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Janus kinase (JAK) inhibitors, including tofacitinib, baricitinib, upadacitinib and filgotinib, are increasingly used in the treatment of rheumatoid arthritis (RA). There has been debate about their safety, particularly following the issuance of guidance by regulatory agencies advising caution in their use in certain patients. The registrational clinical trials and registry data of JAK inhibitors did not identify a difference in the risk of major adverse cardiovascular events (MACEs), venous thromboembolism, malignancies or infections (other than herpes zoster) with a JAK inhibitor versus a biologic DMARD. In the ORAL Surveillance trial, which enrolled patients >50 years of age with ≥1 cardiovascular risk factor, tofacitinib was statistically inferior to TNF inhibitors for the occurrence of MACEs and malignancy. Further post hoc analysis of the data revealed that an age of ≥65 years, a high baseline cardiovascular risk, a history of smoking, sustained inflammation, disease activity and suboptimal treatment of cardiovascular comorbidities all increase the risk of these outcomes. The guidance issued by regulatory agencies should be carefully considered to ensure appropriate and safe treatment of patients with RA without undertreatment of patients who might benefit from JAK inhibitor, as well as biologic, treatment. As always, the risks associated with the use of these agents, treatment goals, costs and patient preferences should be discussed with the patient., (© 2024. Springer Nature Limited.)

Background: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status., Methods: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU)., Findings: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53)., Interpretation: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response., Funding: UK Medical Research Council and Versus Arthritis., Competing Interests: Declaration of interests AF reports grants or contracts from Janssen, GSK, Mestag, Nascient, Bristol Myers Squibb (BMS), Roche, and UCB, and consulting fees from Janssen and Sonoma. AGP reports grants or contracts from GSK, Pfizer, and Gilead, and consulting fees from Inflection Biosciences. CJE reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, BMS, Biogen, Celgene, Roche, Sanofi, and UCB Pharma; consulting fees from Gilead, Galapagos, AbbVie, and Eli Lilly; and support for attending meetings or travel from Eli Lilly. CP reports grants or contracts from GSK, Pfizer, BMS, Sanofi, Novartis, Janssen, Exagen, Genentech, and Navidea; trial funding from the UK Medical Research Council and Versus Arthritis; provision of investigational medicinal products for the trial from Pfizer and Roche; consulting fees from AbbVie, Janssen, Exagen, and Kinikska; and support for attending meetings or travel from EULAR, British Society for Rheumatology, and ACR. DvdH reports consulting fees from GSK, Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, BMS, UCB Pharma, Novartis, Janssen, Argenx, Bayer, and Takeda; is an associate editor for Annals of the Rheumatic Diseases, an editorial board member for the Journal of Rheumatology and RMD Open, an adviser for Axial Spondyloarthritis International Society, and Director of Imaging Rheumatology. EC reports grants or contracts from Pfizer, Biogen, Sanofi, and Bio-Cancer; consulting fees from Gilead, AbbVie, Biogen, Sanofi, UCB Pharma, Janssen, Fresenius Kabi, and R-Pharm; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Galapagos, AbbVie, Eli Lilly, Sanofi, Fresenius Kabi, and Chugai Pharma; support for attending meetings or travel from Galapagos and UCB Pharma. EG reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, Eli Lilly, BMS, Novartis, and Janssen. FR reports consulting fees from Ono Pharmaceutical. HC reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK and UCB Pharma; consulting fees from Pfizer, Galapagos, and Argenx; and participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. IM reports grants or contracts from Pfizer, Gilead, AbbVie, Eli Lilly, BMS, UCB Pharma, Novartis, Janssen, AstraZeneca, Amgen, Causeway Therapeutics, Cabaletta, Sanofi Regeneron, Evelo, Compugen, and Moonlake, and is a trustee for Versus Arthritis. JG reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, Eli Lilly, UCB Pharma, Janssen, and Vifor. JPP reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, AbbVie, Eli Lilly; consulting fees from AbbVie; support for attending meetings or travel from AbbVie and Eli Lilly; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie. MRE reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from GSK, Galapagos, and AbbVie; support for attending meetings or travel from Eli Lilly, AbbVie, and Janssen; and consulting fees from GSK, Fresenius Kabi, and AstraZeneca. MHB reports grants or contracts from Gilead, and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Galapagos, AbbVie, and Boehringer Ingelheim. NN reports support for attending meetings or travel from Janssen. PD reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Pfizer, Galapagos, AbbVie, and Eli Lilly, and support for attending meetings or travel from Galapagos, AbbVie, and Fresenius Kabi. PCT reports consulting fees from GSK, Pfizer, Gilead, Galapagos, AbbVie, Eli Lilly, Biogen, Sanofi, UCB Pharma, Janssen, Fresenius Kabi, and Nordic Pharma; grants or contracts from Galapagos; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from AbbVie; support for attending meetings or travel from Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board from Moonlake, Kymab, and Immunovant. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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.)

