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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 evaluate the effectiveness of short message service (SMS) and/or email reminders in improving influenza vaccination coverage rates among rheumatoid arthritis (RA) patients treated with anti-TNF therapies, and to identify factors associated with vaccination., Methods: A nested randomized controlled trial in the ART e-cohort, an ongoing French nationwide multicentre prospective cohort of RA patients treated with anti-TNF therapy. Patients were 1:1 randomized, with stratification on age. The intervention consisted in regular reminders via SMS and/or emails to get vaccinated against influenza during the vaccination campaign. After the end, all participants received a questionnaire. The primary outcome was the influenza vaccination coverage. Secondary outcomes included the vaccination coverage before and after COVID-19 pandemic, and factors associated with vaccination., Results: Between October 2021 and April 2022, 446 participants were randomized (224 in the intervention group, 222 in the control group). Among them, 325 (73%) reported their vaccination status and 221 (68%) were vaccinated against influenza: 116/158 (73%) in the intervention group, vs 105/167 (63%) in the control group (RR 1.08; 95% CI 0.95-1.23). The vaccination coverage before and after COVID-19 pandemic did not differ (72% vs 72%; 95% CI -8% to8%). Age ≥65 years (OR 6.25; 95% CI 2.88-13.60), and previous influenza vaccination in the years before inclusion (OR 7.81; 95% CI 4.36-14.02) were associated with higher rates of vaccination., Conclusion: SMS and/or e-mails reminders did not significantly improve influenza vaccination rates in our cohort. COVID-19 pandemic did not substantially impact the influenza vaccination coverage. Our results might be counterbalanced by an already high vaccination coverage., Trial Registration Number: www.clinicaltrials.gov; NCT05220423; NCT03062865., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To report 52-week safety and efficacy of ianalumab from phase 2b dose-finding study in patients with Sjögren's disease (SjD)., Methods: Patients randomly received (1:1:1:1) ianalumab (5, 50, or 300 mg) or placebo subcutaneously every 4 weeks till week 24 (treatment period [TP]1). At week 24, patients on 300 mg were re-randomized to continue 300 mg or receive placebo till week 52 (TP2), patients on placebo were switched to ianalumab 150 mg, while patients on 5 and 50 mg directly entered post treatment safety follow-up. Patients who discontinued treatment early or completed treatment entered safety follow-up (≥20 weeks)., Results: During TP1, 190 patients were randomized (placebo=49, 5 mg=47, 50 mg=47, 300 mg=47). Of these 190 patients, 90 (47.4 %; 43 continued 300 mg and 47 received placebo) entered TP2, and 81/90 (90.0%) completed the study treatment. By week 52, efficacy was sustained in patients who continued 300 mg in TP2 (ESSDAI, ESSPRI, PaGA, PhGA change from week 24: -1.45, -0.46, -4.69, -6.86, respectively). Stimulated salivary flow rates and autoantibody levels numerically improved in the 300 mg group. Treatment-emergent adverse events were not dose-dependent, except for injection-site reactions. Cases of decreased neutrophil counts (CTCAE v4.03 grade 3 according to laboratory listings) were observed in 3 patients during the post-treatment follow-up, occurring at 3.5, 5.5, and 3 months, after the last ianalumab administration. None were associated with infection except one incidental finding of asymptomatic cytomegalovirus infection (IgM+)., Conclusion: In patients with SjD, ianalumab 300 mg demonstrated sustained efficacy through week 52 and a favorable safety profile up to two years of follow-up., (This article is protected by copyright. All rights reserved.)

Objectives: To investigate the frequency and factors associated with disease flare following vaccination against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs)., Methods: Data from the European Alliance of Associations for Rheumatology Coronavirus Vaccine physician-reported registry were used. Factors associated with flare in patients with I-RMDs were investigated using multivariable logistic regression adjusted for demographic and clinical factors., Results: The study included 7336 patients with I-RMD, with 272 of 7336 (3.7%) experiencing flares and 121 of 7336 (1.6%) experiencing flares requiring starting a new medication or increasing the dosage of an existing medication. Factors independently associated with increased odds of flare were: female sex (OR=1.40, 95% CI=1.05 to 1.87), active disease at the time of vaccination (low disease activity (LDA), OR=1.45, 95% CI=1.08 to 1.94; moderate/high disease activity (M/HDA), OR=1.37, 95% CI=0.97 to 1.95; vs remission), and cessation/reduction of antirheumatic medication before or after vaccination (OR=4.76, 95% CI=3.44 to 6.58); factors associated with decreased odds of flare were: higher age (OR=0.90, 95% CI=0.83 to 0.98), non-Pfizer/AstraZeneca/Moderna vaccines (OR=0.10, 95% CI=0.01 to 0.74; vs Pfizer), and exposure to methotrexate (OR=0.57, 95% CI=0.37 to 0.90), tumour necrosis factor inhibitors (OR=0.55, 95% CI=0.36 to 0.85) or rituximab (OR=0.27, 95% CI=0.11 to 0.66), versus no antirheumatic treatment. In a multivariable model using new medication or dosage increase due to flare as the dependent variable, only the following independent associations were observed: active disease (LDA, OR=1.47, 95% CI=0.94 to 2.29; M/HDA, OR=3.08, 95% CI=1.91 to 4.97; vs remission), cessation/reduction of antirheumatic medication before or after vaccination (OR=2.24, 95% CI=1.33 to 3.78), and exposure to methotrexate (OR=0.48, 95% CI=0.26 to 0.89) or rituximab (OR=0.10, 95% CI=0.01 to 0.77), versus no antirheumatic treatment., Conclusion: I-RMD flares following SARS-CoV-2 vaccination were uncommon. Factors associated with flares were identified, namely higher disease activity and cessation/reduction of antirheumatic medications before or after vaccination., Competing Interests: Competing interests: BF does not report conflicts of interest. SL-T does not report conflicts of interest. KLH reports non-personal speaker's fees from AbbVie and grant income from BMS and Pfizer, all unrelated to this manuscript; and her institute was supported by EULAR for COVAX database management. LG reports research grants from Amgen, Galapagos, Lilly, Pfizer and Sandoz; and consulting fees from AbbVie, Amgen, BMS, Celltrion, Galapagos, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer, Samsung Bioepis, Sanofi-Aventis and UCB, all unrelated to this manuscript. LC has not received fees or personal grants from any laboratory, but her institute works by contract for laboratories among other institutions, such as Galapagos, Pfizer, Lilly, MSD, Novartis, Roche, Sanofi Aventis, BMS and Sandoz; she also reports safety board participation, not paid personally. AS reports personal fees from lectures for AbbVie, Galapagos, Lilly, Pfizer and Takeda. EFM does not report conflicts of interest. MS does not report conflicts of interest. AR does not report conflicts of interest. EH does not report conflicts of interest. JAG-P does not report conflicts of interest. MM reports having received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, all unrelated to this manuscript. PD reports speaker's fees from AbbVie, Lilly, Galapagos, Janssen and Biogen, all unrelated to this manuscript. LT does not report conflicts of interest. TG does not report conflicts of interest. MC does not report conflicts of interest. ES reports receiving grants from AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Novartis, AbbVie, Pfizer, Eli Lilly, UCB, Sobi, Roche, Sanofi, Boehringer-Ingelheim, Viatris, Sandoz, Mylan, MSD, Amgen and Janssen-Johnson & Johnson; support for attending meetings and/or travel from AbbVie and Janssen-Johnson & Johnson; participation in a data safety monitoring board or advisory board from AbbVie, Eli Lilly, UCB, Sobi, Boehringer-Ingelheim and Janssen-Johnson & Johnson; and is a committee member of Slovak Society of Rheumatology, all unrelated to this manuscript. IB reports receiving speaker's fees from AbbVie, Pfizer, Boehringer Ingelheim and Janssen; and has received support for attending meetings and/or travel from AbbVie, all unrelated to this manuscript. ES does not report conflicts of interest. JZ reports consulting fees from AbbVie, Janssen, Novartis and Boehringer-Ingelheim; speaker's fees from AbbVie, Janssen, Novartis, Boehringer Ingelheim Latvia and UAB Viasana; receiving support for attending meetings and/or travel from AbbVie, UAB Viasana and Johnson & Johnson; and is a board member of Latvian Society of Adult Rheumatology; all unrelated to this manuscript. NR has nothing to disclose. OB has nothing to disclose. EV has nothing to disclose. BR has nothing to disclose. GRB has nothing to disclose. XM reports personal consultant fees from BMS, Galapagos, GSK, Novartis and Pfizer; and having received support for attending meetings and/or travel from Novartis, all unrelated to this manuscript. PMM has received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

