19T13:47:49+00:00","versionOfRecord":{"articleIdentity":"rs-7669680","link":"https://doi.org/10.1371/journal.pone.0344747","journal":{"identity":"plos-one","isVorOnly":true,"title":"PLOS ONE"},"publishedOn":"2026-03-18 00:00:00","publishedOnDateReadable":"March 18th, 2026"},"versionCreatedAt":"2025-10-20 14:24:13","video":"","vorDoi":"10.1371/journal.pone.0344747","vorDoiUrl":"https://doi.org/10.1371/journal.pone.0344747","workflowStages":[]},"version":"v1","identity":"rs-7669680","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7669680","identity":"rs-7669680","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}