Objectives: To evaluate retention, efficacy, and safety of subcutaneous (SC) abatacept over 2 years in patients with moderate-to-severe RA in the Abatacept SubCutaneOus in Routine clinical practicE (ASCORE) study., Methods: Patients with RA who initiated SC abatacept 125 mg once weekly were enrolled in the international, observational, prospective multicentre ASCORE study into biologic-naïve or ≥ 1 prior biologic failure cohorts., Primary Endpoint: abatacept retention rate at 2 years. Secondary endpoints: proportion of patients with good/moderate EULAR response rates based on DAS28 (ESR), low disease activity and/or remission according to DAS28 (ESR; ≤ 3.2/ < 2.6), SDAI (≤ 11/ ≤ 3.3), CDAI (≤ 10/ ≤ 2.8), and Boolean criteria. Retention rate by baseline serostatus was evaluated post hoc., Results: Overall, 47% of patients remained on abatacept for 2 years, irrespective of treatment line. Higher abatacept retention rates were associated with lower prior biologic exposure. Generally, clinical outcomes showed that the proportion of patients with low disease activity/remission was higher in biologic-naïve patients (vs biologic-failure) and similar in those with 1 and ≥ 2 prior biologic failures. In patients on treatment at 2 years, good/moderate EULAR response rates of ~ 80% were consistently noted irrespective of prior biologic exposure. Across treatment lines, retention was greater in patients with seropositive (vs seronegative) RA. Patients with rheumatoid factor/anti-citrullinated protein antibody single-positive RA who were bio-naïve had higher retention than patients who were bio-experienced., Conclusions: In the ASCORE study, SC abatacept retention was 47% at 2 years with good clinical outcomes and was well-tolerated in the real-world setting. Abatacept retention and clinical response rates were higher in patients who received abatacept as an earlier- versus later-line biologic drug treatment and in those with seropositive RA., Trial Registration: ClinicalTrials.gov, NCT02090556., (© 2022. The Author(s).)

The European Alliance of Associations for Rheumatology recently defined difficult to treat (D2T) rheumatoid arthritis (RA) and provided points to consider in its management. This review summarises the key concepts of D2T-RA that underpinned this recent guidance. D2T-RA is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. The basis for progressive disease, however, is not limited to clear inflammatory joint pathology, capturing wider contributors to treatment cycling such as comorbidity, obesity and fibromyalgia. This means D2T-RA comprises a heterogeneous population, with a proportion within this exhibiting bona fide treatment-refractory disease. The management points to consider, however, emphasise the importance of checking for the presence of inflammatory pathology before further treatment change. This review suggests additional considerations in the definition of D2T-RA, the potential value in identifying D2T traits and intervening before the development of D2T-RA state and the need for real world evidence of targeted synthetic DMARD in this population to compare to recent trial data. Finally, the review asks whether the presence of D2T-RA implies a failure to treat effectively from the outset, and the need for pharmacological and non-pharmacological management approaches to address the wider D2T-RA population effectively., Competing Interests: Competing interests: MHB is supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre and is in receipt of an NIHR Senior Investigator award., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite treatment according to the current management recommendations, a significant proportion of patients with rheumatoid arthritis (RA) remain symptomatic. These patients can be considered to have 'difficult-to-treat RA'. However, uniform terminology and an appropriate definition are lacking., Objective: The Task Force in charge of the " Development of EULAR recommendations for the comprehensive management of difficult-to-treat rheumatoid arthritis" aims to create recommendations for this underserved patient group. Herein, we present the definition of difficult-to-treat RA, as the first step., Methods: The Steering Committee drafted a definition with suggested terminology based on an international survey among rheumatologists. This was discussed and amended by the Task Force, including rheumatologists, nurses, health professionals and patients, at a face-to-face meeting until sufficient agreement was reached (assessed through voting)., Results: The following three criteria were agreed by all Task Force members as mandatory elements of the definition of difficult-to-treat RA: (1) Treatment according to European League Against Rheumatism (EULAR) recommendation and failure of ≥2 biological disease-modifying antirheumatic drugs (DMARDs)/targeted synthetic DMARDs (with different mechanisms of action) after failing conventional synthetic DMARD therapy (unless contraindicated); (2) presence of at least one of the following: at least moderate disease activity; signs and/or symptoms suggestive of active disease; inability to taper glucocorticoid treatment; rapid radiographic progression; RA symptoms that are