OBJECTIVE:Sjögren disease (SjD) is a heterogeneous autoimmune disease. We aimed to investigate blood transcriptomic signatures and disease progression among three recently defined clusters of patients with SjD: (1) B cell active disease with low symptom burden (BALS), (2) high systemic activity (HSA), and (3) low systemic activity with high symptom burden (LSAHS). METHODS:We analyzed transcriptomic data from the ASSESS cohort (GSE140161; n = 351). Patients were classified into the three clusters previously described. Within BALS, an evolutive subgroup was defined based on need for new immunosuppressants and/or occurrence of lymphoma (BALS subgroup of patients with progressive/evolving disease [BALS_Evol]). Differential expression analysis and Gene Set Enrichment Analysis were performed to evaluate subgroup-specific signatures and biologic pathways. RESULTS:Both BALS and HSA displayed robust types I/II interferon (IFN)-stimulated gene up-regulation compared to LSAHS. BALS exhibited stronger IFN activity and inflammatory signaling than HSA, particularly in the evolutive subgroup (BALS_Evol). This subgroup showed enrichment of IFNα/γ, tumor necrosis factor α, interleukin-6, complement activation, and mechanistic target of rapamycin (mTOR) complex 1 pathways, indicating a hyperinflammatory and dysregulated immune state linked to disease progression. In contrast, compared with BALS, the HSA cluster displayed attenuated IFN and KRAS pathway activity, coupled with activation of MYC, mTOR, and oxidative phosphorylation, suggesting a molecular shift toward proliferation and metabolism that may promote systemic disease evolution. CONCLUSION:IFN signaling is a hallmark of both HSA and BALS clusters. In BALS, it may drive early disease progression, which can be replaced later by proliferative pathways leading to an HSA. These findings pave the way for new hypotheses regarding the mechanisms driving disease progression in SjD.

OBJECTIVE:FADD (Fas-Associated Death Domain) protein in patients' serum and synovial fluid could be a biomarker of inflammation in rheumatic diseases. We tested whether the baseline serum FADD level would be a predictive factor for meeting the American College of Rheumatology (ACR)/EULAR 2010 criteria for rheumatoid arthritis (RA) in order to facilitate the early diagnosis of RA. METHODS:We measured FADD by enzyme-linked immunosorbent assay in the sera from 659 patients with early arthritis from the Etude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort (at least two swollen joints for more than six weeks and less than six months, no previous exposure to glucocorticoids or disease-modifying antirheumatic drugs). Patients were eligible for inclusion in the cohort if they had a definitive or probable clinical diagnosis of RA or a diagnosis of undifferentiated arthritis (UA) with a potential for progressing to RA, according to the 2010 ACR/EULAR criteria for RA. RESULTS:At inclusion, serum FADD protein was detected in 501 of 659 (76%) patients (range 0-1,503 ng/mL) and levels were independent of patient age and sex. Statistically significant higher levels of FADD were detected in the serum from patients with diagnosed RA at inclusion or who were diagnosed with RA thereafter, than from patients with UA. Receiver operating characteristic curve analysis indicated that a FADD >8 ng/mL had the best sensitivity (50.95%) and specificity (85.71%) for the diagnosis of RA. Moreover, FADD levels were positively associated with anti-citrullinated protein antibody (ACPA), rheumatoid factors, proinflammatory interleukin-1β (IL-1β), IL-6 and IL-2, and APRIL, a marker of B lymphocyte activation. CONCLUSION:Baseline serum FADD level measurement appeared as a helpful biomarker for the early diagnosis of RA, particularly in patients who were ACPA negative.

Background: Systemic lupus erythematosus (SLE) affects mainly women of child-bearing age, and is associated with worse pregnancy and disease outcomes during pregnancy. Physiologically, pregnancy is associated with an immunotolerance state, and in other rheumatic diseases such as rheumatoid arthritis (RA) pregnancy is associated with a lower disease activity. The molecular mechanisms underlying immune differences between healthy, RA and SLE pregnancies are largely unknown. Objectives: To prospectively study the circulating monocyte mRNA and miRNA from healthy, RA and SLE women before, during and immediately after pregnancy. Methods: Patients with RA or SLE and age-matched controls were included in the study. EDTA-anticoagulated blood was drawn within 3 months before pregnancy, at the time of positive pregnancy test, month 3 and 6 of pregnancy, during delivery and 1 month and 3 of post-partum. Monocytes were sorted using CD14 magnetic sorting (Miltenyi). Total RNAs were extracted with a commercial kit (Qiagen) and the transcriptome obtained using paired-end sequencing with a new generation sequencer SOLID 5500 (Life technologies). Sequencing data was processed using the nf-core/rnaseq pipeline, version 3.10.1. Within this pipeline, STAR was used for sequence alignment, while Salmon was used for RNA quantification, resulting in an expression matrix. For miRNAs, mirdeep2 was used to generate the expression matrix. In subsequent steps, DESeq2 was used to study differential expression. For each condition (SLE, RA or control), visits in chronological order were considered as a continuous variable on which transcriptional patterns were explored. In addition, the patient ID was used as a covariate to control for individual variability in gene expression profiles. For enrichment analyses and regulator predictions, Ingenuity Pathway Analysis (IPA) software was used to decipher the expression variations observed. To link miRNAs and downstream mRNA targets, a correlation analysis was performed between mRNA and miRNA signal of the same patients. A miRNA was predicted to negatively regulate a mRNA if it was negatively correlated with that transcript across samples, and predicted as such by miRTarBase. Results: Six patients with SLE, four with RA and five healthy donors were included. During the progression of RA pregnancies, the pathway enrichments highly correlated with the ones from healthy pregnancies (r = 0.82, p = 3.28 x10-6, Figure 1A). Conversely, the enrichments from SLE pregnancies did not correlate with healthy ones (r = 0.02, p = 0.94, Figure 1B), suggesting that SLE pregnancies have a distinct transcriptomic signature. Using pathway analysis we identified a downregulation of the interferon gamma, interleukin 1 and CD40L/CD40 pathways in both healthy and RA pregnancies during the progression of pregnancy. During SLE pregnancies, we identified an upregulation of pathways of interferon gamma, Interleukins 1, 6 and 8 and Tumor Necrosis factor. The upregulation of these inflammatory pathways remained significant after excluding visits with a clinical flare.In contrast to healthy donors and RA patients, SLE patients were characterized by a significant downregulation of miRNAs 106a-5p and 148b-5p (adjusted p-value < 0.05) predicted to control cytokine-mediated signaling pathway and neutrophils activation/degranulation (adjusted p-values < 0.001 and < 0.01, respectively). Conclusion: We identify that SLE pregnancies have a distinct monocyte transcriptomic signature which differs from healthy and RA pregnancies, that accompany increased risk of disease flares and adverse pregnancy events. Furthermore, our data suggest that miRNA may participate to this pro-inflammatory signature, which opens the way for a better understanding of SLE pregnancy and the development of biomarkers of adverse pregnancy events. REFERENCES: NIL. Acknowledgements: This project was founded by the l‘ANR PRCI “SPIRALE“ and by l‘ITI Transplantex. The DRCI of the HUS for promoting the study. MS is supported by ATIP-AVENIR, INSERM, Fondation Bettencourt-Schueller, FOREUM Early Career Grant and Fondation Arthritis. Disclosure of Interests: Eloi Schmauch: None declared, Philippe Georgel: None declared, Raphael Carapito: None declared, Angélique Pichot: None declared, Ghada Alsaleh: None declared, Nicodème Paul: None declared, Anne Molitor: None declared, Catherine Mutter: None declared, Jacques-Eric Gottenberg: None declared, Renaud Felten: None declared, Séiamak Bahram: None declared, Jean SIBILIA: None declared, Marc SCHERLINGER Amgen, AstraZeneca, Biogen, BMS, Fresenius Kabi, Galapagos, GSK, Nordic Pharma, Novartis, Sandoz., Amgen, AstraZeneca, Biogen, BMS, Fresenius Kabi, Galapagos, GSK, Nordic Pharma, Novartis, Sandoz.Figure 1correlation of enriched pathways between healthy and RA (A) and healthy and SLE (B) pregnancies.