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.)

Objective: Our objective was to define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases., Methods: We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells and endothelial cells. We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate., Results: Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid increase of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate., Conclusions: Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might be associated with adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy., Competing Interests: Conflicts of interest: SSM is a consultant for Aurinia, Novartis, BMS, Amgen, Target RWE, Kiniksa, Otsuka/Visterra, and iCell. XM received consultant fees from BMS, GSK, Novartis, Otsuka and Pfizer.

Objectives: The RNA epitranscriptomic modification known as N6 -methyladenosine (m 6 A) represents a novel mechanism of gene regulation that is poorly understood in human autoimmune diseases. Our research explores the role of this RNA m 6 A modification in salivary gland epithelial cells (SGEC) and its impact on the pathogenesis of Sjögren's disease (SjD)., Methods: SGECs from SjD patients and controls were analysed for m 6 A writers METTL3 and METTL14 expression using RNA-seq, quantitative PCR and immunohistochemistry. Functional assays assessed the impact of METTL3 knockdown or pharmacological inhibition on proinflammatory gene expression and immune cell interactions (using transwell and coculture systems). Mechanistic studies examined METTL3-mediated m 6 A modifications in double-stranded RNA (dsRNA) formation through immunofluorescence. Unsupervised clustering identified patterns of interferon activation in salivary glands and their correlation with m 6 A writers., Results: METTL3 and METTL14 were elevated in SGEC from SjD patients in comparison to controls. Paradoxically, inhibiting METTL3 increased proinflammatory gene expression, enhancing SGEC's ability to attract immune cells and activate B cells. Conversely, inhibiting the eraser FTO had the opposite effect. METTL3-mediated m 6 A modifications prevented dsRNA formation and IFN signalling activation. SGEC from SjD showed insufficient METTL3 upregulation compared with controls in response to inflammatory triggers, indicating a limited capacity to regulate the inflammatory response. SjD patients with elevated disease activity and higher interferon signature exhibit reduced METTL3 expression., Conclusions: Impairment of m 6 A modifications in SGEC in response to inflammatory triggers favour the formation of dsRNA, potentially amplifying the interferon loop and contributing to SjD pathogenesis., Competing Interests: Competing interests: XM received an honorarium for consultancy advice on Sjögren’s disease from Argenx, BMS, GSK, Novartis and Otsuka. The rest of the authors declare that they have no relevant conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Sjögren's disease is a clinically and pathophysiologically heterogeneous disease to which precision medicine, on the basis of clinical and biological heterogeneity, has been not always applicable. In patients with Sjögren's disease, the relationship between dysregulated biological pathways and symptoms such as fatigue and pain or clinical manifestations is often difficult to establish. This clinical and biological dissociation also poses challenges when defining appropriate clinical endpoints for clinical trials. In the last few years, however, research efforts have been focused on gaining a better understanding of the considerable heterogeneity of Sjögren's disease by developing stratification models aimed at clustering patients with this condition into homogenous subgroups characterised by distinctive molecular signatures, biomarkers, clinical features, and outcomes. In this Review, we discuss current evidence regarding clinical, laboratory, histological, and biomolecular stratification in Sjögren's disease and examine how available stratification data can guide precision medicine and inform the design of future clinical trials., Competing Interests: Declaration of interests MB reports an unrestricted grant from Janssen, consulting fees from Ono Pharma, honoraria for lectures from GSK, and participation in scientific advisory boards for Janssen and Horizon Therapeutics. XM reports consulting fees from Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer, and Servier. FC reports consulting fees from Eli Lilly, AbbVie, Novartis, GSK, Pfizer, Galapagos, UCB, Janssen, MSD, and AstraZeneca; honoraria for lectures from Eli Lilly, AbbVie, Novartis, GSK, Pfizer, Galapagos, UCB, Janssen, MSD, and AstraZeneca; and support for attending meetings or travel from Novartis, AbbVie, UCB, Eli Lilly, Pfizer, and Galapagos. SJ and J-OP declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: The association between immune-mediated thrombotic thrombocytopenic purpura (iTTP) and Sjögren disease (SjD) has been poorly investigated. This study presents the first retrospective cohort of iTTP-SjD aiming to identify risk factors for iTTP occurrence in SjD patients and examine their clinical course., Methods: Patients with iTTP-SjD were identified within the French TTP Registry based on American College of Rheumatology/European League Against Rheumatism 2016 criteria. A comparative analysis was conducted with two control groups comprising primary SjD (pSjD) patients from the French ASSESS cohort and idiopathic iTTP patients from the French TTP Registry. Demographic, clinical and biological data were retrospectively collected., Results: Thirty iTTP-SjD patients were included and compared with 65 pSjD and 45 idiopathic iTTP patients. The majority of iTTP-SjD patients (n=18) were diagnosed with SjD at the time of iTTP diagnosis. In comparison with the pSjD cohort, iTTP-SjD patients were diagnosed with SjD at a younger age (p=0.039) and showed a higher prevalence of anti-SjS-related antigen A antibody positivity and xerostomia (p=0.015, p=0.035, respectively). EULAR Sjogren's Syndrome Disease Activity Index showed similar activity levels between the two groups. iTTP-SjD patients were treated with plasma exchange (n=28), corticosteroids, rituximab (n=19) and caplacizumab (n=3). In comparison with the idiopathic iTTP cohort, mortality rates (log-rank tests, p=0.228), biological and clinical iTTP relapses (multivariate analysis, p=0.181) were comparable and short-term outcomes (survival at day 30, relapse) were favourable., Conclusion: iTTP can be a rare complication in patients with SjD. Further studies involving larger cohorts and long-term follow-up are warranted to confirm these findings and to explore the efficacy of immunomodulators and caplacizumab in iTTP-SjD patients., Competing Interests: Competing interests: GN received speaker fees from Novartis, Amgen, Galapagos and BMS. AV is a member of the French advisory boards for Sanofi and Takeda and received speaker fees from Sanofi, Octapharma, LFB-Biomédicaments and Takeda. XM received fees from BMS, Galapagos, GSK, Novartis and Pfizer. PC is a member of advisory boards and received speaker fees from Sanofi, Alexion, Octapharma and Takeda. IB received speaker fees from Galapagos. BSJ received speaker fees from Sanofi, Takeda and LFB-Biomédicaments. JL, LG and RB declare no conflicts of interest., (© 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 a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease., Methods: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete., Findings: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period., Interpretation: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials., Funding: Novartis Pharma., Competing Interests: Declaration of interests BAF received consulting fees from Novartis, Roche, BMS, Galapagos, Janssen, Servier, UCB, and Sanofi; and funding to his institution for collaborative research from Janssen, Celgene, Galapagos, and Servier. XM received consulting fees from BMS, Galapagos, GSK, Novartis, Pfizer, and Servier. AP received grants or research support from Novartis, Viela Bio, and Exosome Dx. TG-B received travel assistance from Novartis and has participated in the scientific advisory board of Novartis. W-FN provided consultation services for Novartis, AbbVie, BMS, Sanofi, Argenx, Janssen, Resolve Therapeutics, Bain Capitals, and UCB. SF reports consulting fees from AstraZeneca and Novartis; payment for sponsored talks or courses from AbbVie, Chugai, Galapagos, Novartis, and UCB; participation in the scientific advisory boards of AstraZeneca and Novartis; and a research grant from Novartis for their institution. GN received consulting fees from Novartis and Janssen; and participated in the scientific advisory boards of Novartis and Janssen. JH reported that his institution received research grants and study fees from Novartis, and he received honoraria for lectures from Lilly, MSD, AbbVie, Novartis, and Astro Pharma; travel support from Novartis; and participated in the scientific advisory boards of Lilly and Pfizer. SSM received consulting fees from Novartis, BMS, Otsuka, Visterra, Target RDW, Horizon, Kinksa, and iCell; and payment for educational content development. EA received grants from National Eye Institute, Novartis, Ocular Therapeutics, W.L. Gore & Associates, IRIS Registry Research Fund, and US Department of Defense; received speaker and consultation fees from Adelphi Values, Dompe, FirstString Medical Research, HanAll, Novalique, Regeneron Healthcare Solutions, Sinqi, Xequel, Kyria, and Hawkeye. MS, W-LL, CS, and WH are employees of Novartis and own stocks in Novartis. MM-P was an employee of Novartis at the time of the study and until the initial stages of the development of this manuscript and currently is an employee of Alcon. 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.)