causing a reduction in quality of life; and (3) the management of signs and/or symptoms is perceived as problematic by the rheumatologist and/or the patient., Conclusions: The proposed EULAR definition for difficult-to-treat RA can be used in clinical practice, clinical trials and can form a basis for future research., Competing Interests: Competing interests: All participants provided declaration of interest, the individual declarations are attached as online supplemental file 2., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field., Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items., Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high., Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost., Competing Interests: Competing interests: DA: grants from Abbvie, Novartis, Roche and honoraria from Abbvie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme; MA: honoraria from AbbVie, Astra Zeneca, BMS, Boehringer Ingelheim, Chugai, HEXAL, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; JA: grants from Abbvie, BMS, Lilly, Merck, Pfizer, Roche, Samsung Bioepis, UCB; AB: grants from Pfizer, Bristol-Myers Squibb and honoraria from Pfizer, Roche, AbbVie, Bristol-Myers Squibb, UCB, MSD, Novartis, Sanofi, Biogen, Sandoz, Celltrion, Nordic, Gilead; JWJB: honoraria from Lilly, Roche, Sanofi; MB: honoraria from BMS, Teva, Novartis, Pfizer, GSK; AdB: grants from Abbvie, Biogen, Celltrion and honoraria from Abbvie, Biogen, Boehringer-Ingelheim, Celgene, Fresenius, MSD, Roche.MHB has received grants from Pfizer, Roche and UCB and consulting fees from Abbvie, Eli-Lilly, Merck.Serono, Pfizer, Sandoz, Sanofi; GB: grants from Abbvie, Pfizer, Sanofi, UCB and honoraria from Abbvie, Celgene, Gilead, Lilly, MSD, Novartis, Pfizer, Sanofi, Roche. FB: grants from Abbvie, BMS, Horizon, Medac, Pfizer, Roche, Lilly, Sanofi and honoraria from Abbvie, Galapagos, Horizon, Medac, Pfizer, Roche, Sanofi, Janssen, BMS, MSD, Lilly; RC: honoraria from Abbvie, BMS, Celgene, Celltrion, Gilead, Janssen, Lilly MSD, Mundipharma, Novartis-Sandoz, Pfizer, Roche, Sanofi and UCB; MC; honoraria from Abbvie, Astellas, BMS, Lilly, Pfizer and Roche; DDC: no conflict; CC: honoraria from AbbVie, Accord Healthcare, Alfasigma, Berlin Chemie, Egis, Eli Lilly, Ewopharma, Genesis, MSD, Mylan, Novartis, Pfizer, Roche, Sandoz, UCB; MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz; CJE: grants from Abbvie, Biogen and honoraria from Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB; PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly; AF: grants from BMS, Pfizer and honoraria from AB2 BIO, Abbvie, BMS, Lilly, MSD, Pfizer, Roche, Sanofi; LG: grants from Abbvie, BMS, Lilly, UCB and honoraria from Abbvie, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, UCB; J-EG: grants from BMS, Pfizer and honoraria from Abbvie, BMS, Lilly, Sanofi-Genzyme, Roche, UCB; MLH: grants from Abbvie, Biogen, BMS, Celltrion, MSD, Novartis, Orion, Pfizer, Samsung, UCB; TH: grants from Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boeringher and honoraria from Abblynx, BMS, Janssen, Pfizer, Sanofi-Aventis, Crescendo Bioscience, Galapagos, Lilly; AK: honoraria from BMS, Pfizer, Celgene, MSD; MK: no conflicts of interest; RBML: honoraria from AbbVie, BMS, Celgene, Eli-Lilly, Jansen Pharmaceuticals, Galapagos, Novartis, MSD, Pfizer, UCB and Director of Rheumatology Consultancy BV; XM: honoraria from BMS, Gilead, Pfizer, Samsung, UCB; IBM: grants from Astra Zeneca, UCB, BMS, Janssen, GSK, Compugen, Boehringer, Celgene and honoraria from Abbvie, BMS, Janssen, Novartis, UCB, Astra Zeneca, Celgene, Causeway, Lilly, Leo, Novimmune; EM: grants from Pfizer, Lilly, BMS, AbbVie, GSK, Astra and honoraria from Pfizer, BMS, Roche, Lilly, AbbVie, Gemma, Sanofi; TWJH: grants from Eli Lilly, Merck, UCB, BMS, Janssen, Pfizer, Sanofi-Aventis, Galapagos, Boehringer and honoraria from Abblynx, Abbvie, BMS, Boehringer, Crescendo-Bioscience, Epirus, Galapagos, Janssen, Lilly, Merck, Novartis, Nycomed, Pfizer, Roche, Sanofi-Aventis, Takeda, UCB; ZL: no conflicts of interest; UM-L: honoraria from Abbvie, BMS, MSD, Chugai, Roche, Pfizer, Sanofi, Boehringer, Actelion, Medac, Lilly; GP: no conflicts of interest; JP: grants from BMS, Merck, UCB and honoraria from AbbVie, Actelion, Amgen, BMS, Bayer, GSK, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB; AR-R: honoraria from Abbvie, Chugai, BMS, Sanofi, Roche, Lilly, Janssen, Novartis, Celgene, MSD, UCB; AR-W: grants from Pfizer, Abbvie and honoraria from Abbvie, Amgen, BMS, Janssen, Lilly, Medac, Nordic Pharma, Novartis, Pfizer, Roche-Chugai, Sanofi, UCB; KS: grants from Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda and honoraria from AbbVie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin; MSV: no conflicts of interest. AS: honoraria from Novartis; JSS: grants from Abbvie, AstraZeneca, Janssen, Lilly, Novartis, Roche and honoraria from Abbvie, Amgen, AstraZeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB; AS: grants from AbbVie, Bristol-Myers Squibb, Celltrion, Hexal AG Lilly, MSD Sharp & Dome, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB and honoraria from AbbVie, BMS, MSD, Pfizer, Roche; TT: grants from