Recently, three distinct phenotypes of patients with Sjögren disease (SjD) have been described based on cluster analysis: B cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS). We aimed to assess whether these clusters were associated with distinct biomarkers and the prognostic value of interferon (IFN) signature. The Assessment of Systemic Signs and Evolution in Sjögren's Syndrome cohort is a 20-year prospective cohort of patients with SjD. The following biomarkers were compared: IFN-α2, IFN-γ, CXCL10, CXCL13, BAFF, interleukin (IL)-7, fms-like tyrosine kinase 3 ligand, CCL19, and tumor necrosis factor receptor 2 (TNF-RII). IFN signature was assessed using transcriptomic analysis. We then compared systemic and symptomatic evolution, and the risk of new immunosuppressant prescription and of lymphoma, according to the IFN signature across the three clusters. A total of 395 patients (94% female, median age 53 [interquartile range 43–63] years) were included. Higher levels of CXCL13, IL-7, and TNF-RII were found in the BALS and HSA clusters compared with the LSAHS cluster. A high IFN signature was mainly found in the BALS cluster (57%, vs 48% and 38% in the HSA and LSAHS clusters, respectively). This IFN signature was mainly driven by type I IFN, with higher levels of IFN-α2. In the BALS cluster, a high IFN signature was associated with a higher risk of new immunosuppressant treatment (hazard ratio 9.38; 95% confidence interval 1.22–72.16). All lymphoma occurred in patients with high IFN signature. The three SjD clusters displayed distinct expressions of IFN signature and markers of T and B cell activation, confirming distinct pathophysiologic mechanisms. High IFN signature could predict systemic evolution in the BALS cluster.

Background: Sjögren's disease (SjD) is a heterogenous autoimmune disease, with a wide range of symptoms, from dryness, fatigue, pain, to systemic manifestations, and an increased risk of lymphoma. Recently, three clusters of patients with SjD have been described based on unsupervised clustering analysis according to symptoms, clinical signs and biologic parameters: 1/ BA-LS (B-cell active with low symptoms); 2/ HSA (High systemic activity); 3/ LSA-HS (Low systemic activity with high symptoms). These findings suggest potential heterogeneity in pathophysiological mechanisms. Objectives: To investigate this hypothesis, we examined whether these three clusters were associated with distinct biomarkers. Methods: This study involved SjD patients meeting AECG criteria from the ASSESS cohort. The following biomarkers were measured in sera at the time of inclusion: for IFN pathways—IFN-alpha 2, IFN gamma, CXCL-10; for B cell activation—CXCL-13, BAFF, B2-microglobulin, FLT-3; for T cell activation—IL-7, CCL-19, TNF-RII. Additionally, the IFN signature was assessed using transcriptomic analysis. Kruskal-Wallis rank sum test was used to compare different clusters for continuous variables. Additionally, the risk of lymphoma and of new immunosuppressive drugs prescriptions were compared according to the IFN signature. Results: This analysis included 395 (94% female, median age 53 [43-63] years) patients from the ASSESS cohorts. The three clusters displayed differences in the IFN pathways (IFN signature), primarily driven by type I IFN (IFN-a2 level) elevated only in BA-LS and HSA clusters and not in the LSA-HS cluster (p=0.001). IFN gamma and CXCL-10 were not different between the 3 clusters. The same clusters that exhibit high level of type 1 IFN also had higher CXCL-13 levels (p=0.0032) reflecting B-cell activation, higher IL-7 (p=0.0042) and TNFRII (p<0.001) levels reflecting T-cell activation. Higher levels of FLT-3 were found in the HSA cluster. BAFF level was not different between the 3 clusters. Lastly, there were a trend indicating an increased risk of lymphoma in patients with positive IFN signature (HR 2.53; 95%CI 0.67–9.55), and an increased risk of immunosuppressant prescription during follow-up (HR 2.81; 95%CI 1.26-6.29). Conclusion: The two clusters BA-LS and HSA have a very distinct cytokine signature than the patients with LSA-HS. These two active clusters share a high type 1 IFN level, and elevated markers of both B-cell and T-cell activation. Patients from the BA-LS cluster being younger, it is likely that this cluster represent an earlier disease stage than HSA cluster. In order to go towards personalized medicine, work is in progress for deciphering patients in these two active clusters exhibiting one predominant pathways among type 1 IFN, B-cell and T-cell activation. REFERENCES: [1] Nguyen Y, Nocturne G, Henry J. Identification of distinct phenotypes of Sjögren disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts. Lancet Rheumatology 2024. Acknowledgements: The authors are indebted to all patients for their participation, and to all physicians who included patients in the Paris-Saclay and ASSESS cohorts. The Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) national multicenter prospective cohort was formed in 2006 with a French Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Disclosure of Interests: Yann Nguyen: None declared, Xavier Mariette Xavier Mariette received consulting fees from Astra Zeneca, Bristol Myer Squib, Galapagos, GSK, Novartis and Pfizer, Maxime Beydon: None declared, Divi Cornec: None declared, Jacques-Olivier Pers: None declared, Jacques Morel Jacques Morel received honoraria from Abbvie, Boehringer Ingelheim, Biogen, Lilly, Mylan, Pfizer, Sanofi, Bristol Myers Squib, Fresenius Kabi, Galapagos, Medac, Novartis, Roche Chugai;, Jacques Morel received grants from Bristol Myers Squib, Fresenius Kabi, Lilly, Novartis, Pfizer, and Roche-Chugaï;, Aleth PERDRIGER: None declared, Emmanuelle Dernis Emmanuelle Dernis received consulting fees from BMS, Celgène, Lilly, MSD, Novartis, UCB; honoria for lectures from Abbvie, BMS, Janssen, Lilly, Medac, MSD, Novartis, Roche-Chugaï, Sanofi, UCB, Celgène, Amgen, Galapagos;, Valerie Devauchelle-Pensec: None declared, Damien Sene: None declared, Philippe Dieudé Philippe Dieudé received consulting fees from Pfizer, Roche Chugai, Bristol Myers Squibb, Abbvie, MSD., Philippe Dieudé received grants from Novartis, Marion Couderc: None declared, Anne-Laure Fauchais: None declared, Claire Larroche: None declared, Olivier Vittecoq: None declared, Carine Salliot Carine Salliot received Honoria from Novartis, Roche Chugaï, Eric Hachulla: None declared, Véronique Le Guern: None declared, Jacques-Eric Gottenberg Jacques-Eric Gottenberg consulting fees from Abbvie, Astra Zeneca, Sanofi, Lilly, Galapagos, Gilead, Roche Chugai, Pfizer, Bristol Myer Squib, MSD., Jacques-Eric Gottenberg received grants from Pfizer, Abbvie, Lilly, Raphaèle Seror Raphaèle Seror received consulting fees from GSK, Bristol Myer Squib, Boerhinger and Janssen; honoraria from GSK, Bristol Myer Squib, Boehringer, Amgen, Pfizer and Roche; travel fees from Amgen and GSK;, Gaetane Nocturne: None declared.

