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Objectives: The usefulness of methotrexate-polyglutamates (MTX-PGs) concentration for management of rheumatoid arthritis has been debated. We aimed to clarify the association of MTX-PGs concentration with efficacy and safety in MTX-naïve patients initiating MTX in a prospective interventional clinical trial., Methods: The MIRACLE trial enrolled 300 MTX-naïve patients. Oral MTX was initiated and increased to the maximum tolerated dose by week 12. Patients who did not achieve remission according to the Simplified Disease Activity Index at week 24 were randomised to either the continued dose or reduced dose group and were started on subcutaneous adalimumab. We measured the concentrations of MTX-PGs in erythrocytes using liquid chromatography-tandem mass spectrometry and analysed the association of these concentrations with efficacy and safety., Results: The mean concentration of total MTX-PGs increased with an increasing dose of MTX and continued to elevate for another 12 weeks after the dose was fixed. At week 24, the total MTX-PGs concentration was 110.5 (SD 43.8) nmol/L with MTX dose of 12.6 (3.0) mg/week (0.23 (0.07) mg/kg/week). During MTX monotherapy, the higher MTX-PGs concentration was an independent factor for lower disease activity; however, this association disappeared after adalimumab initiation in patients with continued MTX dose. Hepatotoxicity was related to the higher MTX-PGs concentration regardless of adalimumab use. The total MTX-PGs concentration was significantly elevated by lower estimated glomerular filtration rate, serum albumin and body mass index., Conclusions: The MIRACLE trial demonstrated that higher total MTX-PGs concentration in erythrocytes is related to the higher efficacy and lower safety of MTX., Trial Registration Number: NCT03505008., Competing Interests: Competing interests: HTam received honoraria from AbbVie, Eisai; support for attending meetings from PhRMA. KI received grants from Mitsubishi-Tanabe, Eli Lilly; honoraria from AbbVie, Eisai, Pfizer, Mitsubishi-Tanabe, Janssen, Novartis, UCB, Daiichi-Sankyo, Eli Lilly, Gilead Sciences, AstraZeneca, Asahi Kasei, Chugai, Bristol-Myers Squibb. TM received consulting fees from Eisai, Gilead Sciences; honoraria from Eisai, AbbVie, Eli Lilly, Gilead Sciences, Asahi Kasei. KS received grants/research support from Novartis, Astellas, AbbVie, Bristol-Myers Squibb, Yuhan; consulting fees from KD Bio. SH received grants from AbbVie, Asahi Kasei, Chugai, Eisai, Eli Lily, Otsuka, Taisho, UCB; honoraria from AbbVie, Asahi-Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead Sciences, Glaxo SmithKline, Janssen, Nihon-Shinyaku, Novartis, Otsuka Pharmaceutical, Pfizer, Taisho, Tanabe-Mitsubishi, UCB; participated on advisory boards of AbbVie, Astellas, Bristol Myers Squibb, Eisai, Eli Lilly, Gilead Sciences, Janssen, Taisho, UCB. SS received honoraria from AbbVie, Pfizer. HY received grants from AbbVie, Boehringer Ingelheim, Gilead Sciences, Nippon Shinyaku, Asahi Kasei, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Asahi Kasei, Astellas, Daiichi Sankyo, Eisai, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer Ingelheim, Bayer, Viatris, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis. MK received grants and royalties from MBL; consulting fees from Boehringer Ingelheim, Mochida, Kissei, GSK, AstraZeneca, Mitsubishi-Tanabe, Janssen, Biogen; received honoraria from Boehringer Ingelheim, Chugai, Asahi Kasei; participated on advisory board of Argenx. TI received honoraria from Asahi Kasei, GSK, Chugai, Pfizer, Eli Lilly, Boehringer-Ingelheim, AstraZeneca. HK received a grant from Pfizer, AbbVie, Asahi Kasei, Boehringer Ingelheim, Chugai, Eisai, Mitsubishi-Tanabe, Taisho; consulting fees from Sanofi; honoraria from AbbVie, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer. TK received grant/research support from AbbVie, Astellas, Chugai; honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Pfizer, Eisai, Taisho, UCB; participated on board of JCR subcommittee on Guidelines for RA Therapeutics. YN is a shareholder and employee of Eisai. MM is a shareholder and employee of Eisai. HM is an employee of Eisai. YS received honoraria from Mochida. WT received consulting fees and honoraria from Eli Lilly, Eisai; honoraria from Pfizer. TT received consulting fees from AbbVie, Eli Lilly, Gilead Sciences, Mitsubishi-Tanabe, Taisho; honoraria from AbbVie, Astellas, AstraZeneca, Chugai, Eisai, Eli Lilly, Gilead Sciences, Janssen, Mitsubishi-Tanabe, Pfizer, Taisho. YK received grants from AbbVie, Asahi Kasei, Ayumi, Boehringer Ingelheim, Chugai, Eisai, Gilead Sciences, Mitsubishi-Tanabe, Taisho, UCB; consulting fees from AbbVie, Asahi Kasei, Bristol-Myers Squibb, Eli Lilly, Gilead Sciences, Pfizer, Taisho, UCB; honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, Taisho, UCB. The other coauthors declare no relevant conflicts of interest., (© Author(s) (or their employer(s)) 2024. 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.)