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.)

Objectives: While multiple studies have investigated treatment persistence rates with intravenous abatacept, limited information is available about real-world treatment continuation with the subcutaneous form. The international ASCORE study described the characteristics and treatment persistence of real-world patients with rheumatoid arthritis (RA) receiving subcutaneous abatacept. This article presents the findings of the French cohort., Methods: This was an observational study in French RA patients who initiated subcutaneous abatacept between August 2014 and January 2017. The primary endpoint was treatment maintenance at 2 years, analysed according to the number of previous biologic therapies., Results: Of 546 evaluable patients, 281 (51.5%) were biologic-naive, 265 (48.5%) had experienced failure with 1 (n=134; 24.5%) or ≥2 (n=131; 24.0%) biologic therapies. At enrolment, patients who had experienced failure with ≥1 biologic therapy had more erosions and a longer duration of RA compared with biologic-naive patients, but had comparable mean disease activity scores. Overall, 43.0% of patients (95% confidence interval 38.6-47.2) were still taking subcutaneous abatacept at 2 years, which was comparable with that in other countries participating in ASCORE. The abatacept persistence rate was higher in biologic-naive patients (48.8%) than in those with 1 (40.9%) or ≥2 (32.8%) biologic therapy failures. The main reason for discontinuing abatacept was lack of efficacy (46.6%)., Conclusions: In current practice in France, the rate of subcutaneous abatacept persistence at 2 years was comparable with that of the intravenous form. Treatment persistence was higher when abatacept was used as first-line versus later-line biologic therapy.

Background: Immune checkpoint blockers (ICBs) can induce immune-related adverse events (irAEs) whose management is based on expert opinion and may require the prescription of steroids and/or immunosuppressants (ISs). Recent data suggest that these treatments can reduce the effectiveness of ICBs., Objective: To investigate the relationship between the use of steroids and/or ISs and overall survival (OS) and progression-free survival (PFS) among ICB-treated patients with an irAE., Methods: We prospectively collected data from the medical records of patients with solid tumors or lymphoma in the French REISAMIC cohort and who had been treated with ICBs between June 2014 and June 2020., Results: 184 ICB-treated patients experienced at least one Common Terminology Criteria for Adverse Events grade ≥ 2 irAE. 107 (58.2%) were treated with steroids alone, 20 (10.9%) with steroids plus IS, 57 (31.0%) not received steroids or IS. The median OS was significantly shorter for patients treated with steroids alone (25.2 months [95% confidence interval (CI): 22.3-32.4] than for patients treated without steroids or IS (63 months [95%CI: 40.4-NA]) and those receiving an IS with steroids (53.4 months [95%CI: 47.3-NA]) (p < 0.001). The median PFS was significantly shorter for patients treated with steroids alone (17.0 months [95%CI: 11.7-22.9]) than for patients treated without steroids or IS (33.9 months [95%CI: 18.0-NA]) and those receiving an IS with steroids (41.1 months [95%CI: 26.2-NA]) (p = 0.006). There were no significant intergroup differences in the hospital admission and infection rates., Conclusion: In a prospective cohort of ICB-treated patients, the use of IS was not associated with worse OS or PFS, contrasting with the use of steroids for the management of irAEs., 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 Elsevier Ltd. All rights reserved.)

