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Objective Systemic lupus is a chronic autoimmune disease characterised by its phenotypic heterogeneity. Neutropaenia is a frequent event in SLE occurring in 20%–40% of patients depending on the threshold value of neutrophil count. On a daily basis, the management of neutropaenia in SLE is difficult with several possible causes. Moreover, the infectious consequences of neutropaenia in SLE remain not well defined.Methods 998 patients from the Lupus BioBank of the upper Rhein (LBBR), a large German and French cohort of patients with SLE, mostly of Caucasian origin (83%), were included in this study. Neutropaenia was considered when neutrophil count was below 1800×106/L. An additional analysis of detailed medical records was done for 65 LBBR patients with neutropaenia.Results 208 patients with neutropaenia (21%) were compared with 779 SLE patients without neutropaenia. Neutropaenia in SLE was significantly associated with thrombocytopaenia (OR 4.11 (2.57–10.3)), lymphopaenia (OR 4.41 (2.51–11.5)) and low C3 (OR 1.91 (1.03–4.37)) in multivariate analysis. 65 representative patients with neutropaenia were analysed. Neutropaenia was moderate to severe in 38%, chronic in 31%, and both severe and chronic in 23% of cases. Moderate to severe and chronic neutropaenia were both associated with lymphopaenia and thrombopaenia. Chronic neutropaenia was also associated anti-Ro/SSA antibodies and moderate to severe neutropaenia with oral ulcers.Conclusion This study is to date the largest cohort to describe neutropaenia in SLE. Neutropaenia displays a strong association with other cytopaenias, suggesting a common mechanism. Chronic neutropaenia is associated with anti-Ro/SSA antibodies with or without identified Sjögren’s disease.

The French Society of Rheumatology recommendations for managing rheumatoid arthritis (RA) has been updated by a working group of 21 rheumatology experts, 4 young rheumatologists and 2 patient association representatives on the basis of the 2023 version of the European Alliance of Associations for Rheumatology (EULAR) recommendations and systematic literature reviews. Two additional topics were addressed: people at risk of RA development and RA-related interstitial lung disease (RA-ILD). Four general principles and 19 recommendations were issued. The general principles emphasize the importance of a shared decision between the rheumatologist and patient and the need for comprehensive management, both drug and non-drug, for people with RA or at risk of RA development. In terms of diagnosis, the recommendations stress the importance of clinical arthritis and in its absence, the risk factors for progression to RA. In terms of treatment, the recommendations incorporate recent data on the cardiovascular and neoplastic risk profile of Janus kinase inhibitors. With regard to RA-ILD, the recommendations highlight the importance of clinical screening and the need for high-resolution CT scan in the presence of pulmonary symptoms. RA-ILD management requires collaboration between rheumatologists and pulmonologists. The treatment strategy is based on controlling disease activity with methotrexate or targeted therapies (mainly abatacept or rituximab). The prescription for anti-fibrotic treatment should be discussed with a pulmonologist with expertise in RA-ILD., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The 1-year PROspective sarilumab (preFILled syringe/pen) multinational, obsErvational (PROFILE) study evaluated the real-world effectiveness and safety of sarilumab in patients with moderate-to-severe rheumatoid arthritis (RA)., Methods: Safety endpoints included adverse events (AEs) and lab abnormalities. Effectiveness endpoints included the ACR core set. The primary endpoint was the change from baseline in Clinical Disease Activity Index (CDAI). All statistics are descriptive and p values were nominal., Results: In total, 595 patients were treated, of whom 223 (37.5%) received sarilumab monotherapy and 372 (62.5%) received combination therapy. Upon initiation of sarilumab, an improvement in the mean (SD) CDAI score was observed at week 24 [11.4 (10.3)] and was maintained through week 52 [10.0 (10.5)], resulting in a mean [SD] reduction of -14.9 (12.7) and -14.4 (12.9), respectively. There were consistent improvements in disease activity that were similar for patients on monotherapy vs. combination therapy. An increase in the proportion of patients achieving remission and low disease activity was reported. By week 52, both groups had improved physical function and quality of life. There were no new safety signals. The proportions of any patients reporting a treatment-emergent adverse event (TEAE) or serious treatment-emergent AE (SAE) was 66.2% and 5.9%, respectively, and were similar between both treatment groups. Overall, 15.6% of patients discontinued sarilumab treatment due to TEAEs. The most commonly reported TEAE of interest was neutropenia (14.1%)., Conclusions: In this 1-year, observational real-world study, sarilumab therapy resulted in improved clinical outcomes. The safety profile was consistent with that observed in sarilumab randomized clinical trials. This study was entered on the German website (Paul Ehrlich Institute) on January 11, 2018, with NIS No.: 423., Competing Interests: Declarations Conflict of Interest Alan Kivitz: Shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc., and Novartis; paid consultant for AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, Sun Pharma Advanced Research, and Gilead Sciences, Inc.; speaker and/or a member of speakers’ bureau for Celgene, Merck, Lilly, Novartis, Pfizer, Sanofi, Flexion, and AbbVie. Jacques Eric Gottenberg: Received research grants from Bristol-Myers Squibb, Pfizer, and Roche and speaking/consulting fees from AbbVie, Bristol-Myers Squibb, Chugai, Galapagos, Gilead, Janssen, Lilly, MSD, Pfizer, Sanofi, Roche, and UCB. Martin Bergman: Consultant, advisor, and member of speakers’ bureaus for AbbVie, Amgen, BMS, Genentech/Roche, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi/Regeneron; and a shareholder of Johnson and Johnson (parent company of Janssen). Chunfu Qiu and Hubert van Hoogstraten: Employees of Sanofi and may hold stock and/or stock options in the company. Ron de Nijs has nothing to disclose. Louis Bessette: Received research grants and speaker and consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB. Ethical Approval The study protocol was approved by the institutional review boards/ethics committees (IRBs/ECs), and each enrolled patient provided written informed consent. The study was conducted in accordance with the principles laid by the 18th World Medical Assembly (Helsinki, 1964) and all subsequent amendments., (© 2024. The Author(s).)