Background: Sjögren's disease (SjD) is a chronic autoimmune condition that can affect the musculoskeletal system, nervous system, and/or vascular system. Autoantibodies anti–Sjögren's-syndrome-related antigen A (anti-SSA/Ro) and B (anti-SSB/La) are hallmark autoantibodies in SjD [1], associated with earlier disease onset, extra-glandular manifestations, and more significant glandular dysfunction. Anti-SSA/Ro antibodies are associated with hematologic abnormalities, and extra-glandular disease such as lymphadenopathy [2]. Objectives: The aim of this study is to describe the systemic disease activity of SjD patients with and without the presence of these autoantibodies. Methods: Data were drawn from the Adelphi Real World SjD Disease Specific Programme™, a cross-sectional survey of rheumatologists and their next six consecutively consulting patients with SjD conducted in France, Germany, Italy, Spain, and the United States in June – October 2018. Rheumatologists provided retrospective information regarding patient testing at diagnosis, including the serum anti-SSA/Ro and serum anti-SSB/La antibody tests, as well as patients' current clinical characteristics and systemic involvement. These data were used for the calculation of a proxy clinical EULAR Sjögren's syndrome disease activity index (clinESSDAI) score, calculated using physician-perceived severity scores of the individual organ domains. These same patients were asked to complete patient self-completion questionnaires which included the EQ-5D-3L, EuroQoL Visual Analogue Scale (EQ-VAS), Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue), and work productivity and activity impairment questionnaire (WPAI). All data are reported descriptively. Results: Rheumatologists (n=319) reported data on 1,879 patients; mean (SD) patient age was 53.2 (12.2) years, 89% of patients were female and 89% were white. Table 1 shows the clinical and patient-reported outcomes for both seropositive and seronegative anti-SSA/Ro and anti-SSB/La SjD patients, with a combined group of patients seropositive (49%) or seronegative (4%) for both antibody tests. Of patients with reported antibody test results for anti-SSA/Ro (n=1404), 92% were seropositive. For anti-SSB/La (n=1341) 73% were seropositive. Haematological involvement was reported for 22% of double seropositive patients but only 9% of double seronegative patients. Mean clinESSDAI scores for seropositive patients were 3.1 (anti-SSA/Ro) and 1.8 (anti-SSB/La) points higher than in seronegative patients (Table 1). Patient-reported EQ-5D-3L and WPAI scores are reported in Table 1. Mean (SD) EQ-VAS score for double seropositive patients was 61.5 (18.6), on a scale 0-100 where 100 is equal to the best imaginable health state. Mean (SD) EQ-VAS score for double seronegative patients was 73.4 (26.2). Mean (SD) FACIT-Fatigue scores for double seropositive and seronegative patients were 30.6 (10.46) and 36.3 (13.3) respectively, on a scale of 0-52 with higher scores indicating less fatigue. Conclusion: Patients who were seronegative had a similar level of organ involvement as seropositive patients, but seropositive patients had directionally higher clinESSDAI scores. Therefore, patients who had serum anti-SSA/Ro and/or serum anti-SSB/LA autoantibodies at diagnosis could represent a group of SjD patients likely to experience more clinical activity. Patient-reported outcome measures also suggest seropositive SjD patients may experience a lower health state and greater fatigue than in seronegative SjD patients. Further research is needed to better explore this potential indicator of clinical activity among SjD patients. REFERENCES: [1] Hernández-Molina G, et al. Autoimmun Rev. 2011;10(3):123-125. [2] Alexander EL, et al. Ann Int Med. 1983;98(2):155–159. Acknowledgements: Medical writing support was provided by Panita Maturavongsadit, PhD, of Lumanity Communications Inc., and was funded by Janssen Global Services, LLC. Disclosure of Interests: Jacques-Eric Gottenberg AbbVie, Janssen, BMS, UCB, MSD, Novartis, Pfizer, Gilead, Galapagos, Lilly, Sanofi, Nicola Massey Adelphi Real World, Megan Hughes Adelphi Real World, Victoria Barton Adelphi Real World, Sarah Weatherby Adelphi Real World, Federico Zazzetti May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Andras Borsi May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Wim Noel May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Evo Alemao May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Harman Dhatt May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Angelina Villasis-Keever May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Anna Sheahan May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine, Urbano Sbarigia May own shares/stock options of Johnson & Johnson, Johson & Johnson Innovative Medicine.