The development of sicca in patients treated with immune checkpoint inhibitors (ICIs) is undoubtedly an underestimated complication, but one whose functional consequences and impact on quality of life are significant for patients. This update aims to review the frequency of this complication and different clinical pictures. The authors also propose a diagnostic and therapeutic approach to guide clinicians in daily practice., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints., Methods: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing., Results: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins  and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders  according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell-related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration., Conclusion: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

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.)

Objectives: The objective of this study is to better characterize the features and outcomes of a large population of patients with mixed connective tissue disease (MCTD)., Methods: We performed an observational retrospective multicenter cohort study in France. Patients who fulfilled at least one diagnostic criterion set for MCTD and none of the criteria for other differentiated CTD (dCTD) were included., Results: Three hundred and thirty patients (88% females, median [interquartile range] age of 35 years [26-45]) were included. The diagnostic criteria of Sharp or Kasukawa were met by 97.3% and 93.3% of patients, respectively. None met other classification criteria without fulfilling Sharp or Kasukawa criteria. After a median follow-up of 8 (3-14) years, 149 (45.2%) patients achieved remission, 92 (27.9%) had interstitial lung disease, 25 (7.6%) had pulmonary hypertension, and 18 (5.6%) died. Eighty-five (25.8%) patients progressed to a dCTD, mainly systemic sclerosis (15.8%) or systemic lupus erythematosus (10.6%). Median duration between diagnosis and progression to a dCTD was 5 (2-11) years. The presence at MCTD diagnosis of an abnormal pattern on nailfold capillaroscopy (odds ratio [OR] = 2.44, 95% confidence interval [95%CI] [1.11-5.58]) and parotid swelling (OR = 3.86, 95%CI [1.31-11.4]) were statistically associated with progression to a dCTD. Patients who did not progress to a dCTD were more likely to achieve remission at the last follow-up (51.8% vs. 25.9%)., Conclusions: This study shows that MCTD is a distinct entity that can be classified using either Kasukawa or Sharp criteria, and that only 25.8% of patients progress to a dCTD during follow-up., (© 2023 The Association for the Publication of the Journal of Internal Medicine.)

Objectives: Sjögren's disease (SjD) is a heterogenous disease with a wide range of manifestations, ranging from symptoms of dryness, fatigue, and pain, to systemic involvement. Considerable advances have been made to evaluate systemic activity or patient-reported outcomes, but most of the instruments were not able to assess all domains of this multifaceted disease. The aim of this scoping review was to generate domains that have been assessed in randomized controlled trials, as the first phase of the Outcome Measures in Rheumatology (OMERACT) process of core domain set development., Methods: We systematically searched Medline (Pubmed) and EMBASE between 2002 and March 2023 to identify all randomized controlled trials assessing relevant domains, using both a manual approach and an artificial intelligence software (BIBOT) that applies natural language processing to automatically identify relevant abstracts. Domains were mapped to core areas, as suggested by the OMERACT 2.1 Filter., Results: Among the 5,420 references, we included 60 randomized controlled trials, focusing either on overall disease manifestations (53%) or on a single organ/symptom: dry eyes (17%), xerostomia (15%), fatigue (12%), or pulmonary function (3%). The most frequently assessed domains were perceived dryness (52% for overall dryness), fatigue (57%), pain (52%), systemic disease activity (45%), lacrimal gland function (47%) and salivary function (55%), B-cell activation (60%), and health-related quality of life (40%)., Conclusion: Our scoping review highlighted the heterogeneity of SjD, in the study designs and domains. This will inform the OMERACT SjD working group to select the most appropriate core domains to be used in SjD clinical trials and to guide the future agenda for outcome measure research in SjD., Competing Interests: Declaration of competing interest Yann Nguyen, Maxime Beydon, Nathan Foulquier, Rachael Gordon, Coralie Bouillot, and Katherine M. Hammit declared no competing interest. Simon Bowman reports receiving funds for consulting from Bristol-Myers Squibb, Iqvia, Janssen, Kiniksa, Novartis, Otsuka-Visterra. His-salary is part funded by the NIHR Birmingham Biomedical Research centre, Birmingham, UK. Xavier Mariette received consulting fees from Astra-Zeneca, Bristol Myer Squib, Galapagos, GSK, Novartis and Pfizer; travel fees from Novartis. Sara McCoy received consulting fees from BMS, Novartis, Otuska/Visterra, Horizon, Target RWE, Horizon, and Kiniksa. Her time is supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant 1KL2TR002374 and NIH/NIDCR R03DE031340. Divi Cornec declares no personal financial competing interests and received research funding from Novartis and GSK. Raphaele Seror reports receiving funds for consulting to Bristol-Myers Squibb, Novartis, GSK, Janssen, Amgen, and Boehringher; honoria from Bristol-Myers Squibb, Boehringher, GSK, and travel fees from Amgen and GSK., (Copyright © 2024. Published by Elsevier Inc.)

