Search

Objectives: To investigate the phenotypic heterogeneity of tissue-resident synovial fibroblasts and their role in inflammatory response in rheumatoid arthritis (RA)., Methods: We used single-cell and spatial transcriptomics to profile synovial cells and spatial gene expressions of synovial tissues to identify phenotypic changes in patients with osteoarthritis, RA in sustained remission and active state. Immunohistology, multiplex immunofluorescence and flow cytometry were used to identify synovial fibroblasts subsets. Deconvolution methods further validated our findings in two cohorts (PEAC and R4RA) with treatment response. Cell coculture was used to access the potential cell-cell interactions. Adoptive transfer of synovial cells in collagen-induced arthritis (CIA) mice and bulk RNA sequencing of synovial joints further validate the cellular functions., Results: We identified a novel tissue-remodelling CD45 - CD31 - PDPN + ITGA5 + synovial fibroblast population with unique transcriptome of POSTN, COL3A1, CCL5 and TGFB1, and enriched in immunoregulatory pathways. This subset was upregulated in active and lympho-myeloid type of RA, associated with an increased risk of multidrug resistance. Transforming growth factor (TGF)-β1 might participate in the differentiation of this subset. Moreover, ITGA5 + synovial fibroblasts might occur in early stage of inflammation and induce the differentiation of CXCL13 hi PD - 1 hi peripheral helper T cells (TPHs) from naïve CD4 + T cells, by secreting TGF-β1. Intra-articular injection of ITGA5 + synovial fibroblasts exacerbates RA development and upregulates TPHs in CIA mice., Conclusions: We demonstrate that ITGA5 + synovial fibroblasts might regulate the RA progression by inducing the differentiation of CXCL13 hi PD - 1 hi TPHs and remodelling the proinflammatory microenvironments. Therapeutic modulation of this subpopulation could therefore be a potential treatment strategy for RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To compare two strategies-a hydrocortisone replacement strategy and a prednisone tapering strategy-for their success in glucocorticoid discontinuation in patients with rheumatoid arthritis (RA) with low disease activity (LDA)., Methods: The Strategies for glucocorticoid TApering in Rheumatoid arthritis (STAR) study was a double-blind, double-placebo randomised controlled trial including patients with RA receiving a stable dose of glucocorticoid 5 mg/day for ≥3 months and were in LDA for ≥3 months. Patients were randomly assigned in a 1:1 ratio to either replace prednisone with 20 mg/day of hydrocortisone for 3 months, then reduce to 10 mg/day for 3 months before discontinuation or to taper prednisone by 1 mg/day every month until complete discontinuation, contingent on maintaining LDA. The primary outcome was the percentage of patients achieving glucocorticoid discontinuation at 12 months. Other secondary outcomes were proportion of flares, need for additional glucocorticoid use, disease activity, patient-reported outcomes and the results of adrenocorticotropic hormone (ACTH) stimulation tests., Results: Of the 102 patients randomised in the trial (mean age 62.4 years, 70.6% females), 53 had hydrocortisone replacement and 49 tapered prednisone. At 12 months, 29 patients (55%) in the hydrocortisone replacement group and 23 patients (47%) in the prednisone tapering group achieved glucocorticoid discontinuation (p=0.4). No difference was observed between groups in the secondary outcomes. No cases of acute adrenal insufficiency were observed; however, 17 patients still had an abnormal ACTH stimulation test at 12 months, with no differences between arms., Conclusion: A hydrocortisone replacement strategy was not superior to a prednisone tapering strategy for achieving glucocorticoid discontinuation success in patients with RA in LDA., Trial Registration Number: NCT02997605., Competing Interests: Competing interests: AR-W, CB, MM, VB, MN, ChR, AS, PV-S, RMF, MP, J-EG, MS, PD, SL, LZ, GC, JFB, BJ, YD and AC declare no competing interests. HM declared to have received grants from Celltrion, Healthcare, Lilly, Nordic Pharma, Medac, consulting fees from AbbVie, Accord, CellTrion HealthCare, Johnson & Johnson, UCB, honoraria for presentation from AbbVie, Bristol Myers Squibb, CellTrion HealthCare, Fresenius Kabi, Galapagos, Medac, Nordic Pharma, Novartis, Sanofi, UCB, support for attending meeting from CellTrion HealthCare, Fresenius Kabi, UCB, participated in advisory board for Lilly, Pfizer. CS received grant from Novartis, Roche-Chugai, honoraria for presentations from Novartis, Galapagos, Pfizer, Lilly and support for attending meetings from Lilly, Novartis, Galapagos. JM received grants from Bristol Myers Squib, Fresenius Kabi Novartis, Roche Chugai, Pfizer and Lilly, received honoraria for presentation from AbbVie, Boehringer Ingelheim, Biogen, Lilly, Viatris, Pfizer, Sanofi, from Bristol Myers Squib, Fresenius Kabi, Galapagos, Medac, Novartis, Roche Chugai, support for attending meetings from Bristol Myers Squib, Fresenius Kabi, Lilly, participated in advisory boards for AbbVie, Pfizer, Theramex, Galapagos, Fresenius Kabi and Sanofi. CR received grants from Biogen, Lilly, Nordic Pharma, consulting fees from Novartis, Lilly, AstraZeneca, AbbVie, Pfizer and GSK, received honoraria for presentations from AbbVie, Boehringer Ingelheim, Novartis, Lilly, Galapagos, Pfizer, UCB, support for attending meeting from UCB, Novartis and AstraZeneca. LG received grants from AbbVie, Biogen, Lilly, Novartis, UCB, consulting fees from AbbVie, Amgen, BMS, Celltrion, Janssen, Novartis, Pfizer, UCB, honoraria for presentations from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB, support for attending meeting from MSD, Novartis, Pfizer, participated in advisory boards for Janssen, Pfizer, UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study., Methods: Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission., Results: A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE., Conclusion: The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA., Competing Interests: Competing interests: The analysis was funded by JSC R-Pharm. EF: research grants from BMS, Eli Lilly, Novartis, Roche; consulting fees from Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Novartis, Roche, Sanofi, Sobi; speakers’ bureau for Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Medac, Novartis, Roche, Sanofi, Sobi; RF: Consultant for AbbVie, Arthrosi, BMS, Galvani, Genentech, Gilead, GSK, InventisBio, Janssen, Eli Lilly, Novartis, Pfizer, Proviant, Recor, UCB, Vyne; Clinical Study grants: AbbVie, Acceleron, Arthrosi, Biosplice, BMS, Cugene, Flexion, Galvani, Gilead, GSK, Horizon, Idorsia, Janssen, LG Chem, Eli Lilly, Novartis, Pfizer, Proviant, Sankyo, UCB, Viela. SF: consulting fees from ICON and PPD contract research organisations, shareholder of Pfizer, INC stocks, consulting fees from R-Pharm; EK: employee of R-Pharm, with no R-Pharm stock; ML: research grants from Amgen, Biogen, UCB, Sun Pharmaceuticals, Abbvie, Pfizer, Novartis, Lilly, GSK, R-Pharm; EN: speakers’ bureau for AbbVie, Eli Lilly, Janssen, Novartis, Pfizer; DB, SG, SK and MS: employee of R-Pharm, with no R-Pharm stock; JS: Editor-in-Chief of ARD, research grants from Abbvie, Astra-Zeneca, Lilly; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; RF: consulting fees from AbbVie, BMS, Gilead, Galvani, GSK, Janssen, Eli Lilly, Novartis, Pfizer, R-Pharm, UCB; speakers bureaus for AbbVie; Pfizer; R-Pharm. Disclosure forms provided by the authors are available in the full text of this article., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA)., Methods: A meta-epidemiological study was performed on randomised trials investigating biologics and targeted agents compared with placebo or conventional disease-modifying antirheumatic drugs in patients with RA. The main outcome measures were ORs for the ACR 20% response and at least one of the eight core domains according to the existing RA core outcome set (COS) analysed based on standardised mean differences., Results: 115 trials involving 