Background: Delayed diagnosis of axial spondyloarthritis (axSpA) remains a challenge for multiple reasons, including lack of awareness in primary care and difficulty in distinguishing chronic inflammatory back pain from other, more prevalent back pain types. Longer diagnostic delays are associated with worse clinical, psychological, social and economic outcomes [1]. Investigating the time to diagnosis and associated comorbidity burden will help inform targets for improvement and raise awareness. Objectives: To describe the patient characteristics and comorbidity burden at the time of earliest recorded back pain in general practice and at the time of axSpA diagnosis, and to estimate the time to diagnosis of axSpA from earliest recorded back pain in general practice. Methods: This retrospective descriptive study utilized data from the French electronic health records THIN® database from a representative sample of 2,000 general practitioners (GPs) between January 2010 and August 2023. Adult patients with axSpA and at least 3 years of continuous enrollment with their GP prior to axSpA diagnosis with documented back pain in their medical history prior to axSpA diagnosis were included. Patients diagnosed with rheumatoid arthritis and psoriatic arthritis within one year preceding axSpA diagnosis were excluded. Musculoskeletal, non-musculoskeletal manifestations and comorbidities were assessed at 1) the time of earliest recorded back pain by the GP and 2) the time of axSpA diagnosis. Time to diagnosis was defined as time between these two time points. Results were reported descriptively using summary statistics. Results: A total of 4,402 patients with axSpA were included, with a mean (standard deviation, SD) number of years with available data before axSpA diagnosis of 10.4 (4.9) years. In this cohort, 43% were male and the mean (SD) age was 40 (14) at earliest back pain diagnosis and 47 (14) years at axSpA diagnosis. The burden of musculoskeletal, non-musculoskeletal manifestations and comorbidities increased between the time of earliest recorded back pain and the time of axSpA diagnosis, with the number of patients with multiple comorbidities increasing from 32% to 60%. The largest increases were seen for enthesitis, fatigue, depression and anxiety (Figure 1). The mean (SD) time in years between the earliest back pain diagnosis recorded by the GP and the first axSpA diagnosis was 6.3 (4.5) years, with 38% of patients experiencing a time to diagnosis longer than 7 years. No differences in time to diagnosis between males and females were observed. Patients had a median (Q1, Q3) of 3 (2, 7) documented back pain episodes recorded in their GP records prior to their axSpA diagnosis, with 26,857 total back pain consultations recorded for the entire cohort over the study period. The distribution of specific locations and types of back pain diagnoses are shown in Figure 2. Conclusion: Diagnostic delay remains a key challenge for patients with axSpA in France, with several consultations for back pain in primary care prior to diagnosis and an average time to diagnosis of over 6 years after the earliest back pain consultation. An increased number of musculoskeletal, non-musculoskeletal manifestations and comorbidities were observed at the time of axSpA diagnosis compared to when back pain was first consulted for, highlighting worsening disease burden over time. Importantly, patients may have experienced pain long before consulting their GP, further contributing to diagnostic delays. Interventions are needed to support GPs in recognising chronic back pain patients who could benefit from a timely referral to rheumatology. Earlier diagnosis of axSpA may ultimately lower the burden on patients, healthcare systems and society. REFERENCES: [1] Yi E et al. Rheumatol Ther. 2020 Mar;7(1):65-87. Acknowledgements: Funded by UCB Pharma. Disclosure of Interests: Clément Prati Speakers bureau for AbbVie, Janssen, Novartis, Sandoz and UCB Pharma, Consultant for Celltrion, Janssen, Lilly, Novartis and Sandoz, Grant/research support from Fresenius and Pfizer, Arnaud Constantin Speakers bureau for AbbVie, Amgen, Biogen, BMS, Boehringer Ingelheim, Celltrion, Fresenius Kabi, Galapagos, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, Sandoz, UCB Pharma and Viatris, Consultant for AbbVie, Amgen, Boehringer Ingelheim, Celltrion, Fresenius Kabi, Galapagos, Janssen, Lilly, Novartis, Pfizer, Sanofi and UCB Pharma, Grant/research support from AbbVie, Biogen, BMS, Galapagos, Lilly, Hoffman-La Roche, MSD, Janssen, Novartis, Pfizer, Sanofi and UCB Pharma, Emmanuelle Dernis Speakers bureau for Abbvie, BMS, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche and UCB Pharma, Consultant for Janssen, Lilly, Novartis, Pfizer and UCB Pharma, Grant/research support from Lilly and Novartis, Stéphane Le Mouel Paid instructor for Amgen and Sanofi, Consultant for Boiron, Kappa Santé and LEO Pharma, Marc Rozenblat: None declared, Jacques-Eric Gottenberg Speakers bureau for Abbvie, BMS, Galapagos, Gilead, Lilly, MSD, Novartis, Pfizer, Sanofi and UCB Pharma, Cheikh Tamberou As a consultant in a research firm, we are called upon to collaborate with the entire pharmaceutical industry, Elise Arnee Previous employee of Biocodex and Novartis, As a consultant in a research firm, we are called upon to collaborate with the entire pharmaceutical industry, Anneleen Vyncke Employee of UCB Pharma, Marie Ducros As a consultant in a research firm, we are called upon to collaborate with the entire pharmaceutical industry, Julie Gandrup Horan Shareholder of UCB Pharma, Employee of UCB Pharma.

Introduction L’allongement des délais diagnostiques de la spondyloarthrite axiale (axSpA) est associé à une détérioration des résultats cliniques, psychologiques, sociaux et économiques [1]. L’étude du délai diagnostique et de l’impact des comorbidités associées contribue à définir des objectifs d’amélioration et à sensibiliser l’opinion publique à cette question. Patients et méthodes Cette étude descriptive rétrospective a utilisé les données de la base de données THIN® qui comprend les dossiers de santé électroniques d’un échantillon représentatif de 2 000 médecins généralistes entre janvier 2010 et août 2023 en France. Les patients (pts) adultes atteints d’axSpA ayant eu au moins 3ans de consultations en continu avec leur médecin généraliste avant le diagnostic d’axSpA et avec des douleurs dorsales documentées dans leurs antécédents médicaux avant le diagnostic d’axSpA ont été inclus. Les manifestations musculo-squelettiques, non musculo-squelettiques et les comorbidités ont été évaluées 1) au moment de la première douleur dorsale enregistrée par le médecin généraliste et 2) au moment du diagnostic d’axSpA. Le délai avant le diagnostic a été défini comme le temps écoulé entre ces deux moments. Résultats In total, 4402 pts atteints d’axSpA ont été inclus, avec un nombre moyen (écart-type) d’années avec des données disponibles avant le diagnostic d’axSpA de 10,4 (4,9) ans. 43 % étaient des hommes et l’âge moyen était de 40 (14) ans au moment du premier diagnostic de douleur dorsale ; 47 (14) ans au moment du diagnostic d’axSpA. Le poids des manifestations musculo-squelettiques, non musculo-squelettiques et des comorbidités a augmenté entre le moment où la douleur dorsale a été enregistré pour la première fois et le moment où la maladie a été diagnostiquée, le nombre de pts souffrant de comorbidités multiples passant de 32 % à 60 %. Les augmentations les plus importantes ont été observées pour l’enthésite, la fatigue, la dépression et l’anxiété (Figure 1). Le délai moyen (écart-type) en années entre le premier diagnostic de douleur dorsale enregistré par le médecin généraliste et le premier diagnostic d’axSpA était de 6,3 (4,5) années, 38 % des pts ayant un délai de diagnostic supérieur à 7ans. Aucune différence n’a été observée entre les hommes et les femmes. Les patients avaient une médiane (Q1, Q3) de 3 (2,7) épisodes de douleurs dorsales documentées avant le diagnostic d’axSpA, avec 26 857 consultations totales pour des douleurs dorsales au cours de la période d’étude. La répartition des localisations spécifiques et des types de diagnostics de douleurs dorsales est présentée dans la Figure 2. Conclusion Le retard diagnostique reste un défi majeur pour les pts atteints d’axSpA en France, avec plusieurs consultations pour des douleurs dorsales en soins primaires avant le diagnostic et un délai moyen de diagnostic de plus de 6ans après la première consultation pour douleur dorsale. Les pts peuvent avoir ressenti des douleurs longtemps avant de consulter leur médecin généraliste, ce qui contribue encore à retarder le diagnostic. Des interventions sont nécessaires pour aider les médecins généralistes à reconnaître les pts souffrant de douleurs dorsales chroniques qui pourraient bénéficier d’une orientation rapide vers un rhumatologue.