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity., Competing Interests: Declaration of competing interest Valerie Devauchelle reports receinving funds for consulting to Novartis, Abbvie, Fresenius Kabi. Divi Cornec declares no personal financial competing interests and received research funding from Novartis and GSK. Benjamin A. Fisher has undertaken consultancy for Novartis, BMS, Servier, Galapagos, Roche, UCB, Sanofi and Janssen, and received grant/research support from Janssen, Celgene, Galapagos, Servier. Alberta Hoi reports receiving research funding from AstraZeneca, Bristol-Myers Squibb, Novartis, Janssen. Chiara Baldini reports receiving funds for consulting to GSK, Novartis and Horizon, honoraria for educational events from GSK and Sanofi, support for attending meetings from Abbvie and Bristol-Myers Squibb. WF Ng has consulted for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Resolves Therapeutics, Janssen and UCB. Simon Bowman receiving funds for consulting from Bristol-Myers Squibb, Iqvia, Janssen, Kiniksa, Novartis, Otsuka-Visterra. His-salary is part funded by the Birmingham Biomedical Research Centre, Birmingham, UK. Karina Torralba reports receiving funds for consulting to Horizon, AstraZeneca, Janssen; for contracted research work with Bioclinica; for clinical trial funding from Novartis, AstraZeneca, GlaxoSmithKline, Amgen. Athena Papas declares grant funding from Novartis and Horizon; advisory board for Novartis. Ionut Pintilie reports receiving funds for consulting to Abbvie, Novartis, Pfizer, Sandoz, Ewopharma, KRKA, Stada, Boehringer Ingelheim, MagnaPharm, MSD. Xavier Mariette declares consulting fee from Astra Zeneca, BMS, Galapagos, GSK, Novartis, and Pfizer. Maria Antonietta D'Agostino, MD, PhD Speakers, or consultant fees from Amgen, Abbvie, BMS, Novartis, Galapagos, UCB, Pfizer, Lily, Janssen. Alan Baer reports receiving funds for consulting to Bristol-Myers Squibb and iCell Gene Therapeutics. Blake M. Warner declares research funding and material transfer agreements with Pfizer, Inc., and Mitobridge, Inc. Soumya D. Chakravarty is an employee of Janssen Scientific Affairs, LLC, and owns stock or stock options in Johnson & Johnson, of which Janssen Scientific Affairs, LLC is a wholly owned subsidiary. Nevsun Inanc reports claims to have received speakers fee from Novartis, Abbvie, Pfizer, UCB, Eli-Lilly and consultancy fee from Abbvie, UCB, Eli-Lilly. Vibeke Strand reports being a founding member of the executive committee of Outcome Measures in Rheumatology (OMERACT) [1992 – present], an international consensus organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and has received arms-length funding from as many as 36 sponsors. Md Yuzaiful Md Yusof has received speaker fees from Roche and Novartis and consultancy fees from Aurinia Pharmaceuticals and UCB. Suzanne Arends declares consultancy fees from Argenx and Novartis. Anas Alexis Benyoussef is a consultant for Horus Pharma and Quantel Medical. Sharmila Masli is a consultant for Stellular Bio Inc. and Proteris Biotech. Maureen Rischmueller has undertaken consultancy/speaker engagements for AbbVie, Boehringer Ingelheim, Janssen Global Services, Novartis, Pfizer and Sandoz, and received grant/research support from AbbVie, Amgen, AstraZeneca, BMS, GSK, Janssen, Lilly, Novartis, Pfizer, Servier and UCB. Sara McCoy reports receiving funds for consulting to Bristol-Myers Squibb, Horizon, Novartis, Kiniksa, Targe RWE, Otsuka, Visterra, and iCell. Her time is supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant 1KL2TR002374 and NIH/NIDCR R03DE031340. Raphaele Seror reports receiving funds for consulting to Bristol-Myers Squibb, Novartis, GSK, Janssen, Amgen. Hendrika Bootsma declares consultancy fees from Argenx, Novartis, BMS, AztraZeneca, Galapagos.Independent grants from AstraZeneca, Novartis, BMS., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Multiple myeloma (MM) frequently causes vertebral fractures (VF). Some are lytic lesions and others have the aspect of benign osteoporotic fractures not requiring anti-myeloma treatment. We explored outcome of these patients with smoldering myeloma (SM) and osteoporotic VF. In this retrospective bi-centric study, patients were identified using a systematic keyword search on electronic medical records. Patients with SM and isolated VF of osteoporotic aspect without indications for myeloma-specific therapy were included. Overall, 13 (7 %) of the 184 identified patients had SM and VF confirmed to be osteoporotic (median number of VF was 3). During follow-up, 12 (92 %) patients evolved to symptomatic MM, 7 (54 %) of them within 18 months (early progressors). Myeloma defining events were new lytic bone lesions in 7 patients (53.8 %). The serum calcium level was significantly higher in the early progressor group (median 2.35 IQR [2.31-2.38] and 2.28 IQR [2.21-2.29] respectively, p  = 0.003). Early progressors had a higher number of VF at diagnosis (3.0 [2.0-5.5] vs 1.0 [1.0-2.5], p  = 0.18) and more frequently evolved to symptomatic MM because of lytic bone lesions (5 [71 %] vs 2 [33 %], p  = 0.13) compared to late progressors. VF of osteoporotic appearance in the context of SM is a rare situation but at high risk of rapid progression to symptomatic MM, suggesting that they may represent bone fragility linked to MM infiltration rather than solely osteoporotic fractures. Further studies are needed to assess if earlier treatment might be beneficial in this population., Competing Interests: KC has no conflict of interest. SH has no conflict of interest. SB has received grant from SERVIER, unrelated to his work. JH has no conflict of interest. KB has Honoria and research grant from Amgen, Theramex, and Kyowa Kirin, unrelated to his work. RB has received Honoria from Astra Zaneca, unrelated to his work. RC has received Honoria and research grant from ALEXION and research grant from REGENRON, unrelated to his work. XM has received Honoria from BMS, Galapagos, GSK, Novartis, Pfizer, unrelated to his work. RS received consulting fees or honoraria from GSK, Bristol Myer Squib, Boehringer, Janssen, Amgen, Pfizer and Roche, travel fees from Amgen and GSK, unrelated to his work., (© 2024 The Authors.)

Background: Although B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself., Methods: The B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early BCR-depletion (within one-month post-treatment) and early BCR-repopulation (within 6 months post-treatment) on clinical response was assessed., Results: We observed changes in the peripheral blood BCR repertoire after rituximab treatment, i.e., increased clonal expansion, decreased clonal diversification and increased mutation load which persisted up to 12 months after treatment, but started to revert at month 6. Early BCR depletion was not associated with early clinical response but late depleters did show early response. Patients with early repopulation with unmutated BCRs showed a significant decrease in disease activity in the interval 6 to 12 months. Development of anti-drug antibodies non-significantly correlated with more BCR repopulation., Conclusion: Our findings indicate that rather than BCR-depletion it is repopulation with unmutated BCRs, possibly from naïve B cells, which induces remission. This suggests that (pre-existing) differences in B-cell turnover between patients explain the interindividual differences in early clinical effect., (© 2024. The Author(s).)