Objectives: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE)., Methods: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred., Results: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day., Conclusions: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients., Competing Interests: Competing interests: YK received honoraria from Asahi Kasei Pharma, Astellas Pharma, AstraZeneca K.K., Chugai Pharmaceutical, GlaxoSmithKline KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Pfizer Japan, Sanofi KK. EI received honoraria from Bristol-Myers Squibb KK, Eisai and consulting fees from Nippontect Systems. MH received honoraria from AbbVie GK, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Takeda Pharmaceutical, Teijin Pharma, consulting fees from AbbVie GK, Bristol-Myers Squibb K.K., Kissei Pharmaceutical, Nippon Boehringer Ingelheim, Teijin Pharma, grant/research support from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Kissei Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Kayaku, Sekisui Medical, Shionogi, Taisho Pharmaceutical, Takeda Pharmaceutical, Teijin Pharma. AH received honoraria from UCB, Janssen, Sandoz, Eli Lilly, consulting fees from AbbVie, GSK and grant/research support from AstraZeneca, GSK, Bristol Myers Squibb, Janssen, Merck Serono. CSL received honoraria from AstraZeneca UK and consulting fee from AstraZeneca Pharmaceuticals LP. ZL received honoraria from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma and consulting fees from Pfizer, Roche, Janssen, Abbott, AbbVie, Bristol Myers Squibb, MSD, Celgene, Eli Lilly, GSK, Novartis, UCB Pharma. SS received consulting fees from Pfizer, AstraZeneca, ZP Therapeutics and grant/research support from Pfizer, AstraZeneca, ZP Therapeutics. SVN received consulting fees from Biogen, Boehringer Ingelheim, AstraZeneca, grant/research support from Jannsen, Novartis, Pfizer, GSK and support for attending meetings from Biogen. SOon received royalty from Venetoclax. KN is on the advisory board for AbbVie. TT received honoraria from AbbVie GK, Chugai Pharmaceutical, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma, consulting fees from AbbVie GK, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma and grant/research support from AbbVie GK, Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma. YT received honoraria from AbbVie GK, Asahi Kasei Pharma, AstraZeneca K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical, Eisai, Eli Lilly Japan K.K., Gilead Sciences, GlaxoSmithKline K.K., Nippon Boehringer Ingelheim, Pfizer Japan, Taiho Pharmaceutical, Taisho Pharmaceutical and grant/research support from Asahi Kasei Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical. MN received honoraria from Actelion, GSK, Janssen, Pfizer, UCB, consulting fees from Boehringer Ingelheim, Certa Therapeutics, Eli Lilly, GSK, Janssen, Pfizer, UCB and grant/research support from Actelion, AstraZeneca, Bristol Myers Squibb, GSK, Janssen, UCB. EFM received honoraria from AstraZeneca, EMD Serono, Gilead, consulting fees from AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Novartis and grant/research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Biogen, Eli Lilly, EMD Serono, Genentech, GSK, Janssen, UCB. All other authors declare no competing interests., (© 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 efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors., Methods: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12., Results: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups., Conclusions: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population., Trial Registration Number: NCT04134728., Competing Interests: Competing interests: PCT has received consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead Sciences, GSK, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB, and research support from Galapagos. MEW receives research support from AbbVie, Aqtual, Bristol Myers Squibb and Lilly, and consultation fees from AbbVie, Aclaris, Amgen, Bayer, Bristol Myers Squibb, Corvitas, Genosco, Gilead Sciences, GSK, Horizon, Johnson & Johnson, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix and Scipher. IBMcI has received consultancy and research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Causeway, Compugen, Gilead Sciences, GSK, Lilly, Novartis, Pfizer and UCB and holds a leadership role in Evelo, University of Glasgow, Versus Arthritis and is an NHS GGC Board Member and an Annals of the Rheumatic Diseases Editorial Board Member. TA has accepted research grants and/or honoraria for meetings from