Objectives: The Newcastle Sjogren's Stratification Tool (NSST) stratifies Sjogren's disease patients into four subtypes. Understanding the stability of the subtypes is vital if symptom-based stratification is to be more broadly adopted. In this study, we stratify patients longitudinally to understand how symptom-based subtypes vary over time and factors influencing subtype change., Methods: 274 patients from the United Kingdom Primary Sjögren's Syndrome Registry (UKPSSR) with data permitting NSST subtype assignment from two study visits were included. The French Assessment of Systemic Signs and Evolution of Sjogren's Syndrome (ASSESS) cohort (n=237) acted as an independent comparator. Group analyses of significant differences were performed, with logistic regression models used to assess covariates of subtype stability., Results: UKPSSR and ASSESS cohorts showed a broadly similar proportion of subjects in each subtype and similar baseline clinical characteristics except body mass index (BMI). Several baseline characteristics differ significantly between the subtypes, most notably anti-Ro status and BMI. Subtype membership was reasonably stable in both cohorts with 60% and 57% retaining subtype. The high-symptom burden subtype was the most stable over time with 70% and 67% retaining subtype. Higher baseline probability score was the greatest predictor of subtype stability with higher C4 levels, antidepressant use, and a higher CCI score also predicting increased stability., Conclusion: NSST subtype membership remains stable over time in a large proportion of patients. When subtype transition is associated with factors at baseline, it is most strongly associated with an uncertain subtype allocation. Our findings support the hypothesis that symptom-based subtypes reflect genuine pathobiological endotypes and therefore maybe important to consider in trial design and clinical management., Competing Interests: Competing interests: XM received consultant fees from BMS, Galapagos, GSK, Novartis and Pfizer. W-FN has undertaken clinical trials and provided consultancy or expert advice in the area of Sjögren’s syndrome to the following companies: GlaxoSmithKline, MedImmune, UCB, Abbvie, Takeda, Resolves Therapeutics, Sanofi, Novartis, Bain Capitals and Argenx. No other potential conflict of interest relevant to this article was reported., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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