Objectives: To describe the characteristics of patients with Sjögren's disease (SjD) and inclusion-body myositis (IBM), and how they compare to SjD patients with other inflammatory myopathies (IM)., Methods: Patients were retrospectively recruited from 13 French centers and included if they met the ACR/EULAR criteria for SjD and for IM. They were categorized as SjD-IBM if sub-criteria for IBM were met, or as SjD-other IM if not., Results: SjD-IBM patients (n = 22) were mostly females (86%), with a median [Q1; Q3] age of 54 [38.5; 64] years at SjD diagnosis, and 62 [46.5; 70] years at first IBM symptoms. Although most patients displayed glandular and immunological abnormalities, additional extra-glandular manifestations were uncommon, resulting in moderate disease activity at SjD diagnosis (ESSDAI 5.5 [1; 7.8]). Classic IBM features were frequent, such as progressive symptom onset (59%), asymmetrical (27%) and distal (32%) involvements, dysphagia (41%), low CPK (386.5 [221.8; 670.5] UI/l) and CRP (3.0 [3; 8.5] mg/l) levels. Immunosuppressants were reported as efficient in 55% of cases.Compared with SjD-IBM patients, SjD patients with other IM (n = 50) were significantly younger, displayed more frequent additional extra-glandular disease, higher ESSDAI score (11 [3; 30]), shorter delay between SjD diagnosis and myositis onset (0 [-0.5; 26]), more frequent CPK values over 1000 UI/l (36%), and less frequent classic IBM features., Conclusion: IBM can occur in SjD patients, with muscle features reminiscent of classic sporadic IBM characteristics, but mostly affecting women. In SjD patients with muscle involvement, extra-glandular manifestations, high ESSDAI score, elevated CPK values, and shorter delay after SjD diagnosis plead against IBM., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Sjögren syndrome is a phenotypically varied autoimmune disorder that can occur alone in primary Sjögren syndrome or in association with other connective tissue diseases (CTDs), including rheumatoid arthritis, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). The estimation of the prevalence and incidence of Sjögren syndrome varies depending on diagnostic criteria and study design, making it difficult to estimate geographical and temporal trends. Nonetheless, disease phenotype is influenced by geographical origin, which is a risk factor for systemic activity. Whether mortality in primary Sjögren syndrome is increased compared with that of the general population is not yet known, but extra-glandular manifestations, in particular lymphomas, are clear risk factors for mortality. In CTDs associated with Sjögren syndrome, lymphoma risk seems higher than that of patients with CTD alone, and there is potentially lower disease activity in SLE with Sjögren syndrome and in SSc with Sjögren syndrome than in SLE or SSc alone., (© 2023. Springer Nature Limited.)

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.)

Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19., Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care)., Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61-1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64-1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09-0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality., Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19., Funding: Hellenic Foundation for Research and Innovation., Competing Interests: ACK was investigator for the National Institutes of Health Adaptive COVID-19 Treatment Trial. WBE was the site Principal Investigator for a therapeutics study funded by Gilead Sciences (funds to institution) during the past three years. WBE also reports grant funding support from the VA Health Services Research and Development Service (VA HSRD IIR 20-101, 20-076) and from the VA National Artificial Intelligence Institute. OH reports research funds from Roche. The remaining authors (IIS, DB, VCV, ABC, EP, KG, NAX, AK, RP, XM) report no conflicts of interest., (© 2024 The Authors.)

Purpose: To assess risk factors for arterial and venous thromboses (AVT) in patients hospitalized in general wards for COVID-19 pneumonia and requiring oxygen therapy., Methods: Our study was based on three randomized studies conducted as part of the CORIMUNO-19 platform in France between 27 March and 26 April 2020. Adult inpatients with COVID-19 pneumonia requiring at least 3 l/min of oxygen but not ventilation were randomized to receive standard care alone or standard care plus biologics. Patients were followed up for 3 months, and adverse events were documented. Risk factor for AVT and bleeding was identified by analyzing clinical, laboratory, and treatment data at baseline among the 315 patients with complete datasets. A Fine and Gray model was used to take account of competing events., Results: During the 3-month follow-up period, 39 AVT occurred in 38 (10%) of the 388 patients: 26 deep vein thromboses and/or pulmonary embolisms in 25 (6%) patients, and 14 arterial thrombotic events in 13 (3%) patients. A history of diabetes at inclusion [sHR (95% CI) = 2.65 (1.19-5.91), P = .017] and the C-reactive protein (CRP) level (sHR = 1 [1-1.01], P = .049) were significantly associated with an elevated risk of thrombosis. Obesity was not associated with a higher risk of thrombosis (sHR = 1.01 [0.4-2.57], P = .98). The CRP level and diabetes were not risk factors for hemorrhage., Conclusion: Among patients hospitalized in general wards for COVID-19 pneumonia during the first wave of the epidemic, diabetes (but not obesity) and a high CRP level were risk factors for AVT. The use of higher doses of anticoagulant in these high-risk patients could be considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of Postgraduate Medical Journal. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Long COVID is the name given to a syndrome comprising a wide variety of symptoms persisting more than 3 months after acute benign COVID-19, with a prevalence ranging from 10 to 80%. Symptoms are very close to fibromyalgia. Several studies showed that long COVID prevalence was much higher after the first wave of the pandemics and was associated to the fact of thinking having had COVID rather than having had really COVID. Thus, it was the stress of the first wave with the lockdown and not the consequences of the infection that probably induced this high frequency of long COVID. Numbers of studies tried to find objective biological abnormalities for explaining long COVID but none of them could be replicated and convincing. The concept of long COVID seems to be a repetition of history of medicine, in which the doctors and the society gave different names to fibromyalgia with the objective of trying to highlight the fact that fibromyalgia could be a somatic disease with a well understood pathophysiology and to avoid to focus on the psychosomatic aspects of the disease. In conclusion, "to name is to soothe" as said by Roland Barthes. However, "Naming things wrongly adds to the world's unhappiness" was saying Albert Camus. Thus, the term of long COVID, which suggests viral persistence of impaired immune response to the virus, is unappropriated and should be replaced by fibromyalgia-like post-COVID syndrome. Research on the psychosomatic and somatic mechanisms involved in these fibromyalgia-like post-viral syndromes must be encouraged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by a triad of key symptoms affecting almost all patients (salivary and lacrimal dryness, pain and fatigue) and extra-glandular systemic involvement affecting one to two-thirds of patients. Over the past decade, knowledge of the epidemiology, classification criteria, assessment of systemic activity and symptoms presented by patients has grown. In addition, advances in understanding the pathophysiology of SjD have enabled a more targeted therapeutic approach. Current management of SjD is based on EULAR treatment guidelines. But since these recommendations, new drugs targeting specific pathophysiological pathways of the disease, and essentially B lymphocyte activation, have shown efficacy in phase 2 trials. In this review, we will summarize the available evidence on systemic therapies, including: 1. advances in outcome assessment, 2. current evidence on targeted disease-modifying therapies and biologic drugs targeting primarily B lymphocytes, 3. an overview of promising drugs being tested in ongoing trials., (© Société de Biologie, 2024.)