AbbVie, Alexion, Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, GSK, Lilly Japan, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical and UCB Japan. VS has received consulting fees from AbbVie, Alpine, Alumis, Amgen, Aria, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Ermium, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kiniksa, Lilly, Merck, MiMedx, Novartis, Omeros, Pfizer, R-Pharm, RAPT, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, Tonix and Urica. TT received payment or honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, Janssen, Lilly Japan, Mitsubishi-Tanabe, Pfizer Japan and is an Annals of the Rheumatic Diseases Editorial Board Member. MB, DB, JD, CG, AG, SM, CO’S, DS, LAS, CS, JES, MW, RW and SW are employees of GSK and hold GSK stock/shares. RMF has received research support from AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Galvani, Genentech/Roche, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung, Sanofi-Genzyme, Selecta and UCB; consulting fees from AbbVie, Amgen, Arthrosi, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Galapagos, Galvani, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung and UCB and honoraria from AbbVie, GSK and Pfizer and is an Annals of the Rheumatic Diseases Editorial Board Member., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis., Methods: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints., Primary Endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12., Results: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients., Primary Endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups., Conclusions: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib., Trial Registration Numbers: NCT03980483, NCT03970837., Competing Interests: Competing interests: RMF has received research support from AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Galvani, Genentech/Roche, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung, Sanofi-Genzyme, Selecta and UCB; consulting fees from AbbVie, Amgen, Arthrosi, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Galapagos, Galvani, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Priovant, Samsung and UCB; has received honoraria from AbbVie, GSK and Pfizer and is an Annals of the Rheumatic Diseases Editorial Board Member. DvdH has received consulting fees from AbbVie, Bayer, Bristol Myers Squibb, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, UCB Pharma, is Director of Imaging Rheumatology BV and is an Annals of the Rheumatic Diseases Editorial Board Member. VS has received consulting fees from AbbVie, Alpine, Alumis, Amgen, Aria, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Ermium, Genentech/Roche, GSK, Horizon, Inmedix, Janssen, Kiniksa, Lilly, Merck, MiMedx, Novartis, Omeros, Pfizer, R-Pharm, RAPT, Regeneron, Samsung, Sandoz, Sanofi, Scipher, Setpoint, Sorrento, Spherix, Tonix and Urica. TA has accepted research grants and/or honoraria for meetings from AbbVie, Alexion, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, GSK, Lilly Japan, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, and UCB Japan. IBM has received consultancy and research support from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Causeway, Compugen, Gilead Sciences, GSK, Lilly, Novartis, Pfizer, and UCB and holds a leadership role in Evelo, University of Glasgow, Versus Arthritis, and is an NHS GGC Board Member and an Annals of the Rheumatic Diseases Editorial Board Member. TT received payment or honoraria from AbbVie, Asahi Kasei, Astellas, AstraZeneca K.K., Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Gilead Sciences, Janssen K.K, Lilly Japan, Mitsubishi-Tanabe, Pfizer Japan and is an Annals of the Rheumatic Diseases Editorial Board Member. PCT has received consulting fees from AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead Sciences, GSK, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi, and UCB, and research support from Galapagos. MB, DB, JD, CG, AG, SM, CO’S, DS, LAS, CS, JES, MW, RW and SW are employees of GSK and hold GSK stock/shares. MEW receives research support from AbbVie, Aqtual, Bristol Myers Squibb and Lilly, and consultation fees from AbbVie, Aclaris, Amgen, Bayer, Bristol Myers Squibb, Corvitas, Genosco, Gilead Sciences, GSK, Horizon, Johnson & Johnson, Lilly, Novartis, Pfizer, Rami Therapeutics, R Pharma, Roche, Sanofi, Scipher, Sci Rhom, Set Point and Tremeau. He holds stock/stock options of CanFite, Inmedix, and Scipher., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine the efficacy and safety of TAS5315, an irreversible covalent Bruton's tyrosine kinase inhibitor, in Japanese patients with rheumatoid arthritis (RA) refractory to methotrexate., Methods: In part A of this phase IIa double-blind study, patients were randomised to TAS5315 4 or 2 mg or placebo once