Background: Janus kinase inhibitors are an effective option for achieving sustained remission or low disease activity in patients with rheumatoid arthritis (RA) following inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs. Filgotinib is a Janus kinase 1-preferential inhibitor available in two doses for moderate-to-severe RA. We report the long-term efficacy and safety of filgotinib., Methods: In the ongoing long-term extension study FINCH 4 (NCT03025308), patients continue filgotinib 200 mg or 100 mg from FINCH 1, 2 or 3 or receive filgotinib 200 mg or 100 mg de novo. Efficacy assessments up to week 156 include American College of Rheumatology 20% response (ACR20), Disease Activity Score 28 using C-reactive protein of <2.6, Clinical Disease Activity Index of ≤2.8, Simplified Disease Activity Index of ≤3.3 and Boolean remission (1.0 and 2.0) with non-responder imputation., Results: In patients with an inadequate response to methotrexate, 60.2% and 54.6% receiving de novo filgotinib 200 mg and 100 mg had an ACR20 at week 156, respectively, as did 67.3% and 59.5% of those who continued filgotinib 200 mg and 100 mg. At week 156, Boolean remission 1.0 was achieved by 18.8% and 15.4% of patients treated with de novo filgotinib 200 mg and 100 mg, respectively, and by 21.1% and 18.5% when Boolean 2.0 criteria were applied. Similar efficacy data were seen in patients from FINCH 2 and 3. Safety data were consistent with the known safety profile of filgotinib., Conclusion: In FINCH 4, filgotinib 200 mg and 100 mg (continuous or de novo) demonstrated sustained efficacy up to week 156 in patients enrolled from FINCH 1, 2 or 3, with no unexpected safety results., Competing Interests: Competing interests: MHB reports consultancy fees from AbbVie, Boehringer Ingelheim, CESAS Medical, Galapagos, Gilead and Pfizer (all paid to host institution); speaker fees from AbbVie (paid to host institution); and grant/research support from Gilead (paid to host institution). DA reports consultancy fees, speaker fees and grant/research support from AbbVie, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi. BGC reports consultancy fees from AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Janssen and Roche-Chugai; and speaker fees from AbbVie, Celltrion, Eli Lilly, Galapagos, Janssen, Pfizer and Roche-Chugai. YT reports speaker fees and/or honoraria from AbbVie, Asahi Kasei, AstraZeneca, Boehringer Ingelheim, BMS, Chugai, Eli Lilly, Eisai, Gilead, GSK, Pfizer, Taisho and Taiho; and research grants from Asahi Kasei, Chugai, Eisai, Mitsubishi Tanabe and Taisho. RC reports consultancy fees from AbbVie, Accord, Eli Lilly, Fresenius Kabi, Galapagos, MSD, Novartis, Pfizer and UCB; and speaker fees from AbbVie, Amgen, BMS, Celltrion, Eli Lilly, Fresenius Kabi, Galapagos, Janssen, MSD, Novartis, Pfizer and UCB. HS-K reports consultancy fees and speaker fees from AbbVie, Eli Lilly, Galapagos and Pfizer. TT reports consultancy fees from AbbVie, Astellas Pharma, Eli Lilly Japan and Gilead; and speaker fees and/or honoraria from AbbVie, Astellas Pharma, Eisai, Eli Lilly Japan, Gilead and Pfizer Japan. J-EG reports consultancy fees from AbbVie, BMS, Eli Lilly, Galapagos, Gilead, MSD, Novartis and Pfizer; and grant/research support from AbbVie, BMS, Lilly and Pfizer. RB reports consultancy fees from AstraZeneca, Galapagos, Janssen, Novartis and Pfizer; speaker fees from AbbVie, Amgen, BMS, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche and Sanofi; and grant/research support from AbbVie and Roche. PV reports consultancy fees from Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma and Sidekick Health; speaker fees from AbbVie, Eli Lilly, Galapagos and Roularta; and grant/research support from Galapagos and Pfizer. AZ-S has no disclosures of interest to report. FDL is a former employee of, and shareholder in, Galapagos. EVEO reports consultancy fees from Galapagos and Janssen and is a shareholder in UCB. VR is a former employee of Galapagos and current employee of GSK Vaccines. PE reports consultancy fees from AbbVie, BMS, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead and Novartis; speaker fees from AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, Novartis and Samsung; and grant/research support from AbbVie, BMS, Eli Lilly and Samsung., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To develop and validate a web-based ecological momentary assessment (EMA) tool to enhance symptoms monitoring among patients with Sjögren's disease (SjD)., Methods: Consecutive adults with SjD were enrolled in this pilot observational study. Participants used the WebApp over a 3-month period, for the daily collection of individual EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) scales and separate assessment of eyes and mouth dryness, using 0-10 numerical scales. Primary outcome was the measure of the interdaily variability of symptoms. Data collected through the WebApp were compared with those obtained with paper-based questionnaires administered during a final visit, using distinct approaches (predicted error, maximum negative error and maximum positive error). User experience was assessed using the System Usability Scale (SUS) score., Results: Among the 45 participants, 41 (91.1%) were women. Median age was 57 years (IQR: 49-66). Daily variability of symptoms ranged between 0.5 and 0.8 points across the scales. Over the 3-month period, the predicted error ranged between -1.2 and -0.3 points of the numerical scales. The greatest differences were found for fatigue (-1.2 points (IQR: -2.3 to -0.2)) and ESSPRI score (-1.2 points (IQR: -1.7 to -0.3)). Over the last 2 weeks, the predicted error ranged between - 1.2 and 0.0 points. Maximum negative error ranged between -2.0 and -1.0 points, and maximum positive error between -0.3 and 0.0 points. Median SUS score was 90 (IQR: 85-95)., Conclusion: Our results demonstrate the usability and the relevance of our web-based EMA tool for capturing data that closely reflects daily experiences of patients with SjD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sjögren's disease is the autoimmune disease with the highest risk of lymphoma development. There is no consensus on the optimal way to manage Sjögren's disease complicated by lymphoma. We aimed to describe characteristics, therapeutic strategies, and outcomes of non-Hodgkin lymphoma associated with Sjögren's disease, and their effect on lymphoma and Sjögren's disease prognoses., Methods: We did a multicentre, retrospective, observational study including patients with Sjögren's disease according to the 2016 American College of Rheumatology-European League Against Rheumatism criteria who did not fulfil diagnostic criteria for other connective tissue diseases. We included patients with a lymphoma diagnosis made before Jan 1, 2020, from two expert centres in Paris (France); from the French, multicentre, prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome cohort; and via practitioners registered with the Club Rhumatismes et Inflammation. Using inverse probability of treatment weighting, the effect of lymphoma treatment was compared in relation to three endpoints: lymphoma progression-free survival, new Sjögren's disease systemic activity, and overall survival. Exploratory analyses also aimed to identify factors associated with lymphoma relapse, new Sjögren's disease systemic activity, and overall survival. People with lived experience were not involved in this research., Findings: 106 patients with Sjögren's disease who developed lymphoma were included in the study. The most frequent histological subtype was mucosa-associated lymphoid tissue lymphoma (68 [64%] of 106 patients), followed by other marginal zone subtypes (14 [13%] of 106 patients) and diffuse large B-cell lymphoma (14 [13%] of 106 patients). Among the 82 patients with marginal zone lymphoma (72 [88%] women and ten (12%) men; mean age at lymphoma diagnosis 57·5 years [SD 14·8]), multivariable analysis showed that pulmonary localisation was associated with mortality (hazard ratio [HR] 7·92 [95% CI 1·70-37·0]). A watch and wait approach was proposed in 19 (23%) of 82 patients with marginal zone lymphoma, 13 (16%) had first-line localised treatment (surgery or radiotherapy), and 50 (61%) had first-line systemic treatment. After a median follow-up of 7 years, 26 patients (32%) had lymphoma relapse, nine (11%) died, and 27 (33%) had new Sjögren's disease systemic activity. After inverse probability of treatment weighting, patients with systemic treatment at lymphoma diagnosis had a reduced risk of new Sjögren's disease activity (HR 0·43 [95% CI 0·21-0·90]). When comparing patients treated with a combination of chemotherapy and anti-CD20 therapy (n=32) with patients treated with monotherapy (n=18) as a first-line therapy for lymphoma, lymphoma-progression-free survival was improved in patients treated with combination therapy (HR 0·36 [95% CI 0·14-0·94]). The were no differences in new Sjögren's disease systemic activity or overall survival according to combination therapy or monotherapy., Interpretation: A systemic treatment strategy for Sjögren's disease-associated lymphoma, rather than localised treatment or a watch and wait strategy, reduces the risk of new Sjögren's disease systemic activity and combination therapy is associated with decreased risk of lymphoma relapse., Funding: None., Competing Interests: Declaration of interests VLG received consulting fees from Novartis; honoraria from Novartis and Bristol Myers Squibb; and travel fees from AstraZeneca and Novartis. MC received honoraria from Lilly and travel fees from Novartis, Janssen, UCB, and Pfizer. XM received consulting fees from AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, Bristol Myers Squibb, Boehringer, and Janssen; honoraria from GSK, Bristol Myers Squibb, Boehringer, Amgen, Pfizer, and Roche; and travel fees from Amgen and GSK. GN received honoraria from Novartis, Boehringer, AbbVie, and Galapagos SASU and travel fees from Amgen, AbbVie, and UCB. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD., Material and Methods: Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis., Results: BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3 + regulatory and CD3 + CD4 - CD8 - double negative T-cell numbers in SGs., Conclusion: A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To 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.)