55 422 patients with RA were eligible. The OR for achieving ACR 20% response was 3.19 (95% CI 2.96 to 3.44) for the experimental interventions relative to the comparators. The median number of COS domains reported was 6; 18 trials reported only 1 domain, 17 all 8. Univariable meta-regression analyses indicated that each of the eight core domains was significantly associated with ACR 20% response, yet improvements in physical disability explain a successful ACR 20% response the most. Including only trials reporting on all eight core domains, univariable meta-regression analyses proved improvement in fatigue to explain a successful ACR 20% response the most., Conclusions: Within this dataset, it is evident that the conclusions concerning our primary objective were significantly influenced by both the amount and characteristics of missing data. Our data suggest that fatigue could be more important for the primary endpoint than previously assumed, but this is based on limited data., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development., Competing Interests: Competing interests: KDD has received honoraria from BMS, ThermoFisher and Werfen, and in-kind research supplies from Inova Diagnostics; VMH has received equity and funds from Q32 Bio unrelated to this work; PE has received funds for consulting from AnaptysisBio, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis and support for clinical trials from Abbvie, BMS, Lilly, Novartis and Samsung; KM has received honoraria and/or consulting fees from Abbvie, Lilly, Galapagos, Serac Healthcare, Deepcure, UCB, Zura Bio and research grants from Astra Zeneca, Lilly, Gilead, Serac Healthcare and Deepcure. GS has received funds for consulting from BMS, Janssen and Novartis; JAS has received research support from Boehringer Ingelheim and Bristol Myers Squibb unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi and UCB unrelated to this work; RT has received funds for consulting from CSL, AbbVie, Nextera, Sandoz, Viela Bio and Janssen-Cilag and received research contracts from CSL and Viela Bio; APC has received consulting and speaker bureau fees from Abbvie, BMS, Galapagos, UCB, Galvani, Janssen, Roche and Arthrogen, and research grant support from BMS, UCB and Janssen, with funds administered by King’s College London., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis., Methods: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years., Results: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg., Conclusions: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old., Competing Interests: Competing interests: GRB reports consultancy fees from AbbVie, Amgen, BMS, Galapagos, Lilly, Pfizer and Sanofi; and speakers’ bureau fees from AbbVie, Amgen, BMS, Chugai, Galapagos, Lilly, Pfizer and Sanofi. J-EG reports consultancy fees from AbbVie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis and Pfizer; and grant/research support from BMS and Pfizer. RC reports consultancy fees from AbbVie, Fresenius, Galapagos, Lilly, Pfizer, Novartis and UCB; speakers’ bureau fees from AbbVie, Amgen, BMS, Celltrion, Fresenius, Galapagos, Janssen, Lilly, Novartis, Pfizer and UCB. KLW reports consultancy fees from AbbVie, AstraZeneca, BMS, Eli Lilly & Company, Galapagos, Gilead, GSK, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB; and grant/research support from BMS and Pfizer. YT has received speaker fees and/or honoraria from AbbVie, Asahi Kasei, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Taiho, Taisho and Pfizer; and research grants from Asahi Kasei, Chugai, Eisai, Mitsubishi Tanabe and Taisho. EVEO is a consultant for Galapagos. VR is a former employee of, and shareholder in, Galapagos. PVH is a consultant for AOP Health, Aspen and Galapagos; and a previous employee of Janssen, MSD and Schering-Plough. KVB is an employee of, and shareholder in, Galapagos. TT reports consultancy fees from AbbVie GK, Astellas, Chugai, Eli Lilly Japan, Gilead, Janssen Pharma K.K., Mitsubishi Tanabe and Pfizer Japan; speakers’ bureau fees from AbbVie GK, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Gilead, Janssen Pharma K.K., Mitsubishi Tanabe, Pfizer Japan and Sanofi K.K.; and research/grant support from AbbVie GK, Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Mitsubishi Tanabe, Nippon Kayaku and UCB Japan. RW acted as an adviser and speaker for Celltrion, Galapagos and Gilead. DA reports consultancy fees, speakers’ bureau fees and grant/research support from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated ac4C in fibroblast-like synoviocytes (FLSs) functions and synovial immune cell infiltration in rheumatoid arthritis (RA)., Methods: FLSs were obtained from active established patients with RA. Protein expression was determined by western blotting or immunohistochemistry or multiplexed immunohistochemistry. Cell migration was measured using a Boyden chamber. ac4C-RIP-seq combined with RNA-seq was performed to identify potential targets of NAT10. RNA immunoprecipitation was used to validate the interaction between protein and mRNA. NAT10 haploinsufficiency, inhibitor remodelin or intra-articular Adv-NAT10 was used to suppress arthritis in mice with delayed-type hypersensitivity arthritis (DYHA) and collagen II-induced arthritis (CIA) and rats with CIA., Results: We found elevated levels of NAT10 and ac4C in FLSs and synovium from patients with RA. NAT10 knockdown or specific inhibitor treatment reduced the migration and invasion of RA FLSs. Increased NAT10 level in the synovium was positively correlated with synovial infiltration of multiple types of immune cells. NAT10 inhibition in vivo attenuated the severity of arthritis in mice with CIA and DTHA, and rats with CIA. Mechanistically, we explored that NAT10 regulated RA FLS functions by promoting stability and translation efficiency of N4-acetylated PTX3 mRNA. PTX3 also regulated RA FLS aggression and is associated with synovial immune cell infiltration., Conclusion: Our findings uncover the important roles of NAT10-mediated ac4C modification in promoting rheumatoid synovial aggression and inflammation, indicating that NAT10 may be a potential target for the treatment of RA, even other dysregulated FLSs-associated disorders., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA)., Methods: We analysed data from patients included in BIOBADASER 3.0 and treated with JAKi or TNFi from 2015 to 2023 and estimated the incidence rate ratio (IRR) of adverse events and persistence., Results: A total of 6826 patients were included. Of these, 52% had RA, 25% psoriatic arthritis and 23% axial SpA. Treatment was with TNFi in 86%. The mean duration of treatment was 2.2±2.0 years with TNFi versus 1.8±1.5 with JAKi. JAKis were prescribed in older patients with longer term disease, greater comorbidity and later treatment lines and more frequently as monotherapy. The IRR of all infections and gastrointestinal events was higher among patients with RA treated with JAKi. Drug persistence at 1, 2 and 3 years was 69%, 55% and 45% for TNFi and 68%, 54% and 45% for JAKi. Multivariate regression models showed a lower probability of discontinuation for JAKi (HR=0.85; 95% CI 0.78-0.92) and concomitant conventional synthetic disease-modifying antirheumatic drugs (HR=0.90; 95% CI 0.84-0.96). The risk of discontinuation increased with glucocorticoids, comorbidities, greater disease activity and later treatment lines., Conclusions: Infections, herpes zoster and gastrointestinal adverse events in patients with RA tended to be more frequent with JAKi. However, prognosis was poor in patients receiving JAKi. Persistence was similar for TNFi and JAKi, although factors associated with discontinuation differed by diagnostic group., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Introduction: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain., Method: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR<60 mL/min/1.73 m 2 ) and stage G3b (eGFR<45 mL/min/1.73 m 2 ). Results were adjusted for relevant time-fixed and time-varying covariates., Results: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m 2 ) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of -0.83 mL/min/1.73 m 2 and estimated additional annual declines (95% CI) of -0.09 (-0.15 to -0.03) in low, -0.17 (-0.23 to -0.10) in moderate and -0.18 (-0.27 to -0.08) mL/min/1.73 m 2 in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity., Conclusions: Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR., Competing Interests: Competing interests: WCW reports having served as a scientific advisor or consultant to Actos, Akebia, Ardelyx, AstraZeneca, Bayer, Cadrenal, GlaxoSmithKline, Lilly, Merck, Natera, Pharmacosmos, Unicycive, Vera and Zydus. SKT reports consulting fees from Novartis. LH reports employment of CorEvitas, consultant to AbbVie, Bristol Myers Squibb, Pfizer, Roche and speakers bureau for Bristol Myers Squibb. DHS reports salary support through research contracts to his institution from CorEvitas, Janssen and Novartis., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: T helper 9 (Th9) cells are recognised for their characteristic expression of the transcription factor PU.1 and production of interleukin-9 (IL-9), which has been implicated in various autoimmune diseases. However, its precise relationship with rheumatoid arthritis (RA) pathogenesis needs to be further clarified., Methods: The expression levels of PU.1 and IL-9 in patients with RA were determined by ELISA, western blotting (WB) and immunohistochemical staining. PU.1-T cell-conditional knockout (KO) mice, IL-9 KO and IL-9R KO mice were used to establish collagen antibody-induced arthritis (CAIA), respectively. The inhibitor of PU.1 and IL-9 blocking antibody was used in collagen-induced arthritis (CIA). In an in vitro study, the effects of IL-9 were investigated using siRNAs and IL-9 recombinant proteins. Finally, the underlying mechanisms were further investigated by luciferase reporter analysis, WB and Chip-qPCR., Results: The upregulation of IL-9 expression in patients with RA exhibited a positive correlation with clinical markers. Using CAIA and CIA model, we demonstrated that interventions targeting PU.1 and IL-9 substantially mitigated the inflammatory phenotype. Furthermore, in vitro assays provided the proinflammatory role of IL-9, particularly in the hyperactivation of macrophages and fibroblast-like synoviocytes. Mechanistically, we uncovered that PU.1 and IL-9 form a positive feedback loop in RA: (1) PU.1 directly binds to the IL-9 promoter, activating its transcription and (2) Th9-derived IL-9 induces PU.1 via the IL-9R-JAK1/STAT3 pathway., Conclusions: These results support that the PU.1-IL-9 axis forms a positive loop in Th9 dysregulation of RA. Targeting this signalling axis presents a potential target approach for treating RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Helicobacter pylori infection has been reported to aggravate rheumatoid arthritis (RA), but the relevant mechanism remains unclear. This study aimed to investigate the underlying pathogenic mechanism of H. pylori infection in the progression of RA., Methods: The Disease Activity Score (DAS-28) and serum anticitrullinated protein antibody (ACPA) levels were compared between H. pylori -negative and H. pylori -positive patients with RA. MH7A cells were stimulated with polyclonal ACPA purified from the peripheral blood of patients with RA. The citrullination levels were assessed by western blot in GES-1 cells and sera. ChIP, luciferase reporter assays, mass spectrometry and ELISA were applied to explore the molecular mechanism of H. pylori infection in RA progression., Results: The DAS-28 and ACPA levels of patients with RA in the H. pylori -positive group were significantly higher than those in the H. pylori -negative group. Polyclonal ACPA derived from H. pylori -positive patients promoted cell proliferation and induced secretion of IL-6 and IL-8. For the first time, we found that H. pylori infection induces cellular protein citrullination by upregulating protein arginine deiminase type 4 (PAD4). Furthermore, we confirmed a direct functional binding of hypoxia-inducible factor 1α on the PADI4 gene promoter. We demonstrated that PAD4 interacts with and citrullinates keratin 1 (K1), and serum and synovial fluid levels of anti-Cit-K1 antibody were markedly increased in H. pylori -infected patients with RA., Conclusion: Our findings reveal a novel mechanism by which H. pylori infection contributes to RA progression. Therapeutic interventions targeting H. pylori may be a viable strategy for the management of RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis., Competing Interests: Competing interests: JPT is scientific cofounder of MetaImmune., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT)., Methods: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking., Results: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks., Conclusions: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice., Trial Registration Number: EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815., Competing Interests: Competing interests: LP reports institutional support for the present manuscript from Amsterdam University Medical Centers. MLH reports institutional grants from AbbVie, Bristol Myers Squibb, Eli Lilly, MSD, Pfizer, Sandoz, Novartis, Nordforsk and UCB; speaker honoraria from Medac, Novartis, Pfizer, Sandoz and UCB; institutional data safety monitoring board or advisory board fees from AbbVie. MLH has chaired the steering committee of the Danish Rheumatology Quality Registry (DANBIO, DRQ), which receives public funding from the hospital owners and funding from pharmaceutical companies. MLH co-chairs EuroSpA, which generates real-world evidence of treatment of psoriatic arthritis and axial spondyloarthritis based on secondary data and is partly funded by Novartis and UCB. DCN reports research grant from MSD; consulting fees from Bristol Myers Squibb, Lilly, Novartis, Pfizer, and UCB; speaker honoraria from Pfizer and UCB; participation on a data safety monitoring board or advisory board fees from UCB. MØ reports institutional grants from AbbVie, Amgen, Bristol Myers Squibb, Merck, Celgene, Eli Lilly Novartis and UCB; personal speaker honoraria from AbbVie, Bristol Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB; participation on a data safety monitoring board or advisory board personal fees from AbbVie, Bristol Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Galapagos, Gilead, Hospira, Janssen, MEDAC, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB. EAH reports institutional grant from research council of Norway; personal speaker honoraria from Pfizer, UCB and Novartis; and participation on a data safety monitoring board or advisory board fees from AbbVie, Pfizer and Eli Lilly. TU reports personal speaker honoraria from Lilly, Pfizer, UCB and Galapagos. TR reports a patent application (TR is the inventor) based on the use of bioengineered IgG targets for the characterisation of rheumatoid factor reactivity patterns. RFvV reports institutional support for the present manuscript from Bristol Myers Squibb; institutional grants for research or education from Alfasigma, AstraZeneca, Bristol Myers Squibb, Galapagos, MSD, Novartis, Pfizer, Roche, Sanofi and UCB; consulting fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer, RemeGen and UCB; speaker honoraria from AbbVie, AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer and UCB; and participation on a data safety monitoring board or advisory board fees from AbbVie, AstraZeneca, Biogen, Bristol Myers Squibb, Galapagos, GSK, Janssen, Pfizer, RemeGen and UCB. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Competing Interests: Competing interests: None declared.