daily for 12 weeks; in part B, all patients received TAS5315 for another 24 weeks. The proportion of patients meeting American College of Rheumatology criteria for 20% improvement (ACR20) at week 12 was assessed (primary endpoint)., Results: Ninety-one patients were randomised in part A, and 84 entered part B. At week 12, 78.9% of patients achieved ACR20 in the TAS5315 combined group vs 60.0% with placebo (p=0.053), 33.3% vs 13.3% achieved ACR50 (p=0.072) and 7.0% vs 0.0% achieved ACR70 (p=0.294), respectively. More patients receiving TAS5315 than placebo had low disease activity or remission at week 12. Clinical and biomarker improvements were maintained during part B. Adverse event (AE) incidence in TAS5315 was similar to placebo in part A; common AEs with TAS5315 were nasopharyngitis (10.3%), pruritus (6.9%) and cystitis (5.2%). Over 36 weeks, nine patients experienced bleeding events of whom four and two patients recovered with drug continuation and interruption, respectively. Three patients recovered after TAS5315 discontinuation., Conclusions: The primary endpoint was not achieved. TAS5315 appears to have some bleeding risks, but nevertheless demonstrated numerical differences, compared with placebo, in the improvement rates of all measures of RA disease activity. Future analysis of the risk-benefit of TAS5315 should be considered., Trial Registration Numbers: NCT03605251, JapicCTI-184020, jRCT2080223962., Competing Interests: Competing interests: TT has received consulting fees from Taiho, AbbVie, Gilead, Mitsubishi-Tanabe, Chugai and Eli Lilly; has received research grants from AbbVie, Chugai, Eisai, Mitsubishi-Tanabe, ONO and AYUMI; has received honoraria from AbbVie, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe, Pfizer and Janssen. ST has received consulting fees from Taiho, Mitsubishi-Tanabe, Gilead, Chugai, AbbVie, Astellas and Eli Lilly; has conducted joint research with Eli Lilly; has received honoraria for lectures and presentations from Mitsubishi-Tanabe, Pfizer, ONO, Bristol-Myers Squibb, Gilead, Eisai, Chugai, AbbVie, Astellas and Eli Lilly; has received travel fees from Mitsubishi-Tanabe, Pfizer, ONO, Bristol-Myers Squibb, Gilead, Eisai, Chugai, AbbVie, Astellas and Eli Lilly; serves as a board member for the Japan College of Rheumatology, the Japanese Society for Clinical Rheumatology and Related Research, the Japan Society for Rheumatism and Joint Surgery and the Japan Rheumatism Foundation. MM has received consulting fees from Taiho; and serves as a executive director of the Japanese Society of Thrombosis and Hemostasis. YT has received consulting fees from Taiho; has received speaker’s fees and/or honoraria from Boehringer-Ingelheim, Eli Lilly, AbbVie, Gilead, AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe and GlaxoSmithKline; and has received research grants from Asahi-Kasei, AbbVie, Chugai, Eisai, Takeda, Daiichi Sankyo, Boehringer-Ingelheim and Asahi-Kasei., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway., Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document., Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring., Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers., Competing Interests: Competing interests: DA: Grants or contracts from any entity: AbbVie, Amgen, Eli Lilly, Novartis, Roche, SoBi and Sanofi; Consulting fees: AbbVie, Amgen, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche and Sandoz; Support for attending meetings and/or travel: AbbVie, Gilead, Sandoz, Pfizer, BMSAK: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Bristol-Myers Squibb, Celgene, Eli-Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis and PfizerKK: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Boehringer Ingelheim, UCB Pharma and AbbVie; Support for attending meetings and/or travel: AbbVie, Gilead, Sandoz, Pfizer and BMSJI: Grants or contracts from any entity: Pfizer, GSK and Janssen; Consulting fees: AbbVie, Gilead and BMS; Payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing or educational events: AbbVie, Gilead and Roche; Support for attending meetings and/or travel: Eli Lilly and Gilead; Participation on a Data Safety Monitoring Board or Advisory Board: Eli Lilly; Leadership or fiduciary role in other board, society, committee or advocacy group: Versus Arthritis Board member (unpaid) NS: Grants or contracts from any entity: AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics; Consulting fees: Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, MSD, Novartis, Novo Nordisk, Pfizer and SanofiMV: Grants or contracts from any entity: PfizerBC: Grants or contracts from any entity: Pfizer, Roche, Chugai and Novartis; Consulting fees: AbbVie, Celltrion, Janssen, Gilead-Galapagos, Eli Lilly, Novartis, Roche-Chugai; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, BMS, Celltrion, Gilead-Galapagos, Janssen, Eli