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Primary Sjögren disease (pSD) is an autoimmune disease characterized by lymphoid infiltration of exocrine glands leading to dryness of the mucosal surfaces and by the production of autoantibodies. The pathophysiology of pSD remains elusive and no treatment with demonstrated efficacy is available yet. To better understand the biology underlying pSD heterogeneity, we aimed at identifying Consensus gene Modules (CMs) that summarize the high-dimensional transcriptomic data of whole blood samples in pSD patients. We performed unsupervised gene classification on four data sets and identified thirteen CMs. We annotated and interpreted each of these CMs as corresponding to cell type abundances or biological functions by using gene set enrichment analyses and transcriptomic profiles of sorted blood cell subsets. Correlation with independently measured cell type abundances by flow cytometry confirmed these annotations. We used these CMs to reconcile previously proposed patient stratifications of pSD. Importantly, we showed that the expression of modules representing lymphocytes and erythrocytes before treatment initiation is associated with response to hydroxychloroquine and leflunomide combination therapy in a clinical trial. These consensus modules will help the identification and translation of blood-based predictive biomarkers for the treatment of pSD., Competing Interests: Declaration of competing interest While engaged in the research project, C.B., B.C. and E.D. were PhD students financed by Institut de Recherches Internationales Servier when they contributed to the research project. P.S., A.B., A.A., P.M., M.G., L.L., C.L., S.H., and E.Be were employees Institut de Recherches Internationales Servier when they contributed to the research project. W.F.N. has provided consultation for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Argenx, Janssen, Resolves Therapeutics, Astella and UCB. J.R. received funding from ZonMW and ReumaNederland., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: To investigate whether the efficacy and safety data from drug-registration trials can be extrapolated to real-life RA patients receiving RTX., Methods: The 'AutoImmunity and Rituximab' (AIR-PR) registry is a French multicentre, prospective cohort of RA patients treated with RTX in a real-life setting. We compared treatment responses at 12 months and serious adverse events (AEs) between eligible and non-eligible patients, by retrieving the eligibility criteria of the three rituximab-registration trials. We determined critical eligibility criteria and modelled the benefit-risk ratio according to the number of fulfilled critical eligibility criteria., Results: Among 1984 RA patients, only 9-12% fulfilled all eligibility criteria. Non-eligible patients had fewer EULAR responses at 12 months (40.3% vs 46.9%, P = 0.044). Critical inclusion criteria included swollen joints count ≥4, tender joints count ≥4, CRP ≥15 mg/l and RF positivity. Critical exclusion criteria were age >80 years, RA-associated systemic diseases, ACR functional class IV, DMARD other than MTX and prednisone >10 mg/day. Only 20.8% fulfilled those critical eligibility criteria. During the first year, serious AEs occurred for 182 (9.2%) patients (70.3% serious infections) and patients with ≥1 critical exclusion criterion were at higher risk (hazard ratio 3.03; 95% CI 2.25-4.06; for ≥3 criteria vs 0). The incremental risk-benefit ratio decreased with the number of unmet critical inclusion criteria and of fulfilled exclusion criteria., Conclusion: Few real-life RA patients were eligible for the drug-registration trials. Non-eligible patients had lower chance of response, and higher risk of serious AEs. Efficacy and safety data obtained from those trials may not be generalizable to RA patients receiving RTX in real-world clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cartilage, an important connective tissue, provides structural support to other body tissues, and serves as a cushion against impacts throughout the body. Found at the end of the bones, cartilage decreases friction and averts bone-on-bone contact during joint movement. Therefore, defects of cartilage can result from natural wear and tear, or from traumatic events, such as injuries or sudden changes in direction during sports activities. Overtime, these cartilage defects which do not always produce immediate symptoms, could lead to severe clinical pathologies. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine, providing a promising platform for generating various cell types for therapeutic applications. Thus, chondrocytes differentiated from iPSCs become a promising avenue for non-invasive clinical interventions for cartilage injuries and diseases. In this review, we aim to highlight the current strategies used for in vitro chondrogenic differentiation of iPSCs and to explore their multifaceted applications in disease modeling, drug screening, and personalized regenerative medicine. Achieving abundant functional iPSC-derived chondrocytes requires optimization of culture conditions, incorporating specific growth factors, and precise temporal control. Continual improvements in differentiation methods and integration of emerging genome editing, organoids, and 3D bioprinting technologies will enhance the translational applications of iPSC-derived chondrocytes. Finally, to unlock the benefits for patients suffering from cartilage diseases through iPSCs-derived technologies in chondrogenesis, automatic cell therapy manufacturing systems will not only reduce human intervention and ensure sterile processes within isolator-like platforms to minimize contamination risks, but also provide customized production processes with enhanced scalability and efficiency., (© 2024. The Author(s).)

Background: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups., Methods: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues., Findings: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only., Interpretation: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials., Funding: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology., Competing Interests: Conflicts of interest GN received honoraria from Boehringer and Novartis and travel fees from Amgen and AbbVie. W-FN received consulting fees from Resolve Therapeutics, Argenx, and Novartis and participated on data safety monitoring boards or advisory boards for Sanofi and Janssen Pharmaceuticals. JM received grants from Bristol Myers Squibb (BMS), Fresenius Kabi, Lilly, Novartis, Pfizer, and Roche-Chugai; received honoraria from AbbVie, Boehringer Ingelheim, Biogen, Lilly, Mylan, Pfizer, Sanofi, BMS, Fresenius Kabi, Galapagos, Medac, Novartis, and Roche-Chugai; received travel fees from BMS, Lilly, and Fresenius Kabi; and participated on advisory boards for AbbVie, Pfizer, and Galapagos. ED received consulting fees from BMS, Celgene, Lilly, Merck Sharp & Dohme (MSD), Novartis, and UCB; honoraria for lectures from AbbVie, BMS, Janssen Pharmaceuticals, Lilly, Medac, MSD, Novartis, Roche-Chugai, Sanofi, UCB, Celgene, Amgen, and Galapagos; and travel fees from AbbVie, BMS, Janssen Pharmaceuticals, Lilly, Medac, MSD, Novartis, Roche-Chugai, Sanofi, UCB, Celgene, Amgen, and Galapagos. PD received grants from Novartis and consulting fees from Pfizer, Roche-Chugai, BMS, AbbVie, and MSD. MC received travel fees from Janssen Pharmaceuticals, UCB, and Pfizer. CS received honoraria from Novartis and Roche-Chugai and travel fees from Novartis, Biogen, and Lilly. VLG received travel fees from AstraZeneca and Novartis. J-EG received grants from Pfizer, AbbVie, and Lilly and consulting fees from AbbVie, AstraZeneca, Sanofi, Lilly, Galapagos, Gilead Sciences, Roche-Chugai, Pfizer, BMS, and MSD. XM received consulting fees from AstraZeneca, BMS, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, BMS, Boehringer Ingelheim, and Janssen Pharmaceuticals; honoraria from GSK, BMS, Boehringer Ingelheim, Amgen, Pfizer, and Roche-Chugai; and travel fees from Amgen and GSK. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission., Methods: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression., Results: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4)., Conclusion: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: We aimed to evaluate the value of the Fibrosis-4 (FIB-4) score as a prognostic factor in RA in the prospective ESPOIR cohort. Methods: We included patients from the ESPOIR cohort with a diagnosis of RA according to ACR/EULAR criteria. The formula for the FIB-4 score is as follows: [age (years) × aspartate transaminase level (U/L)]/[platelet count (10 9 /L) × alanine aminotransferase level (U/L) 1/2 ]. We used a linear mixed-effects model with a random effect of patient to account for repeated measures over time. Results: Overall, 647 of the 813 patients included met the ACR/EULAR criteria for RA, with no differential diagnosis during the first 10 years of follow-up. Of these patients, at baseline, 633 had a calculable FIB-4 score. Median FIB-4 score was 0.75 (interquartile range 0.53-0.99). On multivariate analysis, FIB-4 score was not independently associated with progression of Disease Activity Score in 28 joints over 10 years of follow-up, unlike baseline C-reactive protein level and SJC. Baseline FIB-4 score was not associated with the modified Sharp score at 5-year follow-up, unlike age and ACPAs. FIB-4 score was not associated with mortality (hazard ratio 1.1 [95% CI 0.46; 2.8], p = 0.77) or major adverse cardiovascular events (0.46 [0.13; 1.6], p = 0.22) over the 10-year follow-up. No significant change in FIB-4 score over time was related to treatments. Conclusions: The present prospective cohort study did not find a prognostic role of FIB-4 score in RA. Reassuringly, FIB-4 score was not increased with DMARD treatment after 10 years of follow-up.