Introduction La maladie de Sjögren est une maladie systémique hétérogène, touchant principalement les femmes. Les symptômes principaux incluent des symptômes subjectifs, dont la sécheresse buccale ou oculaire, de la fatigue et des douleurs articulaires, impactant considérablement la qualité de vie. De plus, des manifestations systémiques surviennent chez environ 30 à 50 % des patients et peuvent toucher tous les organes. Récemment, trois phénotypes distincts de patients ont été décrits à partir d’une analyse en clusters : 1/ biologiquement actifs avec peu de symptômes (BALS) ; 2/ forte activité systémique (HSA) ; 3/ symptomatiques avec faible activité systémique (LSAHS). Nous avons cherché à évaluer si ces clusters étaient associés à des biomarqueurs distincts et à la valeur pronostique de la signature IFN. Patients et méthodes La cohorte ASSESS est une cohorte prospective de 20 ans de patients atteints de SjD. Les biomarqueurs suivants ont été comparés : IFN-a2, IFN-b, CXCL10, CXCL13, BAFF, IL7, CCL19 et TNF-RII. La signature IFN a été évaluée par analyse transcriptomique. Nous avons ensuite comparé l’évolution systémique et symptomatique, ainsi que le risque de nouvelle prescription d’immunosuppresseurs et de lymphome, en fonction de la signature IFN dans les trois clusters. Résultats Trois cent quatre-vingt-quinze patients (94 % de femmes, âge médian 53 [43–63] ans) ont été inclus. Des niveaux plus élevés de CXCL-13, IL7 et TNF-RII ont été observés dans les clusters BALS et HSA par rapport au cluster LSAHS. Une signature IFN élevée a été principalement retrouvée dans le cluster BALS (57 % contre 48 % et 38 % dans les clusters HSA et LSAHS, respectivement). Cette signature IFN était principalement due à l’IFN de type I, avec des niveaux plus élevés d’IFN-a2. Dans le cluster BALS, une signature IFN élevée était associée à un risque accru de traitement immunosuppresseur (HR 9,38 ; IC 95 % 1,22–72,16) (Fig. 1). Tous les lymphomes du cluster BALS sont survenus chez des patients avec une signature IFN élevée (Fig. 2). Conclusion Notre étude a démontré que notre stratification, définie par les symptômes, les signes cliniques systémiques et les données biologiques de routine, repose sur différents mécanismes physiopathologiques, en particulier l’activation des lymphocytes B et T et la voie de l’interféron alpha. L’activation de la voie interféron pourrait aider à prédire l’évolution du cluster BALS, un cluster biologique mais peu symptomatique, pour envisager une surveillance plus étroite et/ou des traitements précoces afin de prévenir les complications. Ces résultats plaident également pour une meilleure stratification des essais thérapeutiques et contribuent à la compréhension de l’hétérogénéité des patients atteints de maladie de Sjögren.

Background: The epidemiological and immunopathogenic association between Sjögren disease (SD) and non-Hodgkin’s lymphoma (NHL) is well-established. However, the epidemiological data on this complication mostly relies on data from tertiary centers, introducing selection bias and limiting comprehensive case capture. Objectives: This study aimed to evaluate accurately the characteristics of lymphoma in primary or associated SD using data from the French nationwide healthcare information system (“système national des données de santé” [SNDS]). Methods: SD patients were identified in the SNDS database based on a validated algorithm [1] (ICD10 code for SD and reimbursement for at least 2 SD-prescribed drugs). Primary SD was defined in the absence of an ICD10 code for other autoimmune diseases, and associated SD was defined otherwise. The study analyzed, primary, associated and all SD patients and lymphoma occurrences between 2009 and 2022. Analysis of risk factors of lymphoma included demographic variables such as age, sex, disease duration, and proxy reflecting disease activity including notably cryoglobulinemic vasculitis and monoclonal gammopathy of unknown significance (MGUS). Results: •Patients with primary SD•In the 30,221 patients with primary SD (65.7% of the total cohort of patients with SD; 88.8% women, median age 60 [48;70], median follow-up 11.6 years [9.4;13.2]; hydroxychloroquine use in 35.1%, methotrexate [11.5%], leflunomide [1.2%], azathioprine [4.4%], mycophenolate [3.1%], cyclophosphamide [0.4%], and rituximab [5.5%]), lymphoma occurred in 1228 patients with a prevalence of 4.1%. Marginal zone lymphomas (MZL) were the predominant lymphoma subtype (53.8%) (especially MALT-MZL [30.9%]) followed by diffuse large B-cell lymphoma (DLBCL) (25.4%), follicular lymphoma (FL) (12.1%), Hodgkin’s lymphoma (8.2%), and T/NK lymphoma (7.2%). Mortality was higher in patients with lymphoma (379/1228 [30.9%] versus 4335/28993 [15%], p<0.001). Preliminary risk factor analysis revealed associations with MGUS and cryoglobulinemic vasculitis: MGUS was observed in 3.2% of SD patients without lymphoma, compared to 10.8% in those with lymphoma (p < 0.001), and cryoglobulinemic vasculitis occurred in 2.2% of SD patients without lymphoma, as compared with 10% of patients with lymphoma (p < 0.001).•Patients with associated SD•In the 15,791 patients with associated SD (34.3% of the total cohort, including rheumatoid arthritis [20.4%], systemic lupus [10%], systemic sclerosis [6.2%], other connective tissue disorders [3.2%], and juvenile arthritis [0.3%]), 483 patients developed lymphoma (3.1%).•Total SD cohort•In the total SD cohort, including 46,012 patients with either primary or associated SD (89.4% women, median age 59 [47;69], median follow-up 11.8 years [9.5;13.2]), lymphoma occurred in 1749 patients, with a 3.8% prevalence. Lymphoma subtypes were distributed similarly to the primary SD cohort, and associations between lymphoma and MGUS and cryoglobulinemic vasculitis were observed. Mortality was higher in patients with lymphoma compared to those without lymphoma (30.9% versus 14.8% [p < 0.001]). Conclusion: This extensive epidemiological nationwide study demonstrates a 4% prevalence of lymphoma in primary SD, and 3% prevalence in associated SD. Preliminary risk factor analysis confirms the association between SD-related lymphoma and MGUS and cryoglobulinemic vasculitis. REFERENCES: [1] Seror et al. (2024 in press) Development of an Algorithm to Identify Sjögren’s Syndrome Patients in the French National Healthcare Claims Database. RMD Open. Acknowledgements: NIL. Disclosure of Interests: None declared.