Lilly, Merck, Pfizer and Roche-ChugaiNB: All support for the present manuscript: Vienna Medical Academy; Consulting fees: Amgen, EULAR, Galapagos, Global Alliance for Patient Access, Grunenthal, Eli Lilly, Pfizer and Sanofi; Support for attending meetings and/or travel: EULAR and Global Alliance for Patient Access; Receipt of equipment, materials, drugs, medical writing, gifts or other services: GalapagosJB: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Eli Lilly and Galapagos; Participation on a Data Safety Monitoring Board or Advisory Board: SyneosGRB: All support for the present manuscript: Sanofi; Consulting fees: AbbVie, Galapagos, Lilly, Pfizer, Roche and Sanofi; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Galapagos, Lilly, Pfizer, Roche and SanofiVPB: Grants or contracts from any entity: NIH (NIAID/NIAMS), The Cedar Hill Foundation, Amgen and BMS; Consulting fees: Amgen, BMS, Genzyme, Gilead, Janssen, Pfizer and Sanofi-Aventis; Participation on a Data Safety Monitoring Board or Advisory Board: KAI for NIHRC: noneEC: Grants or contracts from any entity: Bio-Cancer, Biogen, Novartis, Pfizer and Sanofi; Consulting fees: AbbVie, Amgen, BMS, Biocon, Eli Lilly, Galapagos, Chugai Pharma, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi and RPharm; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, BMS, Chugai Pharma, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, RPharm and Sanofi; Support for attending meetings and/or travel: Gilead, Galapagos, AbbVie and Eli LillyMT: Grants or contracts from any entity: Albireo, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, Alnylam and Ultragenyx; Consulting fees: Albireo, BioMX, Boehringer Ingelheim, Falk, Genfit, Intercept, Janssen, MSD, Gilead, Novartis, Shire, Phenex and Regulus; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Falk Foundation, Gilead, Intercept and MSD; Support for attending meetings and/or travel: AbbVie, Falk, Gilead and Intercept; Patents planned, issued or pending: Co-Inventor patent on medical use of nor-UDCATS: Grants or contracts from any entity: AbbVie and Roche; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Roche, Sanofi, Takeda and NovartisCC: Grants or contracts from any entity: AbbVie, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Consulting fees: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma, Lilly, Novartis and Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Amgen, Boehringer Ingelheim, Ewopharma and Pfizer; Leadership or fiduciary role in other board, society, committee or advocacy group: Romanian Society of Rheumatology, Romanian Registry of Rheumatic Diseases and Romanian League against RheumatismMKC: Grants or contracts from any entity: Gilead; Consulting fees: AstraZeneca, BMS, GSK and Shannon Pharmaceuticals; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AstraZeneca and Gilead; Leadership or fiduciary role in other board, society, committee or advocacy group: Arthritis Foundation, New York Chapter; Stock or stock options: Johnson and Johnson, Regeneron and AmgenMD: All support for the present manuscript: Medical academy of Vienna; Grants or contracts from any entity: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCB; Consulting fees: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCB; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Sanofi, Pfizer, AbbVie, Eli Lilly, BMS, Merck, Galapagos and UCBGP: none. DvdH: Consulting fees: AbbVie, Bayer, BMS, Cyxone, Eisai, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Lilly, Novartis, Pfizer and UCB Pharma; Other financial or non-financial interests: Director of Imaging Rheumatology bv.PE: Grants or contracts from any entity: Abbvie, BMS, Lilly, Novartis, Pfizer, Roche and Samsung; Consulting fees: Abbvie, Astra-Zeneca, Boehringer Ingelheim, Galapagos, Gilead, Eli Lilly and Novartis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Abbvie, BMS, GSK, Eli Lilly and NovartisEM: All support for the present manuscript: University of Vienna funding; Grants or contracts from any entity: Roche, Jansen, Pfizer, AbbVie and Novartis; Consulting fees: GSK, Roche, Novartis, AbbVie, Pfizer, Janssen, Eli Lilly and AstraZeneca; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: GSK, Pfizer, AbbVie, Lilly, Amgen, Janssen and AstraZeneca; Participation on a Data Safety Monitoring Board or Advisory Board: GSKRF: Consulting fees: AbbVie, Amgen, BMS, GSK, Gilead, Pfizer, Novartis and Eli Lilly; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie and Pfizer; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVie, Pfizer, Eli Lilly and GSKCG: noneKH: Grants or contracts from any entity: Pfizer and BMS; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbViePAM: Grants or contracts from any entity: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi and Takeda; Royalties or licenses: UpToDate; Consulting fees: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda and TalarisTT: Grants or contracts from any entity: Chugai Pharmaceutical; Consulting fees: Chugai, Janssen and Rpharma; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Chugai, BMS, Janssen and SanofiXM: Consulting fees: BMS, Novartis, Galapagos, Sanofi, GSK, Pfizer, Janssen and UCBKW: Grants or contracts from any entity: BMS and Pfizer; Consulting fees: AbbVie, BMS, Eli Lily, Galapagos, Gilead, Pfizer, Roche, UCB, GSK, Novartis, AstraZeneca, Regeneron and SanofiMdW: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer, Celgene, Eli Lilly and UCBKP: Payments for lectures: Roche, AbbVie, Pfizer, Eli Lilly, Amgen, SOBI, UCB and MSD; Advisory Board: Roche, AbbVie, Pfizer, Eli Lilly, Amgen, SOBI, UCB and MSDPN: Grants or contracts from any entity: Roche, Abbvie, Pfizer, Janssen, Gilead/Galapagos, BMS, Novartis and Eli Lilly; Consulting fees: Abbvie, Pfizer, janssen, BMS, Novartis, Lilly, Roche and Gilead/Galapagos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Abbvie, Pfizer, janssen, BMS, Novartis, Lilly, Roche and Gilead/GalapagosYT: Grants or contracts from any entity: Asahi-Kasei, Abbvie, Chugai, Mitsubishi-Tanabe, Eisai, Takeda, Corrona, Daiichi-Sankyo, Kowa and Behringer-Ingelheim; Consulting fees: Eli Lilly, Daiichi-Sankyo, Taisho, Ayumi, Sanofi, GSK and Abbvie; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Gilead, AbbVie, Boehringer-Ingelheim, Eli Lilly, Mitsubishi-Tanabe, Chugai, Amgen, YL Biologics, Eisai, Astellas, Bristol-Myers and AstraZenecaCD: Grants or contracts from any entity: FWF Austria and Celgene; Consulting fees: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Support for attending meetings and/or travel: AbbVie, MSD, Pfizer, Roche, Sanofi, Janssen, Novartis, Eli Lilly and Galapagos; Receipt of equipment, materials, drugs, medical writing, gifts or other services: MSDMLH: Grants or contracts from any entity: Novartis, Roche and Sandoz; Consulting fees: BMS and Samsung Bioepis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: MSD, AbbVie, Novartis, Merck, Eli Lilly, Medac and Sandoz; Support for attending meetings and/or travel: The DANBIO registry; Participation on a Data Safety Monitoring Board or Advisory Board: CellTrion and Eli Lilly; Leadership or fiduciary role in other board, society, committee or advocacy group: Chair of the DANBIO steering committee, Member of the Danish Rheumatism Association’s Board, Member of the Danish Rheumatism Association’s research council, Member of EULAR Quality of Care Committee, Co-chair of the EuroSpA collaboration; Receipt of equipment, materials, drugs, medical writing, gifts or other services: Study drug for the NORD-STAR study/ Abatacept and Certolizumab pegolHSK: Consulting fees: Roche, Chugai and Sanofi-Aventis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, Chugai and Sanofi-Aventis; Participation on a Data Safety Monitoring Board or Advisory Board: Roche, Chugai and Sanofi-AventisMN: Grants or contracts from any entity: Pfizer, Amgen, Galapagos and AbbVie; Consulting fees: AbbVie; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Celgene and AbbVie; Participation on a Data Safety Monitoring Board or Advisory Board: AbbVieAS: Grants or contracts from any entity: oint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Hexal, Lilly, MSD, Viatris, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis and UCB; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, Pfizer, Roche, Sanofi and UCBAL: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, MSD, Alfasigma, Celltrion, BMS, Celgene, Eli-Lilly, Sanofi Genzyme, Pfizer, Galapagos, Gilead, Novartis and SOBIAR: Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Angelini, Pfizer, Novartis, Reckitt Benckiser and SOBI; Leadership or fiduciary role in other board, society, committee or advocacy group: President, Pediatric Rheumatology European Society (PReS)ARR: Consulting fees: Sanofi, Roche, AbbVie, Eli Lilly, Gilead, BMS and Novartis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie, Pfizer, Sanofi, UCB, BMS, Gilead, Roche, Novartis and Janssen; Payment for expert testimony: AbbVie, Novartis and Gilead; Support for attending meetings and/or travel: AbbVie and Sanofi; Participation on a Data Safety Monitoring Board or Advisory Board: RPharmIM: Grants or contracts from any entity: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, UCB, Amgen and Novartis; Consulting fees: AbbVie, BMS, Eli Lilly, Janssen, Pfizer, Sanofi, Novartis, Gilead, Amgen, UCB, GSK and Moonlake; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AbbVie; Leadership or fiduciary role in other board, society, committee or advocacy group: Vice Principal & Head of MVLS College/University of