Objective: The C reactive protein polymyalgia rheumatica activity score (CRP-PMR-AS) is a composite index that includes CRP levels and was developed specifically for PMR. As treatments such as interleukin-6 antagonists can normalise CRP levels, the erythrocyte sedimentation rate (ESR) of PMR-AS, the clinical (clin)-PMR-AS and the imputed-CRP (imp-CRP)-PMR-AS have been developed to avoid such bias. Our primary objective was to measure the correlation of these activity scores. Our secondary objective was to evaluate the concordance between different cutoffs of the PMR-ASs., Method: Data from the Safety and Efficacy of tocilizumab versus Placebo in Polymyalgia rHeumatica With glucocORticoid dEpendence (SEMAPHORE) trial, a superiority randomised double-blind placebo-controlled trial, were subjected to post hoc analysis to compare the efficacy of tocilizumab versus placebo in patients with active PMR. The CRP-PMR-AS, ESR-PMR-AS, clin-PMR-AS and imp-CRP-PMR-AS were measured at every visit. The concordance and correlation between these scores were evaluated using kappa correlation coefficients, Bland-Altman correlations, intraclass correlation coefficients (ICCs) and scatter plots., Results: A total of 101 patients were included in the SEMAPHORE trial, and 100 were analysed in this study. The correlation between the PMR-ASs was excellent, as the ICC and kappa were >0.85 from week 4 until week 24 (CRP-PMR-AS ≤10 or >10). Bland-Altman plots revealed that the differences between the CRP-PMR-AS and the other threescores were low. The cut-off values for the clin-PMR-AS were similar to those for the CRP-PMR-AS 86% of the time., Conclusion: The correlation between all the PMR-ASs was excellent, reflecting the low weight of CRP. In clinical trials using drugs that have an impact on CRP, the derived activity scores can be used., Trial Registration Number: NTC02908217., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology., Competing Interests: Competing interests: KLW has received research grants and/or consulting honoraria from Janssen Pfizer, AbbVie, Union Chimique Belge (UCB), Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis; JDI has received grants and/or consulting honoraria from Janssen, GSK, Pfizer, Abbvie, BMS, Gilead, Roche, Eli Lilly, Anaptys Bio, Sonoma; PM has received grants and/or consulting honoraria from AbbVie, Acelyrin, Aclaris, Amgen, Boehringer Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Moonlake, Novartis, Pfizer, Sun Pharma, Takeda, UCB, Ventyx; JEG has received grants and/or consulting honoraria from Abbvie, BMS, Gilead, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche Chugai, Sanofi; MHB has received grants and/or consulting honoraria (all paid to host institution) from Abbvie, Boehringer-Ingelheim, Galapagos, Gilead and Pfizer Ltd. MKC has received grants or consulting honoraria from AMPEL BioSolutions, Astra Zeneca, BMS, Gilead Sciences, and GSK; JK has received research grants (paid to UMass Chan Medical School) from Aker BioMarine AS; Galapagos NV; and Novartis Pharmaceuticals Corp.; and consulting honoraria from Alvotech Swiss AG; Boehringer Ingelheim GmbH; Bristol Myers Squibb Co.; Fresenius Kabi; Inmagene LLC; Kolon TissueGene, Inc.; Novartis Pharmaceuticals Corp.; Organon LLC; Pfizer Inc.; Samsung Bioepis; Sandoz Inc.; Scipher Medicine; Teijin Pharma Ltd.; Viatris Inc.; and UCB Inc; LC serves on a Data Safety Monitoring Board for Kezar Life Sciences and has research grants from Argenyx; AK has received grants and/or consulting honoraria from Amgen, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, UCB and Pfizer; XB has received grants and/or consulting honoraria from AbbVie, BMS, MSD, Celgene, Chugai, Merck, Novartis, Pfizer, Sandoz, and UCB; RFvV has received grants and/or consulting honoraria; CO has no competing interests; HPK has received grants and/or consulting honoraria from SS has received grants and/or consulting honoraria from Amgen, AbbVie, AstraZeneca, Boehringer-Ingelheim, BMS, Eli Lilly, GSK, Janssen and UCB; MK has received grants and/or consulting honoraria (all paid to institution) from UCB, Pfizer, Novartis, Galapagos, CHDR and Jansen; DA has received grants and/or consulting honoraria from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz, and Sanofi; IBM has received grants and/or consulting honoraria from AbbVie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB, Evelo, Compugen, AstraZeneca, Moonlake, and serves as a NHS GGC board member, Evelo Board of Directors, Versus Arthritis Trustee Status; TWJH has no competing interests to disclose; REV has received grants and/or consulting honoraria from AbbVie, Amgen, Boehringer Ingelheim, BMS, Janssen-Cilag, GSK, Hexal, Neutrolis, Novartis, and Pfizer; EMG: serves as an associate editor at the New England Journal of Medicine and receives royalties from Elsevier; FCB has no competing interests to disclose; JSS has received research grants and/or consulting honoraria from AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Chugai, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, and UCB serves as the editor of Annals of Rheumatic Diseases but was not involved in the handling or review of this manuscript., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate and compare the use of oral glucocorticoids with three classes of bDMARDs in patients with rheumatoid arthritis (RA)., Methods: We included patients from 13 observational registries treated with a TNF-inhibitor, abatacept or tocilizumab and with available information on the use of oral glucocorticoids. The main outcome was oral glucocorticoid withdrawal. A McNemar test was used to analyse the change in the use of glucocorticoids after 1 year. Kaplan-Meier estimates and Cox regressions, adjusted for patient, treatment, and disease characteristics, were used to evaluate glucocorticoid discontinuation in patients with glucocorticoids at baseline. Because of heterogeneity, analyses were done by registers and pooled using random-effects meta-analysis., Results: A total of 12,334 participants treated with TNF-inhibitors, 2100 with tocilizumab and 3229 with abatacept were included. At one-year, oral glucocorticoid use decreased in all treatment groups (odds ratio for stopping vs. starting of 2.19 [95% CI 1.58; 3.04] for TNF-inhibitors, 2.46 [1.39; 4.35] for tocilizumab; 1.73 [1.25; 2.21] for abatacept). Median time to glucocorticoid withdrawal was ≈2 years or more in most countries, with a gradual decrease over time. Compared to TNF-inhibitors, crude hazard ratios of glucocorticoid discontinuation were 0.65[0.48-0.87] for abatacept, and 1.04 [0.76-1.43] for tocilizumab, and adjusted hazard ratios were 1.1 [0.83-1.47] for abatacept, and 1.30 [0.96-1.78] for tocilizumab., Conclusion: After initiation of a bDMARD, glucocorticoid use decreased similarly in all treatment groups. However, glucocorticoid withdrawal was much slower than advocated by current international guidelines. More effort should be devoted to glucocorticoid tapering when low disease activity is achieved., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Although airway disease associated with Sjögren's disease (Sjo-AD) is common, it is poorly studied compared with interstitial lung disease (ILD). In this study, we aimed to assess factors associated with Sjo-AD, the characteristics and prognosis of this manifestation., Methods: We performed a retrospective multicentric study involving nine centres. We included Sjo-AD patients confirmed by at least one clinician and one CT scan report. Clinical and biological data, pulmonary function test (PFT), and CT scans were collected. A single radiologist specialist in thoracic diseases reviewed CT scans. Sjo-AD patients were compared with Sjo controls without pulmonary involvement, randomly selected after matching for age and disease duration., Results: We included 31 Sjo-AD and 62 Sjo controls without pulmonary history. Sjo-AD had a higher disease activity (ESSDAI) compared with controls, even when excluding the pulmonary domain of the score (7 vs 3.8, p<0.05), mainly due to the biological activity. Sjo-AD was multilobar (72%) and associated with signs of both bronchiectasis and bronchiolitis (60%). Obstructive lung disease occurred in 32% at the time of Sjo-AD diagnosis. Overall, PFT was stable after 8.7±7 years follow-up but repeated CT scans showed extended lesions in 41% of cases within 6±3.2 years. No patient developed Sjo-ILD. Sjo-AD progression was independent of the global disease activity., Conclusions: Sjo-AD preferentially affects Sjo patients with higher biological activity. It is often characterised as a diffuse disease, affecting both proximal and distal airways, with a slow evolution over time and no progression to Sjo-ILD., Competing Interests: Competing interests: GN received honorarium from Biogen, Pfizer, Novartis, Lilly and Amgen. XM received honorarium from Astra-Zeneca, BMS, Galapagos, GSK, Novartis, Pfizer. M-PD received honorarium from Boehringer-Ingelheim and GSK. P-AJ received honorarium from Galapagos. ED received honorarium from Abbvie, BMS, Janssen, Lilly, Medac, MSD, Novartis, Roche-Chugai, Sanofi, UCB, Celgène, Amgen and Galapagos., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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