Introduction Au cours du lupus érythémateux systémique (LES), l’activation plaquettaire corrèle avec l’activité de la maladie [1], [2]. Les polynucléaires neutrophiles (PNN) expriment des niveaux élevés de PSGL-1, ligand de la P-sélectine (CD62P), suggérant une interaction entre ces deux types cellulaires. L’objectif de cette étude était d’étudier qualitativement et quantitativement les agrégats plaquettes-neutrophiles chez des patients atteints de LES, afin d’identifier des sous-types de neutrophiles interagissant de façon préférentielle avec les plaquettes. Patients et méthodes Nous avons inclus de façon prospective des patients atteints de LES remplissant les critères ACR-EULAR 2019 (considérés actifs si SLEDAI clinique ≥1). Nous avons analysé par cytométrie spectrale (Cytek Aurora) des échantillons de sang frais avec un panel de 37 marqueurs immunologiques (plaquettes, des PNN et d’autres cellules immunitaires). Les agrégats plaquettes-neutrophiles étaient identifiés comme les PNN (CD66b+) co-exprimant les marqueurs plaquettaires CD41a±CD62P. Des analyses ont été réalisées avec le logiciel FlowJo v10. Résultats Nous avons recruté 56 patients (dont 11 avec des prélèvements multiples dans le temps et 70 prélèvements au total). Les agrégats plaquettes-neutrophiles étaient augmentés chez les patients ayant un LES actif par rapport à ceux ayant un lupus inactif (p=0,0337). Le pourcentage d’agrégats n’était toutefois pas corrélé à l’activité de la maladie. Après exclusion des patients traités par anti-agrégants plaquettaires (connus pour diminuer les agrégats plaquettes-leucocytes, n=16 patients), il existait une différence significative du pourcentage d’agrégats entre les patients lupiques et les donneurs sains, et nous retrouvions une corrélation statistiquement significative entre le pourcentage d’agrégats et le score d’activité SLEDAI (r=0,408 ; p=0,005). Une analyse non supervisée montrait que les agrégats plaquettes-neutrophiles de patients lupiques présentaient un phénotype atypique (ICAM1↑, CXCR4↑, CXCR1↓, voir Figure 1). Cette sous-population neutrophiles (ICAM1↑, CXCR4↑, CXCR1↓) était fortement enrichie en agrégats plaquettaires (en moyenne 16,5 % d’agrégats vs 6,8 % parmi les PNN ne présentant pas ce phénotype ; p<0,0001). Discussion Une sous-population de PNN ICAM1↑, CXCR4↑, CXCR1↓est décrite chez la souris comme capable d’une transmigration inverse de la peau (après activation par les UVB) vers les glomérules rénaux afin de promouvoir les lésions d’organes [3]. Conclusion Nous avons identifié dans le LES une sous-population de neutrophiles évocatrice de neutrophiles remigrants fortement agrégés aux plaquettes. L’identification de ces cellules par scRNAseq (sang) et en transcriptomique spatiale (biopsies rénales) est en cours. L’identification de ce phénotype de PNN « remigrant » chez l’homme et son interaction avec les plaquettes pourrait ouvrir de nouvelles voies thérapeutiques dans le LES.

Background: Denosumab is an anti-resorptive therapy with dual indications: anti-osteoporosis (marketed as PROLIA) and prevention of bone complications in solid tumors (marketed as XGEVA). Several case series since 2013 have reported an elevated risk of vertebral fractures, particularly multiple fractures, following the discontinuation of denosumab. However, limited extensive nationwide data exists on fracture incidence after discontinuation of denosumab. Methods: This study analysed data from from the French nationwide healthcare information system (SNDS) on patients initiating denosumab treatment between 2015 and 2021. Incidence of fractures and the time between the last administration and vertebral fracture were compared between patients classified as discontinuers (no denosumab delivery for 6 months + 30 days or more since the last delivery) and persistent users. Results: The study analysed 271,295 patients, of whom 181,275 initiated PROLIA and 90,020 initiated XGEVA. The PROLIA group consisted of 93.8% women with a median age of 73 years, while the XGEVA group had 52.4% women with a median age of 68 years. The median follow-up duration was 3.8 years for the PROLIA group and 1.4 years for the XGEVA group. Mortality was observed in 10.1% of patients treated with PROLIA and 57.3% of those treated with XGEVA. Prior to starting denosumab, bisphosphonates had been prescribed to 36% of patientsinitiating Prolia and 5% of patients initiatingXgeva. In addition, 6% of Prolia patients and 0.1% of Xgeva patients had previously been prescribed Teriparatide. Between 2015 and 2021, 83,823 patients stopped taking denosumab (no denosumab delivery for 6 months + 30 days or more since the last delivery), while 187,472 continued treatment. The total rate of fractures was 11.2% in Prolia discontinuers and 8.5% in persistent users (p < 0.001). Vertebral fractures were reported in 5.4% of Prolia discontinuers and 4% of persistent users (p<0.001). Peripheral fractures occurred in 8.4% of Prolia discontinuers and 6.4% of persistent users (p<0.001). 6.2% of Xgeva discontinuers experienced fractures, compared to 2.5% of persistent users (p < 0.001).Regarding immediate follow-up (relay) treatment within 7 months after the last denosumab injection, 7.1% of the participants received a bisphosphonate, including 4.4% Zoledronic Acid, in the Prolia group, and 1.2% in the Xgeva group (p<0.001). Conclusion: This nationwide study demonstrates that cessation of Denosumab is associated with an increased fracture risks and that an immediate relay with bisphosphonate is often poorly executed, despite recommendations. Further investigations are needed to confirm and elucidate the determinants of these findings. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Introduction L’apparition d’une vascularite au cours de la maladie de Sjögren (SjD) est un signe d’activité dans le score Eular Sjögren Syndrome Disease Activity index (ESSDAI) et est associée au mauvais pronostic notamment en raison du risque accru de développer une hémopathie lymphoïde B. Elle est rapportée chez 9 à 15 % des patients, l’atteinte cutanée étant la plus fréquente (80 à 90 % des cas). Cependant, plusieurs types de vascularites cutanées (VC) ont été décrits au cours de la SjD, notamment les vascularites cryoglobulinémiques, hypergammaglobulinémiques et urticariennes. L’objectif était d’évaluer les caractéristiques cliniques, immunologiques et le pronostic des différents types de VC au cours de la SjD. Matériel et méthodes Étude rétrospective multicentrique incluant des patients atteints de SjD avec VC identifiés par (1) le codage des services d’anatomopathologie de 3 hôpitaux universitaires, (2) par appel à cas national. Le diagnostic de SjD était défini selon les critères ACR/EULAR. Le diagnostic de VC était défini comme certain (prouvée par biopsie) ou fortement suspecté sur la base des caractéristiques cliniques et biologiques compatibles et après évaluation faite par un dermatologue. Les étiologies de VC étaient classées selon l’addendum dermatologique de la classification de Chapel-Hill. L’activité de la SjD était évaluée par le score ESSDAI. Résultats Au total, 54 patients ont été inclus ; 49 (90,7 %) étaient des femmes. Les manifestations cutanées des vascularites comprenaient un