Glasgow, Board Member/ NHS Greater Glasgow & Clyde and Evelo; Stock or stock options: Causeway Therapeutics, Compugen, Cabaletta and EveloBio; JS: grants to his institution from Abbvie, Astro, AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer, and Roche; Expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharm, Roche, Samsung, Sanofi and UCB., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA)., Methods: This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022., Results: Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission., Conclusion: The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA., Competing Interests: Competing interests: AK: Speakers bureau, Consultancy: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB and Pfizer. AS: received speaker/consulting fees from UCB, Novartis and Lilly. SAB: received an ASPIRE grant from Pfizer. JSS received grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. DvdH: received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv. RC received consulting fees from Abbvie, BMS, Amgen, Celltrion, Eli-Lilly, Fresenius-Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB Pharma. CJE has received fees from Abbvie, Astra Zeneca, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sanofi for advisory boards, speakers bureau and research support. PV received consulting fees from Abbvie, BMS, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Sidekick Health, UCB and speaker's fees from Eli Lilly, Galapagos, MSD and Roularta and holds the Pfizer Chair Early RA Management at KU Leuven. JEP received research grants from AbbVie, Frensenius Kabi, Mallinckrodt Pharmaceuticals, Pfizer, Seattle Genetics and consulting fees from AbbVie, Amgen, Astra Zeneca, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, GSK, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sandoz, Samsung, Sobi, Viatris. TT received grants from AbbVie, Asahikasei, AYUMI, Chugai, Eli Lilly Japan, Mitsubishi-Tanabe, Ono, and honoraria from AbbVie, Asahikasei, Astellas, Bristol-Myers Squibb, Chugai., Daiichi Sankyo., Eisai, Eli Lilly Japan, Gilead Sciences, Janssen K.K., Mitsubishi-Tanabe, Pfizer Japan. KLH received speaker’s fees from Abbvie and research grants from Pfizer and BMS. KLW received research grants from Pfizer, BMS, and GSK, and scientific consulting fees from UCB, Abbvie, BMS, Galapagos, Gilead, Lilly, GSK, Roche, and Novartis. DA received grants, speaker fees, or consultancy fees from Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi. TAS has received grant/research support from AbbVie and Roche, has been a consultant for AbbVie and Sanofi Genzyme, and has been a paid speaker for AbbVie, Novartis, Roche, Sanofi, and Takeda. RBML: received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Roche, UCB and is Director of Rheumatology Consultancy bv, (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA)., Methods: SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used., Results: Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi., Conclusion: The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation., Competing Interests: Competing interests: AS: received speaker/consulting fees from UCB, Novartis and Lilly AK: Speakers bureau, Consultancy: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB und Pfizer SAB: received an ASPIRE grant from Pfizer JS received grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB DvdH: received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv RC received consulting fees from Abbvie, BMS, Amgen, Celltrion, Eli-Lilly, Fresenius-Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB Pharma. CJE Has received fees from Abbvie, Astra Zeneca, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sanofi for advisory boards, speakers bureau and research support PV received consulting fees from Abbvie, BMS, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Sidekick Health, UCB and speaker’s fees from Eli Lilly, Galapagos, MSD and Roularta. Holds the Pfizer Chair Early RA Management at KU Leuven. SdS: none JEP received research grants from AbbVie, Frensenius Kabi, Mallinckrodt Pharmaceuticals, Pfizer, Seattle Genetics and consulting fees from AbbVie, Amgen, Astra Zeneca, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, GSK, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sandoz, Samsung, Sobi, Viatris TT received grants from AbbVie, Asahikasei, AYUMI, Chugai, Eli Lilly Japan, Mitsubishi-Tanabe, Ono, and honoraria from AbbVie, Asahikasei, Astellas, Bristol-Myers Squibb, Chugai., Daiichi Sankyo., Eisai, Eli Lilly Japan, Gilead Sciences, Janssen K.K., Mitsubishi-Tanabe, Pfizer Japan KLH: Honoraria from Abbvie (Speakers’ fees) and Research Grants from Pfizer and BMS KLW received research grants from Pfizer, BMS, and GSK, and scientific consulting fees from