Objectives: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes., Method: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST., Results: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6., Conclusions: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes., Competing Interests: Competing interests: VD-P has undertaken clinical trials and provided consultancy or expert advice in the area of Sjogren’s disease to the following companies: MedImmune, UCB, Abbvie, Sanofi, Novartis and BMS. BF has undertaken consultancy for Novartis, BMS, Servier, Galapagos, Roche, Sanofi and Janssen and received research funding from Janssen, Galapagos, Servier and Celgene. SJB has undertaken consultancy for Novartis, BMS, Iqvia and Janssen and accepted hospitality from Novartis to attend a working dinner at the BSR conference regarding secukinumab in inflammatory arthritis in the last year. MB has received consultancy and/or advisory board fees and/or grant support from GSK, Janssen, Ono Pharmaceutical, Horizon Therapeutics in the last two years. W-FN has undertaken clinical trials and provided consultancy or expert advice in the area of Sjogren’s syndrome to the following companies: GlaxoSmithKline, MedImmune, UCB, Abbvie, Roche, Eli Lilly, Takeda, Resolves Therapeutics, Sanofi, Novartis and BMS. No other potential conflict of interest relevant to this article was reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes., Methods: Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database., Results: We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated., Conclusion: This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Patients with psoriatic arthritis (PsA) are at a significantly increased risk of hyperuricaemia and development of gout, and those with hyperuricaemia have been found to respond poorly to PsA treatment and have more peripheral and destructive joint damage. We present a comprehensive post hoc analysis using pooled data from the FUTURE 2-5 studies and the MAXIMISE study to further evaluate the impact of hyperuricaemia on clinical presentation/disease severity and response to secukinumab in patients with PsA., Methods: Patients were stratified into two groups based on baseline serum uric acid (SUA) level (threshold of 360 µmol/L). A sensitivity analysis was also performed based on SUA thresholds of 300 µmol/L and 420 µmol/L. Demographics, clinical, radiological characteristics and comorbidities data were collected., Results: At baseline, patients with hyperuricaemia were mostly male, reported a higher prevalence of hypertension, with more clinical dactylitis, more psoriasis and more severe skin disease compared with patients with normouricaemia. A similar proportion of patients in the normouricaemic and hyperuricaemic cohorts achieved American College of Rheumatology responses, resolution of enthesitis and dactylitis, inhibition of structural damage progression and improvement in health-related quality of life across all secukinumab doses at week 52., Conclusion: Patients with PsA and hyperuricaemia have different clinical characteristics from patients with PsA and normouricaemia. Identification of these patients at an early stage may facilitate a personalised treatment approach and improved management of comorbidities. Furthermore, secukinumab provided a rapid and sustained response across all manifestations of PsA up to week 52, irrespective of baseline uricaemia status., Competing Interests: Competing interests: RF: Consulting fees and advisory boards (Novartis); J-EG: Consulting fees and advisory boards (Novartis); CG and WB are employees and shareholders of Novartis., (© 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.)