Objectives: To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis., Methods: IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α ( Hif1a ) in IECs ( Hif1a ∆IEC ) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1a ∆IEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA., Results: IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis., Conclusion: Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss., Methods: Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development., Results: Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis., Conclusion: Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Rheumatoid arthritis (RA) exhibits common characteristics with numerous other autoimmune diseases, including the presence of susceptibility genes and the presence of disease-specific autoantibodies. Anti-citrullinated protein antibodies (ACPA) are the hallmarking autoantibodies in RA and the anti-citrullinated protein immune response has been implicated in disease pathogenesis. Insight into the immunological pathways leading to anti-citrullinated protein immunity will not only aid understanding of RA pathogenesis, but may also contribute to elucidation of similar mechanisms in other autoantibody-positive autoimmune diseases. Similarly, lessons learnt in other human autoimmune diseases might be relevant to understand potential drivers of RA. In this review, we will summarise several novel insights into the biology of the anti-citrullinated protein response and their clinical associations that have been obtained in recent years. These insights include the identification of glycans in the variable domain of ACPA, the realisation that ACPA are polyreactive towards other post-translational modifications on proteins, as well as new awareness of the contributing role of mucosal sites to the development of the ACPA response. These findings will be mirrored to emerging concepts obtained in other human (autoimmune) disease characterised by disease-specific autoantibodies. Together with an updated understanding of genetic and environmental risk factors and fresh perspectives on how the microbiome could contribute to antibody formation, these advancements coalesce to a progressively clearer picture of the B cell reaction to modified antigens in the progression of RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objective: Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process of RA and relative mechanism needs to be further clarified., Methods: The level of EPO in serum and synovial fluid from patients with RA and healthy controls was determined by . Collagen-induced arthritis (CIA) mice were constructed to confirm the role of EPO on RA pathogenesis. Differentially expressed genes (DEGs) of EPO-treated fibroblast-like synoviocyte (FLS) were screened by transcriptome sequencing. The transcription factor of neuraminidase 3 (NEU3) of DEGs was verified by double luciferase reporting experiment, DNA pulldown, electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (qPCR) assay., Results: The overexpression of EPO was confirmed in patients with RA, which was positively associated with Disease Activity Score 28-joint count. Additionally, EPO intervention could significantly aggravate the joint destruction in CIA models. The upregulation of NEU3 was screened and verified by transcriptome sequencing and qPCR in EPO-treated FLS, and signal transducer and activator of transcription 5 was screened and verified to be the specific transcription factor of NEU3. EPO upregulates NEU3 expression via activating the Janus kinase 2 (JAK2)-STAT5 signalling pathway through its receptor EPOR, thereby to promote the desialylation through enhancing the migration and invasion ability of FLS, which is verified by JAK2 inhibitor and NEU3 inhibitor., Conclusion: EPO, as a proinflammatory factor, accelerates the process of RA through transcriptional upregulation of the expression of NEU3 by JAK2/STAT5 pathway., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to cluster patients with rheumatoid arthritis (RA) based on comorbidities and then examine the association between these clusters and RA disease activity and mortality., Methods: In this population-based study, residents of an eight-county region with prevalent RA on 1 January 2015 were identified. Patients were followed for vital status until death, last contact or 31 December 2021. Diagnostic codes for 5 years before the prevalence date were used to define 55 comorbidities. Latent class analysis was used to cluster patients based on comorbidity patterns. Standardised mortality ratios were used to assess mortality., Results: A total of 1643 patients with prevalent RA (72% female; 94% white; median age 64 years, median RA duration 7 years) were studied. Four clusters were identified. Cluster 1 (n=686) included patients with few comorbidities, and cluster 4 (n=134) included older patients with 10 or more comorbidities. Cluster 2 (n=200) included patients with five or more comorbidities and high prevalences of depression and obesity, while cluster 3 (n=623) included the remainder. RA disease activity and survival differed across the clusters, with cluster 1 demonstrating more remission and mortality comparable to the general population., Conclusions: More than 40% of patients with prevalent RA did not experience worse mortality than their peers without RA. The cluster with the worst prognosis (<10% of patients with prevalent RA) was older, had more comorbidities and had less disease-modifying antirheumatic drug and biological use compared with the other clusters. Comorbidity patterns may hold the key to moving beyond a one-size-fits-all perspective of RA prognosis., Competing Interests: Competing interests: JMD has received research support from Pfizer, has a patent pending for assessing and treating arthritis, has licensed intellectual property with Girihlet and Remission Medical and serves on a data safety monitoring board for a rheumatoid arthritis clinical trial sponsored by the US National Institutes of Health, all unrelated to this work. All other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

A hallmark of rheumatoid arthritis (RA) is the increased levels of autoantibodies preceding the onset and contributing to the classification of the disease. These autoantibodies, mainly anti-citrullinated protein antibody (ACPA) and rheumatoid factor, have been assumed to be pathogenic and many attempts have been made to link them to the development of bone erosion, pain and arthritis. We and others have recently discovered that most cloned ACPA protect against experimental arthritis in the mouse. In addition, we have identified suppressor B cells in healthy individuals, selected in response to collagen type II, and these cells decrease in numbers in RA. These findings provide a new angle on how to explain the development of RA and maybe also other complex autoimmune diseases preceded by an increased autoimmune response., Competing Interests: Competing interests: RH is named as an inventor in an approved patent protecting the E4 antibody., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Objectives: To investigate the number of children per man and the proportion of childless men as a proxy of fertility in a national cohort of men with inflammatory joint diseases (IJDs), compared with matched controls from the general population., Methods: This is a nationwide, population-based retrospective cohort study. Male patients with IJDs (n = 10 865) in the Norwegian Arthritis Registry were individually matched 1:5 on birth year and county of residence with men without IJDs obtained from the National Population Register (n = 54 325). Birth data were obtained from the Medical Birth Registry of Norway. We compared the mean number of children per man and the proportion of childless men and analysed the impact of age and year of diagnosis., Results: The mean number of children per man in the patient group was 1.80 versus 1.69 in the comparison group (p <0.001), and 21% of the patients in the patient group were childless versus 27% in the comparison group (p <0.001). The finding of less childlessness and higher number of children per man remained consistent across age at diagnosis, except for those diagnosed at age 0-19 years. The difference in childlessness was most pronounced for men diagnosed after year 2000, especially when diagnosed at 30-39 years of age (22% vs 32%, p<0.001)., Conclusion: In this large cohort study we found that patients with IJD have a higher number of children and are less