Objective: We previously reported an increased expression of microRNA-155 (miR-155) in the blood monocytes of patients with rheumatoid arthritis (RA) that could be responsible for impaired monocyte polarization to anti-inflammatory M2-like macrophages. In this study, we employed two preclinical models of RA, collagen-induced arthritis and K/BxN serum transfer arthritis, to examine the therapeutic potential of antagomiR-155-5p entrapped within PEGylated (polyethylene glycol [PEG]) liposomes in resolution of arthritis and repolarization of monocytes towards the anti-inflammatory M2 phenotype., Methods: AntagomiR-155-5p or antagomiR-control were encapsulated in PEG liposomes of 100 nm in size and -10 mV in zeta potential with high antagomiR loading efficiency (above 80%). Mice were injected intravenously with 1.5 nmol/100 μL PEG liposomes containing antagomiR-155-5p or control after the induction of arthritis., Results: We demonstrated the biodistribution of fluorescently tagged PEG liposomes to inflamed joints one hour after the injection of fluorescently tagged PEG liposomes, as well as the liver's subsequent accumulation after 48 hours, indicative of hepatic clearance, in mice with arthritis. The injection of PEG liposomes containing antagomiR-155-5p decreased arthritis score and paw swelling compared with PEG liposomes containing antagomiR-control or the systemic delivery of free antagomiR-155-5p. Moreover, treatment with PEG liposomes containing antagomiR-155-5p led to the restoration of bone marrow monocyte defects in anti-inflammatory macrophage differentiation without any significant functional change in other immune cells, including splenic B and T cells., Conclusion: The injection of antagomiR-155-5p encapsulated in PEG liposomes allows the delivery of small RNA to monocytes and macrophages and reduces joint inflammation in murine models of RA, providing a promising strategy in human disease., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The management of Sjögren's disease is challenging because of several factors. Indeed, the clinical presentations are heterogeneous, and one must be able to identify prognostic markers to adapt the follow-up. In addition, there is no validated treatment. Nevertheless, international experts have been working for several years to establish recommendations to guide management. Since research in this field is extremely active, we anticipate the development of effective treatments for our patients in the near future., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: The clinical outcome of COVID-19 pneumonia is highly variable. Few biological predictive factors have been identified. Genetic and immunological studies suggest that type 1 interferons (IFN) are essential to control SARS-CoV-2 infection., Objective: To study the link between change in blood IFN-α2 level and plasma SARS-Cov2 viral load over time and subsequent death in patients with severe and critical COVID-19., Methods: One hundred and forty patients from the CORIMUNO-19 cohort hospitalized with severe or critical COVID-19 pneumonia, all requiring oxygen or ventilation, were prospectively studied. Blood IFN-α2 was evaluated using the Single Molecule Array technology. Anti-IFN-α2 auto-Abs were determined with a reporter luciferase activity. Plasma SARS-Cov2 viral load was measured using droplet digital PCR targeting the Nucleocapsid gene of the SARS-CoV-2 positive-strand RNA genome., Results: Although the percentage of plasmacytoid dendritic cells was low, the blood IFN-α2 level was higher in patients than in healthy controls and was correlated to SARS-CoV-2 plasma viral load at entry. Neutralizing anti-IFN-α2 auto-antibodies were detected in 5% of patients, associated with a lower baseline level of blood IFN-α2. A longitudinal analysis found that a more rapid decline of blood IFN-α2 was observed in fatal versus surviving patients: mortality HR=3.15 (95% CI 1.14-8.66) in rapid versus slow decliners. Likewise, a high level of plasma SARS-CoV-2 RNA was associated with death risk in patients with severe COVID-19., Conclusion: These findings could suggest an interest in evaluating type 1 IFN treatment in patients with severe COVID-19 and type 1 IFN decline, eventually combined with anti-inflammatory drugs., Clinical Trial Registration: https://clinicaltrials.gov, identifiers NCT04324073, NCT04331808, NCT04341584., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Joly, Desjardins, Porcher, Péré, Bruneau, Zhang, Bastard, Cobat, Resmini, Lenoir, Savale, Lécuroux, Verstuyft, Roque-Afonso, Veyer, Baron, Resche-Rigon, Ravaud, Casanova, Le Grand, Hermine, Tharaux and Mariette.)

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.)

Background: Older studies uncovered an increased risk of cancer in patients with rheumatoid arthritis between 10% and 30% compared to the general population, with a lack of data concerning infrequent cancers. In recent year, major therapeutic breakthroughs might have affected this risk of cancer by mitigating disease activity or on the contrary by impairing antitumoral immune response. The objectives of this study are to compare cancer risk in patients with treated rheumatoid arthritis to the general population, in all treated patients and according to treatment exposure., Methods: This is a nationwide population-based study within the French national claims database "Système National des Données de Santé" (SNDS) between January 1st 2010 and December 31st 2020, to estimate the age and sex-standardized incidence ratios of cancer (all sites and site specific) of treated rheumatoid arthritis patients, with the French population as reference (by use of the French Network of Population-Based Cancer Registries [FRANCIM])., Findings: During the study period, 257,074 treated patients with rheumatoid arthritis contributed to a total of 2,098,238 person-years for the main analysis. The all-cancer risk was increased in rheumatoid arthritis patients, with a SIR (Standardized Incidence Ratio) of 1.20 (95% CI [1.17-1.23]). This risk was increased particularly for lung (SIR 1.41, 95% CI [1.36-1.46], bladder (SIR 2.38 95% CI [2.25-2.51]), cervix (SIR 1.80, 95% CI [1.62-2.01]), prostate (SIR 1.08, 95% CI [1.04, 1.13]) cancers, melanoma (SIR 1.37, 95% CI [1.29-1.46]), diffuse large B cell lymphoma (SIR 1.79, 95% CI [1.63-1.96], multiple myeloma (SIR 1.42, 95% CI [1.27-1.60]) and Hodgkin's lymphoma (SIR 2.73, 95% CI [2.31-3.23]). Some cancers were less frequent than in the general population such as pancreatic (SIR 0.90, 95% CI [0.83-0.97]) as well as breast and endometrial cancers (SIR 0.91, 95% CI [0.88-0.94] and SIR 0.77, 95% CI [0.71-0.84] respectively). Although we observed a modest but significant relative increase of all-cancer risk over-time in rheumatoid arthritis patients, there was a trend towards a decrease in risk of non-Hodgkin's lymphoma. Patients treated with rituximab were the patients displaying the highest risk of cancer., Interpretation: Compared to the general population, treated rheumatoid arthritis patients were at greater risk of all-cancer and some site specific cancers, except for breast, pancreatic and endometrial cancers which were less frequent than in the general population., Funding: This work was supported by unrestricted grants from the InCA (national institute against cancer) and AP-HP (Assistance Publique des Hôpitaux de Paris)., Competing Interests: XM received fees from Astra-Zeneca, BMS, Galapagos, GSK, Novartis, Pfizer; RS received consulting fees from GSK, Bristol Myer Squib, Boerhinger, Amgen, Pfizer and Janssen; travel fees from Amgen and GSK; BF received research grants from AbbVie, Pfizer, Lilly, MSD, and consulting fees from AbbVie, Amgen, Biogen, BMS, Celltrion, Chugai, Fresenius Kabi, Galapagos, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, OWKIN, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Viatris and support for meetings/travel from Lilly; FT redistributed to her hospital consulting fees from MSD and Novartis., (© 2023 The Authors. Published by Elsevier Ltd.)