purpura vasculaire n=50 (92,6 %), une éruption maculopapuleuse érythémateuse n=15 (27,8 %), des lésions nécrotiques/ulcérées n=15 (27,8 %), une éruption urticarienne (n=4 ; 7,4 %). Dix-huit (33,3 %) patients avaient une atteinte extra-cutanée de la vascularite : neurologique périphérique (n=15 ; 27,8 %), neurologique centrale et musculaire (n=1 respectivement). La VC était principalement classée en vascularite cryoglobulinémique (n=29 ; 56,9 %) dont 24 de type II et en vascularite hypergammaglobulinémique (n=15 ; 27,8 %). Comparés à des contrôles SjD sans VC, appariés sur la durée de suivi, issus d’une cohorte multicentrique prospective, les patients avec VC avaient une tendance à une fréquence plus élevée de lymphomes B (11,8 % vs 3,5 % ; p=0,08). Comparés aux autres types de VC, les patients avec vascularite cryoglobulinémiques de type II avaient un score ESSDAI plus élevé au moment de la VC (médiane : 15 ; IQR : 12–23 ; p=0,005), une atteinte rénale (29,2 % vs 4 % ; p=0,02) et neurologique périphérique (62,5 % vs 12 % ; p=0,0003) plus fréquentes. En utilisant le modèle de Cox, il existait un risque significativement plus élevé de décès ou de lymphome B dans les années suivant le diagnostic de VC chez les patients atteints de vascularite cryoglobulinémique de type II par rapport aux autres types de VC [hazard ratio : 6,8 (intervalle de confiance à 95 % ; 1,8–25,5) ; p=0,0046]. Discussion Nous rapportons une cohorte originale de patients atteints de SjD compliqué de VC et mettons en évidence le pronostic défavorable des cryoglobulinémies de type II comparé aux autres formes de VC. Parmi les limites on trouve le caractère rétrospectif de l’étude et l’absence de biopsie chez 48 % des patients. Conclusion Parmi les VC compliquant la maladie de Sjögren, seule la vascularite cryoglobulinémique de type II semble être associée à un pronostic péjoratif.

Background: Pneumococcal vaccination is recommended for patients with chronic inflammatory rheumatism treated with immunosuppressants. Methotrexate (MTX) is the first-line treatment used in rheumatoid arthritis (RA), but can decrease the immune response of anti-pneumococcal vaccination in RA patients. It is recommended to vaccine before initiation of MTX but it is also recommended to start MTX as soon as the diagnosis of RA is made. Objectives: The main objective of VACIMRA study was then to compare, in the context of a prospective, randomized, multicenter, open trial, the rate of immunological response in RA patients receiving the pneumococcal 13 -valent conjugate vaccine (PCV13) either 1 month before MTX initiation (group DELAY: GD) or simultaneously with MTX (group IMMEDIATE: GI). Methods: RA patients (ACR/EULAR 2010 criteria) were vaccinated with PCV13 at randomization and two months later with 23-valent pneumococcal polysaccharide vaccine (PPV23). Ig G concentrations of the 13 serotypes contained in PCV13 were measured at baseline and during follow-up at 1, 3, 6 and 12 months. After randomization 1:1, MTX was initiated immediately in GI or at one month in GD. Oral steroids were allowed but less than 10mg/day. Disease activity, infections and side effects were collected throughout the study. Outcomes were serotype-specific IgG concentrations of the 13 pneumococcal serotypes contained in PCV13 using ELISA and functional antibody activity using an opsonophagocytic killing assay (OPA), reported as the opsonisation indices (OIs). Positive antibody response was defined as ≥ 2-fold increase in the IgG concentration by ELISA. For OI, response was defined as a value ≥ to the serotype threshold provided by the laboratory. Main outcome was the responder rates at one month after PCV13, defined by at least 3 positives antibody responses out of 5 of the target serotypes (1, 3, 5, 7F, 19A) by ELISA or OPA. The main analysis was performed in the full analysis set (FAS) with a logistic mixed model. Results: 276 RA patients were randomized: 188 in GI and 188 in GD. For the primary end point, data of 249 patients were analyzed in FAS and 224 for per protocol (PP). Characteristics of the RA patients at baseline were similar between the two groups: 70% female, mean age 55.6 years, RA duration 2 months, 69% ACPA+, 21% erosive, DAS28-CRP 4.6. Compared to GI, the rates of responders were significantly higher in GD: 88% versus 75% (p<0.01) and 96% versus 88% (p=0.02) by ELISA and OPA respectively, in FAS. These differences were also observed without imputation of missing values in FAS and PP analysis. The proportions of responders at 12 months were still higher in GD with ELISA or OPA tests. Evolution of geometric mean concentrations during the year of follow-up were higher for most of the 13 serotypes in GD compared to GI. The cumulative doses of steroids were similar between GI and GD during the follow-up. As expected, cumulative dose of MTX was higher in GI than in GD during follow-up. However, the weekly mean doses of MTX were similar at 3, 6 and 12 months between the two groups. The use of targeted DMARDs at 1 year was comparable between the two groups. There was no difference in terms of serious adverse events between groups with one pneumococcal infection in the GD during follow-up. There were no unexpected side effects observed with PCV13 and PPV23. At 1 month, DAS28 scores were higher in GD than in GI: 3.95 vs 3.38 for DAS28-ESR and 3.54 vs 3.01 for DAS28-CRP (p<0.01). Beyond the 1st month, DAS28 scores were similar between the two groups. Conclusion: This study clearly demonstrates that in RA, PCV13 vaccine administered 1 month prior starting MTX, allows a significantly higher immunological response at 1 month, in comparison to patients vaccinated simultaneously with MTX. The proportions of responders were also significantly higher in GD at 1 year with no differences on disease control and treatments used for RA such as glucocorticoids or targeted DMARDs. These results strongly support to vaccinate patients before MTX initiation REFERENCES: NIL. Acknowledgements: F-CRIN networks: i REIVAC and CRI-IMMIDIATE. Disclosure of Interests: Jacques Morel Abbvie, Amgen, Biogen, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Glaxo Smith Kline, Lilly, Médac, Nordic-Pharma, Novartis, Pfizer, Sandoz, Sanofi, Abbvie, Bristol Myers Squibb, Boerhinger Ingelheim, Fresenius Kabi, Galapagos, Glaxo Smith Kline, Lilly, Novartis, Sanofi, Abbvie, Biogen, Bristol Myers Squibb, Fresenius Kabi, Lilly, Novartis, Pfizer, Sanofi, Servier, Emmanuelle Dernis: None declared, Christian Roux: None declared, Christophe Richez: None declared, Olilvier Brocq: None declared, Bruno Fautrel: None declared, Carine Salliot: None declared, Olivier Vittecoq: None declared, Xavier Mariette: None declared, Frederic Lioté: None declared, Slim Lassoued: None declared, Cécile Gaujoux-Viala: None declared, Arnaud Constantin: None declared, Martin Soubrier: None declared, Valerie Devauchelle-Pensec: None declared, Vincent Goeb: None declared, Jacques-Eric Gottenberg: None declared, Hubert Marotte: None declared, Anouck Remy Moulard: None declared, Claire Daien: None declared, Gael Mouterde: None declared, helena Huguet: None declared, Odile Launay: None declared, Florence Galtier: None declared, Marie Christine Picot: None declared.