likely to be childless compared with controls. Factors associated with developing or having an IJD might influence fertility and this requires further investigation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In a clinical trial setting, patients with rheumatoid arthritis (RA) taking the Janus kinase inhibitor (JAKi) tofacitinib demonstrated higher adverse events rates compared with those taking the tumour necrosis factor inhibitors (TNFi) adalimumab or etanercept., Objective: Compare treatment discontinuations for adverse events (AEs) among second-line therapies in an international real-world RA population., Methods: Patients initiating JAKi, TNFi or a biological with another mode of action (OMA) from 17 registers participating in the 'JAK-pot' collaboration were included. The primary outcome was the rate of treatment discontinuation due to AEs. We used unadjusted and adjusted cause-specific Cox proportional hazard models to compare treatment discontinuations for AEs among treatment groups by class, but also evaluating separately the specific type of JAKi., Results: Of the 46 913 treatment courses included, 12 523 were JAKi (43% baricitinib, 40% tofacitinib, 15% upadacitinib, 2% filgotinib), 23 391 TNFi and 10 999 OMA. The adjusted cause-specific hazard rate of treatment discontinuation for AEs was similar for TNFi versus JAKi (1.00, 95% CI 0.92 to 1.10) and higher for OMA versus JAKi (1.11, 95% CI 1.01 to 1.23), lower with TNFi compared with tofacitinib (0.81, 95% CI 0.71 to 0.90), but higher for TNFi versus baricitinib (1.15, 95% CI 1.01 to 1.30) and lower for TNFi versus JAKi in patients 65 or older with at least one cardiovascular risk factor (0.79, 95% CI 0.65 to 0.97)., Conclusion: While JAKi overall were not associated with more treatment discontinuations for AEs, subgroup analyses suggest varying patterns with specific JAKi, such as tofacitinib, compared with TNFi. However, these observations should be interpreted cautiously, given the observational study design., Competing Interests: Competing interests: RA has nothing to disclose. DM has nothing to disclose. SAB reports grants from Pfizer outside of this work and speaker fees from Benecke. DC has nothing to disclose. CC reports reports personal fees from AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis, Pfizer outside the submitted work. DDC has nothing to disclose. LD reports contract with BMS outside the present work. OE reports consulting and speaker fees from AbbVie, Pfizer, Eli Lilly, Novartis and Jansen. DH has nothing to disclose. KLH reports grant support from Pfizer and Bristol Myers Squibb and speaking fees from AbbVie. FI reports consulting fees from AbbVie, Janssen, UCB, Galapagos and speaker fees from AbbVie, Galapagos, Eli Lilly, Pfizer and UCB. NI reports consulting and speaking fees from AbbVie, Novartis, UCB, Eli Lilly, Pfizer and Celltrion. LKF has nothing to disclose. SSK has nothing to disclose. TKK reports grants from AbbVie, BMS, Galapagos, Novartis, Pfizer and UCB, consulting fees from AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB Grünenthal, Sandoz and speaker fees from Grünenthal, Sandoz. BFL reports consulting fees from Eli Lilly, Pfizer and AbbVie, and speaking fees from Sandoz. GL has nothing to disclose. DN reports grants from MSD, consulting fees from BMS, Lilly, Novartis, Pfizer, UCB and speaker fees from Pfizer and UCB. KP reports speaker fees from Novartis, Eli Lilly, Roche, Pfizer, Sobi, AbbVie, Pfizer and MSD. MPS has nothing to disclose. AR reports grants from Amgen, AstraZeneca, Novartis, AbbVie, Pfizer, MSD, Lilly, Boehringer Ingelheim, speaker fees from Amgen, AbbVie and Novartis. ZR reports consulting fees from AbbVie, Pfizer, Janssen, AstraZeneca, Novartis, Boehringer Ingelheim, Eli Lilly and speaker fees from AbbVie, Pfizer, Janssen, AstraZeneca, Novartis, Boehringer Ingelheim, Eli Lilly, SOBI, Lek (Sandoz). AS reports speaker fees from AbbVie, BMC, MSD, Pfizer and Roche. PV reports grants from Pfizer and Galapagos, consulting fees from Galapagos, Gilead, Pfizer, Sidekick Health, speaking fees from Eli Lilly, Galapagos and Roularta. RW has nothing to disclose. JZ reports speaking fees from AbbVie, Sobi, Pfizer and Eli Lilly. DSC reports consulting fees from Medela AG. AF reports grants from AbbVie, Pfizer, Galapagos and Eli Lilly, consulting fees from Eli Lilly, Pfizer, AbbVie, speaker fees from Pfizer, Eli Lilly, AbbVie, MSD and BMS. KL has received consultancy and/or speaker fees from Pfizer, Viatris, Celltrion and Galapagos paid to her institution., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Objective: Genome-wide association studies have successfully identified more than 100 loci associated with susceptibility to rheumatoid arthritis (RA). However, our understanding of the functional effects of genetic variants in causing RA and their effects on disease severity and response to treatment remains limited., Methods: In this study, we conducted expression quantitative trait locus (eQTL) analysis to dissect the link between genetic variants and gene expression comparing the disease tissue against blood using RNA-Sequencing of synovial biopsies (n=85) and blood samples (n=51) from treatment-naïve patients with RA from the Pathobiology of Early Arthritis Cohort., Results: This identified 898 eQTL genes in synovium and genes loci in blood, with 232 genes in common to both synovium and blood, although notably many eQTL were tissue specific. Examining the HLA region, we uncovered a specific eQTL at HLA-DPB2 with the critical triad of single-nucleotide polymorphisms (SNPs) rs3128921 driving synovial HLA-DPB2 expression, and both rs3128921 and HLA-DPB2 gene expression correlating with clinical severity and increasing probability of the lympho-myeloid pathotype., Conclusions: This analysis highlights the need to explore functional consequences of genetic associations in disease tissue. HLA-DPB2 SNP rs3128921 could potentially be used to stratify patients to more aggressive treatment immediately at diagnosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: Alterations in tryptophan (Trp) metabolism have been reported in inflammatory diseases, including rheumatoid arthritis (RA). However, understanding whether these alterations participate in RA development and can be considered putative therapeutic targets remains undetermined.In this study, we combined quantitative Trp metabolomics in the serum from patients with RA and corrective administration of a recombinant enzyme in experimental arthritis to address this question., Methods: Targeted quantitative Trp metabolomics was performed on the serum from 574 previously untreated patients with RA from the ESPOIR (Etude et Suivi des POlyarthrites Indifférenciées Récentes) cohort and 98 healthy subjects. A validation cohort involved 69 established patients with RA. Dosages were also done on the serum of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) mice and controls. A proof-of-concept study evaluating the therapeutic potency of targeting the kynurenine pathway was performed in the CAIA model., Results: Differential analysis revealed dramatic changes in Trp metabolite levels in patients with RA compared with healthy controls. Decreased levels of kynurenic (KYNA) and xanthurenic (XANA) acids and indole derivatives, as well as an increased level of quinolinic acid (QUIN), were found in the serum of patients with RA. They correlated positively with disease severity (assessed by both circulating biomarkers and disease activity scores) and negatively with quality-of-life scores. Similar profiles of kynurenine pathway metabolites were observed in the CAIA and CIA models. From a mechanistic perspective, we demonstrated that QUIN favours human fibroblast-like synoviocyte proliferation and affected their cellular metabolism, through inducing both mitochondrial respiration and glycolysis. Finally, systemic administration of the recombinant enzyme aminoadipate aminotransferase, responsible for the generation of XANA and KYNA, was protective in the CAIA model., Conclusions: Altogether, our preclinical and clinical data indicate