Objective: To evaluate the efficacy of covid-19 convalescent plasma to treat patients admitted to hospital for moderate covid-19 disease with or without underlying immunodeficiency (CORIPLASM trial)., Design: Open label, randomised clinical trial., Setting: CORIMUNO-19 cohort (publicly supported platform of open label, randomised controlled trials of immune modulatory drugs in patients admitted to hospital with moderate or severe covid-19 disease) based on 19 university and general hospitals across France, from 16 April 2020 to 21 April 2021., Participants: 120 adults (n=60 in the covid-19 convalescent plasma group, n=60 in the usual care group) admitted to hospital with a positive SARS-CoV2 test result, duration of symptoms <9 days, and World Health Organization score of 4 or 5. 49 patients (n=22, n=27) had underlying immunosuppression., Interventions: Open label randomisation to usual care or four units (200-220 mL/unit, 2 units/day over two consecutive days) of covid-19 convalescent plasma with a seroneutralisation titre >40., Main Outcome Measures: Primary outcomes were proportion of patients with a WHO Clinical Progression Scale score of ≥6 on the 10 point scale on day 4 (higher values indicate a worse outcome), and survival without assisted ventilation or additional immunomodulatory treatment by day 14. Secondary outcomes were changes in WHO Clinical Progression Scale scores, overall survival, time to discharge, and time to end of dependence on oxygen supply. Predefined subgroups analyses included immunosuppression status, duration of symptoms before randomisation, and use of steroids., Results: 120 patients were recruited and assigned to covid-19 convalescent plasma (n=60) or usual care (n=60), including 22 (covid-19 convalescent plasma) and 27 (usual care) patients who were immunocompromised. 13 (22%) patients who received convalescent plasma had a WHO Clinical Progression Scale score of ≥6 at day 4 versus eight (13%) patients who received usual care (adjusted odds ratio 1.88, 95% credible interval 0.71 to 5.24). By day 14, 19 (31.6%) patients in the convalescent plasma group and 20 (33.3%) patients in the usual care group needed ventilation, additional immunomodulatory treatment, or had died. For cumulative incidence of death, three (5%) patients in the convalescent plasma group and eight (13%) in the usual care group died by day 14 (adjusted hazard ratio 0.40, 95% confidence interval 0.10 to 1.53), and seven (12%) patients in the convalescent plasma group and 12 (20%) in the usual care group by day 28 (adjusted hazard ratio 0.51, 0.20 to 1.32). In a subgroup analysis performed in patients who were immunocompromised, transfusion of covid-19 convalescent plasma was associated with mortality (hazard ratio 0.39, 95% confidence interval 0.14 to 1.10)., Conclusions: In this study, covid-19 convalescent plasma did not improve early outcomes in patients with moderate covid-19 disease. The efficacy of convalescent plasma in patients who are immunocompromised should be investigated further., Trial Registration: ClinicalTrials.gov NCT04345991., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from Programme Hospitalier de recherche Clinique (DGOS-French Ministry of Health), Fondation pour la Recherche Médicale, Sorbonne Université AAP 2020, and Emergency Support Instrument (ESI), Direction Générale de la Santé, European Commission for the submitted work; PT, PM, and AF are employees of Etablissement Français du Sang (EFS), the French public transfusion service, which collects, manufactures, tests and issues all blood components in France; KL is contributing to the development of monoclonal and polyclonal anti-SARS-CoV Antibodies (Spikimm, Xenothera, Fabentech); no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© 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.)

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment., Competing Interests: DT and AA were employed by NH TherAguix SAS. Authors DL, DT, AA, FS, OD and J-LP are listed as co-inventors on a patent application related to SARS-CoV-2 therapy. AP and J-LP are founding members of Findimmune SAS, an Immuno-Oncology Biotech company. J-LP disclosed research funding not related to this work from NH TherAguix and Wonna Therapeutics. NC disclosed research funding not related to this work from GlaxoSmithKline, Roche, Cytune pharma and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Lécuyer, Nardacci, Tannous, Gutierrez-Mateyron, Deva Nathan, Subra, Di Primio, Quaranta, Petit, Richetta, Mostefa-Kara, Del Nonno, Falasca, Marlin, Maisonnasse, Delahousse, Pascaud, Deprez, Naigeon, Chaput, Paci, Saada, Ghez, Mariette, Costa, Pistello, Allouch, Delelis, Piacentini, Le Grand and Perfettini.)

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.

Objectives: To describe primary Sjögren's disease (SjD) patients presenting no or low level of dryness and to compare them with SjD patients with oral or ocular dryness features., Methods: All patients diagnosed with SjD according to AECG or ACR/EULAR criteria in our tertiary reference centre were included. Patients with high or low subjective symptoms or objective signs of dryness were compared., Results: Overall, 509 patients were included for the comparison of patients with high (n=456) or low (n=53) level of subjective dryness and 472 for the comparison of patients with (n=359) or without (n=113) high objective dryness. Compared with patients with subjective dryness, patients without high subjective dryness were significantly younger (median 49 (39-62) years vs 58 (47-67) years, p<0.01), diagnosed earlier (median time from first symptoms to diagnosis 2 (0.5-4.5) years vs 4 (1-9.25), p=0.0056), more frequently anti-SSA positive ((83% vs 64%, p=0.008) and had less focal sialadenitis in minor salivary gland biopsy (69% vs 83%, p=0.02).The patients without high level of objective dryness (n=113) were also younger (51 (41-60) vs 58 (47-67) years, p<0.001) and were more frequently anti-SSA positive (79% vs 63%, p=0.002).In both groups, no difference was observed regarding disease activity., Conclusions: Among the patients with SjD, those without high subjective or objective dryness features had a younger profile, a faster diagnosis which may result from a more acute onset, were more frequently anti-SSA positive than patients with high dryness features., 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.)

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.)