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1 . Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6 , CXCR5 , and lnc-PHLDB1-1 , among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues., Competing Interests: Competing Interests C.J.L.* and A.D.F. have an active collaborative research agreement with Janssen. E.B. has an active research collaboration with Pfizer. T.M. is employed as medical solutions lead in rheumatology at UCB. R.H.S. is a consultant for Jansen Pharmaceuticals. S.J.B. provided consultancy services for Abbvie, BMS, Galapagos, Iqvia, J&J, Kiniksa, and Novartis in 2020–2021. L.R. provided consultancy services for AstraZeneca. B.M.W. has active collaborative research agreements with Astellas Bio and Pfizer, Inc. M.R. received grants from Amgen, AstraZeneca, Bristol Myers-Squibb, Novartis, and Servier for clinical trials in Sjögren’s Syndrome and SLE. All other authors have reported that they have no competing interests to report.

Objective: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers., Methods: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease., Results: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded., Conclusion: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL)., Methods: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group., Results: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS., Conclusion: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM)., Objectives: To assess the significance of DH/BS in patients with IM., Methods: Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1., Results: 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05)., Conclusion: In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis)., Competing Interests: Competing interests: None declared., (© 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.)

Sjögren's disease (SD), also known as Sjögren's syndrome (SS) or Gougerot-Sjögren's syndrome in France, is a rare systemic autoimmune disease in its primary form and is characterised by tropism for the exocrine glandular epithelia, particularly the salivary and lacrimal glands. The lymphocytic infiltration of these epithelia will clinically translate into a dry syndrome which, associated with fatigue and pain, constitutes the symptom triad of the disease. In about one third of patients, SD is associated with systemic complications that can affect the joints, skin, lungs, kidneys, central or peripheral nervous system, and lymphoid organs with an increased risk of B-cell lymphoma. SD affects women more frequently than men (9/1). The peak frequency is around the age of 50. However, the disease can occur at any age, with paediatric forms occurring even though they remain rare. SD can occur alone or in association with other systemic autoimmune diseases. In its isolated or primary form, the prevalence of SD is estimated to be between 1 per 1000 and 1 per 10,000 inhabitants. The most recent classification criteria were developed in 2016 by EULAR and ACR. The course and prognosis of the disease are highly variable and depend on the presence of systemic involvement and the severity of the dryness of the eyes and mouth. The current approach is therefore to identify at an early stage those patients most at risk of systemic complications or lymphoma, who require close follow-up. On the other hand, regular monitoring of the ophthalmological damage and of the dental status should be ensured to reduce the consequences., (Copyright © 2023. Published by Elsevier Masson SAS.)

Background: Patients with rheumatoid arthritis (RA) have an increased risk of infection and malignancy compared with the general population. Infection risk is increased further with the use of disease-modifying antirheumatic drugs (DMARDs), whereas evidence on whether the use of biologic DMARDs increases cancer risk remains equivocal. This single-arm, post-marketing study estimated the incidence of prespecified infection and malignancy outcomes in patients with RA treated with intravenous or subcutaneous abatacept., Methods: Data were included from seven European RA quality registries: ATTRA (Anti-TNF Therapy in Rheumatoid Arthritis [Czech Republic]), DANBIO (Danish Rheumatologic Database), ROB-FIN (National Registry of Antirheumatic and Biological Treatment in Finland), ORA (Orencia and Rheumatoid Arthritis [France]), GISEA (Italian Group for the Study of Early Arthritis), BIOBADASER (Spanish Register of Adverse Events of Biological Therapies in Rheumatic Diseases), and the SCQM (Swiss Clinical Quality Management) system. Each registry is unique with respect to design, data collection, definition of the study cohort, reporting, and validation of outcomes. In general, registries defined the index date as the first day of abatacept treatment and reported data for infections requiring hospitalization and overall malignancies; data for other infection and malignancy outcomes were not available for every cohort. Abatacept exposure was measured in patient-years (p-y). Incidence rates (IRs) were calculated as the number of events per 1000 p-y of follow-up with 95% confidence intervals., Results: Over 5000 patients with RA treated with abatacept were included. Most patients (78-85%) were female, and the mean age range was 52-58 years. Baseline characteristics were largely consistent across registries. Among patients treated with abatacept, IRs for infections requiring hospitalization across the registries ranged from 4 to 100 events per 1000 p-y, while IRs for overall malignancy ranged from 3 to 19 per 1000 p-y., Conclusions: Despite heterogeneity between registries in terms of design, data collection, and ascertainment of safety outcomes, as well as the possibility of under-reporting of adverse events in observational studies, the safety profile of abatacept reported here was largely consistent with previous findings in patients with RA treated with abatacept, with no new or increased risks of infection or malignancy., (© 2023. The Author(s).)