that alterations in the Trp metabolism play an active role in the pathogenesis of RA and could be considered as a new therapeutic avenue., Competing Interests: Competing interests: HS reports lecture fee, board membership, or consultancy from Amgen, Fresenius, IPSEN, Actial, Astellas, Danone, THAC, Biose, BiomX, Eligo, Immusmol, Adare, Nestle, Ferring, MSD, Bledina, Pfizer, Biocodex, BMS, Bromatech, Gilead, Janssen, Mayoli, Roche, Sanofi, Servier, Takeda, AbbVie; has stocks from Enterome bioscience; and is co-founder of Exeliom Biosciences. JS reports lecture fee, board membership, or consultancy from AbbVie, MSD, Biogen, Pfizer, BMS, Galapagos, Fresenius Kabi, AstraZeneca, UCB, Chugai, Novartis and Janssen. XM report consultancy for AstraZeneca, BMS, Galapagos, GSK, Novartis and Pfizer. D Mulleman received invitation to attend congress: Celltrion healthcare and GSK., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Comparative longitudinal analyses of cellular composition and peripheral blood gene expression in Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and healthy pregnancies., Methods: In total, 335 whole blood samples from 84 RA, SLE and healthy controls before pregnancy, at each trimester, 6 weeks, 6 months and 12 months post partum were analysed. We combined bulk and single cell RNA analyses for cell-type estimation, validated by flow cytometry, before combining this in a cell-type adjusted analysis for an improved resolution of unrecognised gene expression changes associated with RA and SLE pregnancies., Results: Patients were well regulated throughout pregnancy, and few had pregnancy complications. In SLE, the interferon signature was augmented during pregnancy, and the pregnancy signature was continued post partum. An altered cell type composition strongly influences the profile. In the pregnancy signature, transcripts involved in galactosylation potentially altering the effector functions of autoantibodies became more evident. Several genes in the adjusted RA signature are expressed in mucosal associated invariant T cells., Conclusion: We found distinct RA, SLE and pregnancy signatures, and no expression patterns could be attributed to medication or disease activity. Our results support the need for close postpartum follow-up of patients with SLE. Gene expression patterns in RA were closer to healthy controls than to SLE, and primarily became evident after cell-type adjustment. Adjusting for cell abundance unravelled gene expression signatures less associated with variation in cell-composition and highlighted genes with expression profiles associated with changes in specialised cell populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate how individual rheumatoid arthritis (RA) autoantibodies associate with individual signs and symptoms at the time of RA diagnosis., Methods: IgA, IgG, IgM rheumatoid factor (RF), antibodies against cyclic citrullinated peptide version 2 (anti-CCP2) and 16 individual antibodies against citrullinated protein (ACPA) reactivities were analysed centrally in baseline sera from 1600 patients with RA classified according to the 1987 American College of Rheumatology (ACR) criteria. These results were related to C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), number of swollen and tender joints (SJC and TJC), 28-joint disease activity scores (DAS28 and DAS28CRP), global disease activity evaluated by the patients and Health Assessment Questionnaire, all obtained at baseline., Results: Individually, all autoantibodies except immunoglobulin G (IgG) RF associated with low SJC and TJC and with high ESR. In IgM RF-negative patients, ACPA associated strictly with low number of swollen and tender joints. This association persisted in multiple regression and stratified analyses where IgM and IgA RF instead associated with inflammation expressed as ESR. Among subjects without any ACPA peptide reactivity, there was no association between RF isotypes and ESR. The effect of RF on ESR increased with the number of ACPA reactivities, especially for IgM RF. In patients fulfilling the 1987 ACR criteria without taking RF into account, associations between IgM RF and high ESR, as well as between ACPA and low joint counts, remained., Conclusion: Whereas ACPA associate with low counts of affected joints in early RA, RF associates with elevated measures of systemic inflammation in an ACPA-dependent manner. This latter finding corroborates in vitro models of ACPA and RF in immune complex-induced inflammation. These phenotypic associations are independent of classification criteria., Competing Interests: Competing interests: EP and LM-A are employees at Thermo Fisher Scientific. JA has had or have research agreements with AbbVie, BMS, Eli Lilly, Galapagos, MSD, Pfizer, Roche, Samsung Bioepis and Sanofi, mainly for the national safety monitoring of rheumatology immunomodulators in Sweden (ARTIS). JR has been a member of the Scientific Advisory Board for Thermo Fisher Scientific and for Inova/Werfen and has received consulting fees, speaking fees and/ or honoraria by Thermo Fisher Scientific. RH has received consulting fees from Regor, Lipum AB and Cyxone AB and is the founder of Vacara AB. LK has been a co-ordinator of several IMI-funded projects which included collaborations with Janssen, Pfizer, Sanofi, UCB, GSK and Eli-Lilly. This work has been presented as a poster in a preliminary form at EULAR (June 2019) and to the European Workshop for Rheumatology Research (March 2023)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Glucocorticoids used in the treatment of inflammatory rheumatic conditions can impact on health-related quality of life. An underpinning qualitative study developed a long-list of candidate items for a treatment-specific patient-reported outcome (PRO) measure. The objective of this paper is to determine scale structure and psychometric properties of the Steroid PRO., Methods: A cross-sectional survey of adults from the UK, USA, Australia and New Zealand, taking glucocorticoids for a rheumatic disease. Initial survey collected demographics, clinical information, 40 Steroid PRO candidate items and EuroQol-5 Dimensions- 5 levels (EQ-5D-5L). Follow-up, 3-5 days later, collected Steroid PRO candidate items and a condition-change ('transition') question. Analysis included Rasch measurement model, exploratory factor analysis (EFA), and hypothesis testing for discriminative validity, convergence validity and test-retest reliability., Results: Total responses 946: UK n=743 (79%); USA n=139 (15%); Australia/New Zealand n=64 (7%); mean age 57.6 (SD=13.6); 833 (88%) women. Participants with inflammatory arthritis n=197 (21%), connective tissue disease and/or vasculitis n=402 (42%), giant cell arteritis and/or polymyalgia rheumatica n=347 (37%). Twenty-five items were removed due to lack of fit to Rasch model. Of the remaining items, EFA suggested four subscales: Social impact (4 items); Impact on appearance (3 items); Psychological impact (5 items); Treatment concerns (3 items). Rasch modelling supported a four-subscale structure and total score, confirming construct validity and reliability. Hypothesis testing confirmed discriminant and convergence validity. Intraclass correlation coefficient (total score) was 0.809 demonstrating excellent (test-retest) reliability., Conclusions: The Steroid PRO is a 15-item, valid and reliable scale for measuring the impact of glucocorticoid therapy in people with rheumatic diseases., Competing Interests: Competing interests: SB—Grant/research support from: Vifor Pharma; MN—Grant /research support from: Vifor Pharma; JD, PR, CS and CH: None declared; ED—Grant/research support from: Vifor Pharma; SMG—Consultant of: UCB, Grant/research support from: Novartis; SLM reports: Consultancy on behalf of her institution for Roche/Chugai, Sanofi, AbbVie, AstraZeneca, Pfizer; Investigator on clinical trials for Sanofi, GSK, Sparrow; speaking/lecturing on behalf of her institution for Roche/Chugai, Vifor, Pfizer, UCB, Novartis and AbbVie; chief investigator on STERLING-PMR trial, funded by NIHR; patron of the charity PMRGCAuk. No