UCB, Abbvie, BMS, Galapagos, Gilead, Lilly, GSK, Roche, and Novartis DA received grants, speaker fees, or consultancy fees from Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, and Sobi TAS has received grant/research support from AbbVie and Roche, has been a consultant for AbbVie and Sanofi Genzyme, and has been a paid speaker for AbbVie, Novartis, Roche, Sanofi, and Takeda JWS: none RBML received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Roche, UCB and is Director of Rheumatology Consultancy by JSS, DvdH, KLH, KLW, DA and RBML are members of the Editorial Board of ARD., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field., Methods: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item., Results: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations., Conclusions: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Studies on GC efficacy were identified from a separate search on the efficacy of disease-modifying antirheumatic drugs (DMARDs). A combined search was performed for the duration of use and safety of GCs in RA patients. Dose-defined and time-defined GC treatment of any dose and duration (excluding intra-articular GCs) prescribed in combination with other DMARDs were considered. Results are presented descriptively. Two included studies confirmed the efficacy of GC bridging as initial therapy, with equal efficacy after 2 years of initial doses of 30 mg/day compared with 60 mg/day prednisone. Based on a recently performed SLR, in clinical trials most patients starting initial GC bridging are able to stop GCs within 12 (22% patients continued on GCs) to 24 months (10% patients continued on GCs). The safety search included 12 RCTs and 21 observational studies. Well-known safety risks of GC use were confirmed, including an increased risk of osteoporotic fractures, serious infections, diabetes and mortality. Data on cardiovascular outcomes were Inconsistent. Overall, safety risks increased with increasing dose and/or duration, but evidence on which dose is safe was conflicting. In conclusion, this SLR has confirmed the efficacy of GCs in the treatment of RA. In clinical trials, most patients have shown to be able to stop GCs within 12-24 months. Well-known safety risks of GC use have been confirmed, but with heterogeneity between studies., Competing Interests: Competing interests: SAB: received an ASPIRE grant from Pfizer. AS: received speaker/consulting fees from UCB, Novartis and Lilly. AK: Speakers bureau, Consultancy: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck Sharp and Dohme, Novartis, UCB und Pfizer. JWS: received grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. DvdH: received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv. RC received consulting fees from Abbvie, BMS, Amgen, Celltrion, Eli-Lilly, Fresenius-Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB Pharma. CJE Has received fees from Abbvie, Astra Zeneca, BMS, Celgene, Celltrion, Fresenius Kabi, Gilead, Galapagos, GSK, Janssen, Eli Lilly, Pfizer, Roche, Sanofi for advisory boards, speakers bureau and research support. PV received consulting fees from Abbvie, BMS, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Sidekick Health, UCB and speaker’s fees from Eli Lilly, Galapagos, MSD and Roularta. Holds the Pfizer Chair Early RA Management at KU Leuven. SdS: none. JEP received research grants from AbbVie, Frensenius Kabi, Mallinckrodt Pharmaceuticals, Pfizer, Seattle Genetics and consulting fees from AbbVie, Amgen, Astra Zeneca, BI, BMS, Celltrion, EMERALD, Frensenius Kabi, Galapagos, GSK, Janssen, Lilly, Mallinckrodt Pharmaceuticals, Medexus, Mitsubishi Tanabe Pharma, Novartis, Pfizer, Roche, Sandoz, Samsung, Sobi, Viatris. TT received grants from AbbVie GK, Astellas, Asahi Kasei, Chugai, Daiichi Sankyo, Eisai, Takeda, Mitsubishi Tanabe, Nippon Kayaku, and speakers/consulting fees from AbbVie GK, Astellas, Chugai, Daiichi Sankyo, Eli Lilly Japan, Eisai, Gilead, Mitsubishi Tanabe, Pfizer Japan. KLH received speaker’s fees from Abbvie and research grants from Pfizer and BMS. KLW received research grants from Pfizer, BMS, and GSK, and scientific consulting fees from UCB, Abbvie, BMS, Galapagos, Gilead, Lilly, GSK, Roche, and Novartis. DA has received grants and/or speaker/consulting fees from Abbvie, Amgen, Lilly, Janssen, Merck, Novartis, Pfizer, Roche, SoBi, Sanofi, Sandoz, and Roche. TAS has received grant/research support from AbbVie and Roche, has been a consultant for AbbVie and Sanofi Genzyme, and has been a paid speaker for AbbVie, Novartis, Roche, Sanofi, and Takeda. JSS: none. RBML: received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Roche, UCB and is Director of Rheumatology Consultancy bv. JSS, DvdH, KLH, KLW, DD and RBML are members of the Editorial Board of ARD., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)