Previous work has successfully used machine learning and natural language processing for the phenotyping of Rheumatoid Arthritis (RA) patients in hospitals within the United States and France. Our goal is to evaluate the adaptability of RA phenotyping algorithms to a new hospital, both at the patient and encounter levels. Two algorithms are adapted and evaluated with a newly developed RA gold standard corpus, including annotations at the encounter level. The adapted algorithms offer comparably good performance for patient-level phenotyping on the new corpus (F1 0.68 to 0.82), but lower performance for encounter-level (F1 0.54). Regarding adaptation feasibility and cost, the first algorithm incurred a heavier adaptation burden because it required manual feature engineering. However, it is less computationally intensive than the second, semi-supervised, algorithm.

Objective: Innate lymphoid cells (ILCs) are a cell population implicated in the pathogenesis of various chronic inflammatory diseases, but little is known about their role in primary Sjögren's syndrome (pSS). The aim of this study was to assess the frequency of ILC subsets in peripheral blood (PB) and their quantity and location in minor salivary glands (MSGs) in pSS., Methods: The frequency of ILC subsets was analysed in the PB of patients with pSS and healthy controls (HCs) by flow cytometry. The amount and location of ILC subsets in MSGs were studied in patients with pSS and sicca controls by immunofluorescence assay., Results: In PB, the frequency of ILC subsets did not differ between patients with pSS and HCs. The circulating frequency of the ILC1 subset was increased in patients with pSS with positive anti-SSA antibodies and that of the ILC3 subset was reduced in patients with pSS with glandular swelling. In MSGs, the ILC3 number was higher in lymphocytic-infiltrated than non-infiltrated tissue in patients with pSS and normal glandular tissues in sicca controls. The ILC3 subset was preferentially located at the periphery of infiltrates and was more abundant in small infiltrates of recently diagnosed pSS., Conclusion: Altered ILC homeostasis mainly concerns salivary glands in pSS. Most ILCs in MSGs consist of the ILC3 subset, located at the periphery of lymphocytic infiltrates. The ILC3 subset is more abundant in smaller infiltrates and in recently diagnosed pSS. It might play a pathogenic role in the development of T and B lymphocyte infiltrates in the early stages of pSS., Competing Interests: Competing interests: None declared., (© 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.)

To detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. Breakout sessions were convened with experts in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and connective tissue diseases (CTDs). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research, as well as highlight recent progress in meeting formerly identified unmet needs. Clinical trial design innovation was emphasised across all disease states. Within RA, developing therapies and trials for refractory disease patients remained among the most important identified unmet needs and within lupus and spondyloarthritis the need to account for disease endotypes was highlighted. The RA group also identified the need to better understand the natural history of RA, pre-RA states and the need ultimately for precision medicine. In CTD generally, experts focused on the need to better identify molecular, cellular and clinical signals of early and undifferentiated disease in order to identify novel drug targets. There remains a strong need to develop therapies and therapeutic strategies for those with treatment-refractory disease. Increasingly it is clear that we need to better understand the natural history of these diseases, including their 'predisease' states, and identify molecular signatures, including at a tissue level, which can facilitate disease diagnosis and treatment. As these unmet needs in the field of rheumatic diseases have been identified based on consensus of expert clinicians and scientists in the field, this document may serve individual researchers, institutions and industry to help prioritise their scientific activities., Competing Interests: Competing interests: KLW has received research grants and/or consulting honoraria from Janssen Pfizer, AbbVie, Union Chimique Belge (UCB), Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis; JDI has received grants and/or consulting honoraria from Janssen, Pfizer, AbbVie, BMS, Gilead, Roche, UCB, Eli Lilly; PJM has received grants and/or consulting honoraria from AbbVie, Acelyrin, Aclaris, Amgen, Boehringer Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Moonlake, Novartis, Pfizer, Sun Pharma, UCB; DTB has received grants/or consulting honoraria from AstraZeneca, Abbvie, Pfiser, GSK and Lilly; XB has received grants and/or consulting honoraria from AbbVie, BMS, MSD, Celgene, Chugai, Merck, Novartis, Pfizer, Sandoz, and UCB; J-EG has received grants and/or consulting honoraria from Abbvie, BMS, Gilead, Galapagos, Lilly, MSD, Novartis, Pfizer, Roche Chugai, Sanofi; SS has received grants and/or consulting honoraria from Amgen, AbbVie, Biogen, Eli Lilly, GSK, Janssen, UCB, Pfizer, Boehringer Ingelheim and Novartis; MM has received grants and/or consulting honoraria from Lilly, GSK, Astra Zeneca, UCB, Janssen, Abbvie and Pfizer; NB has received grants and/or consulting honoraria from Roche, MSD, Pfizer, GSK, Galapagos, Vifor and Lilly; RL has received grants and/or consulting honoraria from Abbvie, Boehringer-Ingelheim, Celgene, Eli-Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Sandoz, Kabi-Fresenius, Biosplice (formerly Samumed) and UCB; DA has received grants and/or consulting honoraria from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi; IBM has received grants and/or consulting honoraria from AbbVie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB, Evelo, Compugen, AstraZeneca, Moonlake and serves as a NHS GGC board member, Evelo Board of Directors, Versus Arthritis Trustee Status; REV has received grants and/or consulting honoraria from AbbVie, Amgen, Boehringer Ingelheim, BMS, Janssen-Cilag, GSK, Hexal, Neutrolis, Novartis and Pfizer; EMG: serves as an associate editor at the New England Journal of Medicine; JSS has received research grants and/or consulting honoraria from AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Chugai, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung and UCB serves as the editor of Annals of Rheumatic Diseases but was not involved in the handling or review of this manuscript., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Objective: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA)., Methods: Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest., Results: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE)., Conclusion: Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA., (© Japan College of Rheumatology 2022. Published by Oxford University Press.)

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.)

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS., Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa)., Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells., Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS., Methods: This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes., Results: The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2., Conclusion: Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings., Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases., Methods: The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019., Results: Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10). Safety: 11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years). Efficacy: the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued., Conclusion: These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs., Competing Interests: Competing interests: XM received consulting fees from BMS, Novartis, Sanofi, Pfizer, UCB, Janssen, GSK, Galapagos and BMS and is RMD Open associate editor. JE-G received grants from BMS, Lilly, Pfizer (payments made to University of Strasbourg Foundation; no access to TATA data) and consulting fees from BMS, Galapagos, Abbvie, Janssen, Novartis, Pfizer, Sanofi, Gilead, Roche, Chugai and Lilly., (© 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.)