personal remuneration was received for any of the above activities. Support from Roche/Chugai to attend EULAR2019 in person and from Pfizer to attend ACR Convergence 2021 virtually. SLM is supported in part by the NIHR Leeds Biomedical Research Centre. The views expressed in this article are those of the authors and not necessarily those of the NIHR, the NIHR Leeds Biomedical Research Centre, the National Health Service or the UK Department of Health and Social Care; JR—Speakers bureau: Vifor Pharma, Consultant of: Vifor Pharma, Unrestricted Grant/research support from: Vifor Pharma., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany., Methods: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care., Results: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care., Discussion: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To develop and validate definitions for disease flares in rheumatoid arthritis (RA) based on the quantitative Simplified and Clinical Disease Activity Indices (SDAI, CDAI)., Methods: We analysed RA treatment courses from the Norwegian disease-modifying antirheumatic drug registry (NOR-DMARD) and the Vienna RA cohort. In a receiver operating curve analysis, we determined flare definitions for absolute changes in SDAI and CDAI based on a semiquantitative patient anchor. NOR-DMARD was sampled into an 80%-training cohort for cut point derivation and a 20%-test cohort for internal validation. The definitions were then externally validated in the independent Vienna RA cohort and tested regarding their performance on longitudinal, content, face, and construct validity., Results: We analysed 4256 treatment courses from NOR-DMARD and 2557 from the Vienna RA cohort. The preliminary definitions for absolute changes in SDAI and CDAI for flare are an increase of 4.7 and 4.5, respectively. The definitions performed well in the test and external validation cohorts, and showed clinical face and construct validity, as flares significantly impact both functional ( ∆ Health Assessment Questionnaire flare vs no-flare +0.43; p<0.001) and structural ( ∆ modified Sharp Score 43% higher after flare; p<0.001) disease outcomes, and reflect consistent worsening across all disease core sets, both patient reported and objective., Conclusion: We here provide novel definitions for flare in RA based on SDAI and CDAI, validated in two large independent real-world cohorts. In times of highly effective medications for RA, and consideration of their tapering, these definitions will be useful for guiding decision making in clinical practice and designing clinical trials., Competing Interests: Competing interests: VK: None declared. AK: received honoraria (speaker’s bureau, consultancy) from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB and Pfizer. JSS: received grants from AbbVie, AstraZeneca, Galapagos, Eli Lilly, Novartis, Roche and honoraria from AbbVie, Amgen, AstraZeneca, Astro, BMS, Chugai, Janssen, Eli Lilly, MSD, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, UCB, Celltrion, Gilead-Galapagos and Sanofi. EKK: None declared. SAP: received grants from Boehringer Ingelheim and honoraria (consultancy) from Boehringer Ingelheim and Novartis. TKK: received grants from AbbVie, BMS, Galapagos, Novartis, Pfizer and UCB, and honoraria (speaker’s bureau, consultancy) from AbbVie, Galapagos, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, Amgen, Celltrion, Egis, Evapharma, Ewopharma, Grünenthal, Hikma, Janssen, Oktal, Sandoz and Sanofi. DA: received grants from AbbVie, Amgen, Galapagos, Eli Lilly and Sanofi, and honoraria (speaker’s bureau, consultancy) from AbbVie, Amgen, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer and Sandoz. JSS and DA are members of the ARD Editorial Board., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: This study aims to evaluate non-melanoma skin cancer (NMSC) risk associated with abatacept treatment for rheumatoid arthritis (RA)., Methods: This evaluation included 16 abatacept RA clinical trials and 6 observational studies. NMSC incidence rates (IRs)/1000 patient-years (p-y) of exposure were compared between patients treated with abatacept versus placebo, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and other biological/targeted synthetic (b/ts)DMARDs. For observational studies, a random-effects model was used to pool rate ratios (RRs)., Results: ~49 000 patients receiving abatacept were analysed from clinical trials (~7000) and observational studies (~42 000). In randomised trials (n=4138; median abatacept exposure, 12 (range 2-30) months), NMSC IRs (95% CIs) were not significantly different for abatacept (6.0 (3.3 to 10.0)) and placebo (4.0 (1.3 to 9.3)) and remained stable throughout the long-term, open-label period (median cumulative exposure, 28 (range 2-130 months); 21 335 p-y of exposure (7044 patients over 3 years)). For registry databases, NMSC IRs/1000 p-y were 5-12 (abatacept), 1.6-10 (csDMARDs) and 3-8 (other b/tsDMARDs). Claims database IRs were 19-22 (abatacept), 15-18 (csDMARDs) and 14-17 (other b/tsDMARDs). Pooled RRs (95% CIs) from observational studies for NMSC in patients receiving abatacept were 1.84 (1.00 to 3.37) vs csDMARDs and 1.11 (0.98 to 1.26) vs other b/tsDMARDs., Conclusions: Consistent with the warnings and precautions of the abatacept label, this analysis suggests a potential increase in NMSC risk with abatacept use compared with csDMARDs. No significant increase was observed compared with b/tsDMARDs, but the lower limit of the 95% CI was close to unity., Competing Interests: Competing interests: TS was an employee of and shareholder in Bristol Myers Squibb (at the time of the analysis; former employee at present). LD, VK, AD and MAM are employees of and shareholders in Bristol Myers Squibb. SS reports advisory board involvement, speaker fees and grant/research support from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novartis. KM reports grant/research support from Rheumatology Research Foundation. MH is an employee of the University of Maryland School of Medicine (full time) and US Department of Veterans Affairs (part time); reports consultancy fees and advisory board involvement from Bristol Myers Squibb, Eli Lilly, Kolon TissueGene, Inc, Novartis, Pfizer, Samumed and Theralogix; is a member of the Data Safety Monitoring Committee for Galapagos, Roche, and IQVIA; reports royalties from Elsevier and UpToDate; reports stock ownership in BriOri Biotech and Theralogix; and is president of Rheumcon. MB reports consultancy fees from Novartis. JA reports grant/research support from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Merck, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB for ARTIS. AS reports speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Lilly, Merck, Pfizer and Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To study long-term (up to 20-year) mortality of two treat-to-target trial cohorts in undifferentiated arthritis (UA) and early rheumatoid arthritis (RA)., Methods: The BeSt (BehandelStrategieën) study (n=508, early RA) was performed between 2000 and 2012. For 10 years, patients were treated-to-target disease activity score (DAS)≤2.4.The Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED) study (n=610, early RA/UA) was performed between 2007 and 2015. For 5 years, patients were treated-to-target DAS<1.6.Vital status of BeSt/IMPROVED participants was assessed up to and including 31 December 2021. Standardised mortality ratios (SMRs) were calculated. Stratified analyses for anticitrullinated protein antibody (ACPA) and smoking status were performed. Death causes and the potential effect of disease activity during the trial period on late mortality were assessed., Results: Excess mortality was found in both BeSt (SMR 1.32, 95% CI 1.14 to 1.53) and IMPROVED (SMR 1.33, 95% CI 1.10 to 1.63) and became manifest after 10 years. Excess mortality was statistically significant in ACPA+ patients who smoked (BeSt: SMR 2.80, 95% CI 2.16 to 3.64; IMPROVED: 2.14, 95% CI 1.33 to 3.45). Mean survival time was 10 (95% CI 5 to 16) months shorter than expected in BeSt and 