AbbVie, Asahikasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Takeda and honoraria from AbbVie, Astellas, Astra Zeneca, BMS, Chugai, Diaichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nipponkayaku, Novartis, Pfizer, Sanofi, Teijin, Taiho Pharmaceutical, Taisho Pharmaceutical, Takeda, UCB; DvdH: grants from UCB and honoraria from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB and Director Imaging Rheumatology BV; YvE-H: honoraria from Celgene; RFvV: grants from BMS, GSK, Lilly, UCB and honoraria from AbbVie, AstraZeneca, Biotest, BMS, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, Roche, UCB; RW: grants from Roche, BMS and honoraria from Celltrion, Galapagos-Gilead; MdW: honoraria from 'Stichting Tools', Janssen-Cilag., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Biologic disease-modifying antirheumatic drugs (bDMARDs) have revolutionised treatment and outcomes for rheumatoid arthritis (RA). The expanding repertoire allows the option of switching bDMARD if current treatment is not effective. For some patients, even after switching, disease control remains elusive. This analysis aims to quantify the frequency of, and identify factors associated with, bDMARD refractory disease., Methods: Patients with RA starting first-line tumour necrosis factor inhibitor in the British Society for Rheumatology Biologics Register for RA from 2001 to 2014 were included. We defined patients as bDMARD refractory on the date they started their third class of bDMARD. Follow-up was censored at last follow-up date, 30 November 2016, or death, whichever came first. Switching patterns and stop reasons of bDMARDs were investigated. Cox regression identified baseline clinical factors associated with refractory disease. Multiple imputation of missing baseline data was used., Results: 867 of 13 502 (6%) patients were bDMARD refractory; median time to third bDMARD class of 8 years. In the multivariable analysis, baseline factors associated with bDMARD refractory disease included patients registered more recently, women, younger age, shorter disease duration, higher patient global assessment, higher Health Assessment Questionnaire score, current smokers, obesity and greater social deprivation., Conclusions: This first national study has identified the frequency of bDMARD refractory disease to be at least 6% of patients who have ever received bDMARDs. As the choice of bDMARDs increases, patients are cycling through bDMARDs quicker. The aetiopathogenesis of bDMARD refractory disease requires further investigation. Focusing resources, such as nursing support, on these patients may help them achieve more stable, controlled disease., Competing Interests: Competing interests: MHB has received grants from Pfizer Ltd and Roche Pharmaceuticals, as well as expert advice and honoraria from Abbvie, Astra-Zeneca, BMS, Lilly, Roche, Sandoz and UCB. JDI has received research grants from Pfizer Ltd and Roche Pharmaceuticals, as well as honoraria/fees from Abbvie, Roche, Pfizer, Janssen and BMS., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

While biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed outcomes of people with rheumatoid arthritis (RA), a proportion of patients are refractory to multiple bDMARDs. Definitions of refractory RA thus far have been arbitrary, and outcome data and impact of such cohorts remain limited. Extrapolation from randomised controlled trial and some real-life data suggest approximately 20% progress onto a third bDMARD with a more modest proportion failing additional bDMARDs. This viewpoint discusses an opinion of refractory RA disease and proposes key principles to accurately identify refractory cohorts. These include demonstrating presence of persistent inflammation despite multiple therapies and acknowledging development of antidrug antibody. Potential basis of refractory disease is summarised, and suggestions for an initial approach in the future evaluation of refractory disease are offered. Specific investigation of refractory RA disease is necessary to inform the clinical need and provide a basis for robust investigation of underlying mechanisms., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The beginning of the 21st century saw a biopharmaceutical revolution in the treatment of inflammatory rheumatic diseases, particularly rheumatoid arthritis. The fast-evolving use of biologic therapies highlighted the need to develop registers at national and international levels with the aim of collecting long-term data on patient outcomes. Over the past 15 years, many biologics registers have contributed a wealth of data and provided robust and reliable evidence on the use, effectiveness and safety of these therapies. The unavoidable challenges posed by the continuous introduction of new therapies, particularly with regard to understanding their long-term safety, highlights the importance of learning from experience with established biologic therapies. In this Perspectives article, the role of biologics registers in bridging the evidence gap between efficacy in clinical trials and real-world effectiveness is discussed, with a focus on methodological aspects of registers, their unique features and challenges and their role going forward.