13 (95% CI 11 to 16) months in IMPROVED. The HR for mortality was 1.34 (95% CI 0.96 to 1.86; BeSt)/1.13 (95% CI 0.67 to 1.91; IMPROVED) per 1 point increase in mean DAS during the trial. The main cause of death was malignancy., Conclusions: After long-term treatment-to-target, excess mortality occurred in patients with RA after>10 years since treatment start, with smoking as an important risk factor., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To provide an overview and in-depth analysis of temporal trends in prevalence of musculoskeletal (MSK) disorders in women of childbearing age (WCBA) at global, regional and national levels over the last 30 years, with a special focus on their associations with age, period and birth cohort., Methods: Estimates and 95% uncertainty intervals (UIs) for MSK disorders prevalence in WCBA were extracted from the Global Burden of Diseases, Injuries and Risk Factors Study 2019. An age-period-cohort model was adopted to estimate the overall annual percentage change of prevalence ( net drift , % per year), annual percentage change of prevalence within each age group ( local drift , % per year), fitted longitudinal age-specific rates adjusted for period deviations (age effects) and period/cohort relative risks (period/cohort effects) from 1990 to 2019., Results: In 2019, the global number of MSK disorders prevalence in WCBA was 354.57 million (95% UI: 322.64 to 387.68). Fifty countries had at least one million prevalence, with India, China, the USA, Indonesia and Brazil being the highest accounting for 51.03% of global prevalence. From 1990 to 2019, a global net drift of MSK disorders prevalence in WCBA was -0.06% (95% CI: -0.07% to -0.05%) per year, ranging from -0.09% (95% CI: -0.10% to -0.07%) in low-middle sociodemographic index (SDI) region to 0.10% (95% CI: 0.08% to 0.12%) in high-middle SDI region, with 138 countries presenting increasing trends, 24 presenting decreasing trends and 42 presenting relatively flat trends. As reflected by local drift , higher SDI regions had more age groups showing rising prevalence whereas lower SDI regions had more declining prevalence. Globally, an increasing occurrence of MSK disorders prevalence in WCBA beyond adolescent and towards the adult stage has been prominent. Age effects illustrated similar patterns across different SDI regions, with risk increasing with age. High SDI region showed generally lower period risks over time, whereas others showed more unfavourable period risks. High, high-middle and middle SDI regions presented unfavourable prevalence deteriorations, whereas others presented favourable prevalence improvements in successively birth cohorts., Conclusions: Although a favourable overall temporal trend ( net drift ) of MSK disorders prevalence in WCBA was observed over the last 30 years globally, there were 138 countries showing unfavourable rising trends, coupled with deteriorations in period/cohort risks in many countries, collectively raising concerns about timely realisation of the Targets of Sustainable Development Goal. Improvements in the MSK disorders-related prevention, management and treatment programmes in WCBA could decline the relative risk for successively younger birth cohorts and for all age groups over period progressing., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To evaluate which American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) should primarily be used for efficacy claims in future drug approval trials of rheumatoid arthritis (RA)., Methods: We systematically searched EMBASE, Medline and the Cochrane Library for randomised controlled RA drug approval trials of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). We included full-text articles reporting ACR response rates for multiple time points over a 24-week placebo-controlled period and visualised normalised response trajectories over time in different patient populations. Using mixed-effect logistic regression, we calculated the proportion of ACR responders per outcome and time point, and compared the discriminant validity of these metrics at multiple time points., Results: We screened 12 680 records and included 45 in the final analysis. Discriminative capacity of the ACR20 was high across all time points, whereas ACR50 and ACR70 showed highest discrimination towards the end of the placebo-controlled periods. This effect could be observed in all patient populations and compound groups. Faster response to treatment was observed in DMARD naïve patient populations when compared with DMARD insufficient responders., Conclusion: ACR20 remains the most powerful discriminator between active treatment and placebo, especially when early discrimination is of primary interest. At the same time, our results support the selection of more stringent thresholds if later time points shall be evaluated, given their comparable discriminant but higher clinical face validity., Competing Interests: Competing interests: VK: None declared. AK: received honoraria (speaker’s bureau, consultancy) from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB, Pfizer. JSS: received grants from AbbVie, AstraZeneca, Galapagos, Eli Lilly, Novartis, Roche and honoraria from AbbVie, Amgen, AstraZeneca, Astro, BMS, Chugai, Janssen, Eli Lilly, MSD, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, UCB, Celltrion, Gilead-Galapagos, Sanofi. DA received grants from AbbVie, Amgen, Galapagos, Eli Lilly, Sanofi, and honoraria (speaker’s bureau, consultancy) from AbbVie, Amgen, Galapagos, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare the use of glucocorticoids (GC) over time in patients with rheumatoid arthritis (RA) who were or were not treated initially with GC bridging therapy., Methods: Data from the BeSt, CareRA and COBRA trials were combined in an individual patient data (IPD) meta-analysis. We compared GC use between bridgers and non-bridgers at 12, 18 and 24 months from baseline with mixed-effects regression analysis. Secondary outcomes were mean cumulative GC dose until 24 months after baseline with and without the bridging period, Disease Activity Score based on 28 joints (DAS28) over time and number of disease-modifying antirheumatic drug (DMARD) changes., Results: 252/625 patients (40%) were randomised to GC bridging (bridgers). Excluding the period of bridging, later GC use was low in both groups and cumulative doses were similar. Mean DAS28 was similar between the groups, but bridgers improved more rapidly (p<0.001) in the first 6 months and the bridgers required significantly fewer changes in DMARDs (incidence rate ratio 0.59 (95% CI 0.38 to 0.94)). GC use was higher in the bridgers at t=12 months (OR 3.27 (95% CI 1.06 to 10.08)) and the bridging schedules resulted in a difference in cumulative GC dose of 2406 mg (95% CI 1403 to 3408) over 24 months., Conclusion: In randomised trials comparing GC bridging and no GC bridging, bridgers had a more rapid clinical improvement, fewer DMARD changes and similar late use of GC compared with non-bridgers. GC bridging per protocol resulted, as could be expected, in a higher cumulative GC dose over 2 years., Competing Interests: Competing interests: LvO, PHPdJ, RBML, JSS and TWJH declare no competing interests. MB: reports speaker fees from Novartis and Pfizer, and provided expert testimony for Celltrion. PV: holds the Pfizer Chair Early Rheumatoid Arthritis Management as well as the Galapagos Chair in RA at KU Leuven and received consultancy and/or speaker honoraria from AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Roularta and Sidekick Health within the last 24 months. SAB: received an ASPIRE grant from Pfizer. CFA: received study grants for BeSt and IMPROVED from Centocor (now Janssen) and AbbVie, respectively. PE: provided expert advice to AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis, Pfizer, Roche, Samsung. And clinical trials: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, Samsung. WL received study grants from Pfizer and consultancy speaker fees from Eli Lilly, Pfizer, Amgen, Galapagos and UCB., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)