Objective: To determine whether serial ANA testing predicts biological disease modifying antirheumatic drugs (bDMARD)-associated ANA/dsDNA production in patients with rheumatoid arthritis (RA)., Methods: Serial autoantibody profiles, bDMARD treatment sequences and clinical data were collected from patients identified from our database that since 2005 received (i) a first bDMARD (tumour necrosis factor inhibitor (TNFi)) and (ii) tocilizumab and/or abatacept., Results: Of over 1000 patients, 454 RA patients received a first TNFi. Infliximab group demonstrated higher ANA seroconversion rates (31.2%) compared with etanercept (11.8%) and adalimumab (16.1%) (p<0.001). Median (range) treatment duration prior to ANA seroconversion was 10.9 (1.3-80.0) months. Positive anti-dsDNA titres of IgG class (median (range) of 77 IU/mL (65-109)) were noted in six (7.2%) patients, within a median (range) of 2.0 (0.8-4.2) years. Three patients developed classifiable lupus. 4 of 74 (5.4%) primary non-responders and 24 of 111 (21.6%) secondary non-responders developed positive ANA antibodies after TNFi initiation (p=0.003). Seven (9.5%) tocilizumab-treated patients changed to positive ANA; five (8.6%) abatacept-treated patients changed to positive ANA status., Conclusions: This study demonstrates no utility of serial ANA/dsDNA testing that could be used to predict onset of seroconversion and therefore the development of lupus/vasculitis. An association however between seroconversion and the development of a secondary non-response to bDMARD therapy is suggested., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To update the evidence for the efficacy of biological disease-modifying antirheumatic drugs (bDMARD) in patients with rheumatoid arthritis (RA) to inform the European League Against Rheumatism(EULAR) Task Force treatment recommendations., Methods: Medline, Embase and Cochrane databases were searched for articles published between January 2009 and February 2013 on infliximab, etanercept, adalimumab, certolizumab-pegol, golimumab, anakinra, abatacept, rituximab, tocilizumab and biosimilar DMARDs (bsDMARDs) in phase 3 development. Abstracts from 2011 to 2012 American College of Rheumatology (ACR) and 2011-2013 EULAR conferences were obtained., Results: Fifty-one full papers, and 57 abstracts were identified. The randomised controlled trials (RCT) confirmed the efficacy of bDMARD+conventional synthetic DMARDs (csDMARDs) versus csDMARDs alone (level 1B evidence). There was some additional evidence for the use of bDMARD monotherapy, however bDMARD and MTX combination therapy for all bDMARD classes was more efficacious (1B). Clinical and radiographic responses were high with treat-to-target strategies. Earlier improvement in signs and symptoms were seen with more intensive initial treatment strategies, but outcomes were similar upon addition of bDMARDs in patients with insufficient response to MTX. In general, radiographic progression was lower with bDMARD use, mainly due to initial treatment effects. Although patients may achieve bDMARD- and drug-free remission, maintenance of clinical responses was higher with bDMARD continuation (1B), but bDMARD dose reduction could be applied (1B). There was still no RCT data for bDMARD switching., Conclusions: The systematic literature review confirms efficacy of biological DMARDs in RA. It addresses different treatment strategies with the potential for reduction in therapy, particularly with early disease control, and highlights emerging therapies.