Background: Sjögren's disease (SjD) is a chronic, systemic autoimmune disease characterized by the presence of specific autoantibodies (AAb) and lymphocytic infiltration of exocrine glandular tissues. The pathophysiology of SjD results from dysregulated humoral immunity involving aberrant B-lymphocyte activity, leading to abnormally elevated immunoglobulin G (IgG) and IgG AAb levels, particularly anti-Ro and anti-La, which are associated with disease severity. Nipocalimab is an anti-neonatal Fc receptor (FcRn) monoclonal antibody that reduces circulating IgG, including AAb, by selectively blocking the interaction of IgG with FcRn. In phase 2 studies in AAb/alloantibody-mediated diseases, nipocalimab treatment resulted in rapid, deep, dose-dependent, reversible reductions in serum total IgG and AAb, suggesting therapeutic potential in other AAb-associated diseases, including SjD. Objectives: To evaluate the efficacy and safety of nipocalimab in patients with primary SjD. Methods: A phase 2 study (DAHLIAS; NCT04968912) was conducted in adults (18-75 years) with moderately-to-severely active primary SjD (total Clinical European League Against Rheumatism Sjögren's Syndrome Disease Activity Index [clinESSDAI] ≥6) who were seropositive for anti-Ro60 and/or -Ro52 IgG antibodies. Randomized patients (1:1:1) received IV nipocalimab at 5 or 15 mg/kg, or placebo every 2 weeks (wks) through Wk 22 and protocol-permitted background standard of care. The primary endpoint of change from baseline in clinESSDAI score at Wk 24 was chosen to avoid mechanistic bias with IgG levels. Safety assessments were conducted through Wk 30. Results: In total, 163 patients were enrolled (nipocalimab: 5 mg/kg, n=53; 15 mg/kg, n=54; placebo, n=56). Baseline characteristics were comparable between groups. The nipocalimab 15 mg/kg group met the primary endpoint versus placebo (least squares mean difference for 15 mg/kg, –2.65; 90% CI, –4.03, –1.28; p=0.002; for 5 mg/kg: –0.34; 90% CI, –1.71, 1.03; p=0.681; Table 1). Similar improvements in the 15 mg/kg nipocalimab group versus placebo were observed in most secondary/exploratory endpoints (Table 1), including change from baseline in Physician Global Assessment of Disease Severity at Wk 24 (PhGA), change from baseline in ESSDAI score at Wk 24, treatment response according to Sjögren's Tool for Assessing Response (STAR), Composite of Relevant Endpoints for Sjogren's Syndrome (CRESS), and disease activity level (DAL) response (a decrease in ≥1 clinESSDAI domain), among others. Patient-reported outcome measures were numerically improved in the 15 mg/kg nipocalimab group versus placebo. Efficacy outcomes in the 5 mg/kg nipocalimab group were generally similar to placebo. Serious adverse events were reported in 7.5%, 7.4%, and 5.4% of participants with nipocalimab 5 mg/kg, 15 mg/kg, and placebo, respectively (Table 2). Significant nipocalimab dose-dependent reductions in IgG and AAb were observed. Severe infections or infections requiring IV anti-infectives occurred in 3.8%, 1.9%, and 1.8% of participants, respectively, without a clear correlation with IgG nadir; none were deemed related to study treatment. At Wk 24, changes from baseline in albumin, low-density lipoprotein cholesterol, and total cholesterol were reported at –6.9%, 6.6% and 8.3%, respectively. No opportunistic infections or severe hypoalbuminemia were observed; no deaths were reported. Conclusion: DAHLIAS is the first study of a FcRn blocker in SjD and shows that nipocalimab treatment led to significant improvement over placebo in clinESSDAI and similar trends in other key efficacy endpoints at Wk 24 and is well-tolerated. These results demonstrate the mechanistic relevance of FcRn inhibition in SjD, indicating the potential pathogenicity of IgG AAb. Together, these findings establish proof of concept for nipocalimab in SjD and support further evaluation in patients with moderate-to-severe AAb-positive SjD. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Jacques-Eric Gottenberg AbbVie, Janssen, BMS, UCB, MSD, Novartis, Pfizer, Gilead, Galapagos, Lilly, and Sanofi, Kathy Sivils owns shares/stock options of Johnson & Johnson, Employee of Janssen, Kim Campbell owns shares/stock options of Johnson & Johnson, Employee of Janssen, Jada Idokogi owns shares/stock options of Johnson & Johnson, Employee of Janssen, Kim Hung Lo Employee of Janssen, Sophia Liva Owns shares/stock options of Johnson & Johnson, Employee of Janssen, Harman Dhatt owns shares/stock options of Johnson & Johnson, Employee of Janssen, Jonathan Hubbard owns shares/stock options of Johnson & Johnson, Employee of Janssen, Ghaith Noaiseh: None declared

Introduction La maladie de Sjögren est une maladie systémique hétérogène, touchant principalement les femmes. Les symptômes principaux incluent des symptômes subjectifs, dont la sécheresse buccale ou oculaire, de la fatigue et des douleurs articulaires, impactant considérablement la qualité de vie. De plus, des manifestations systémiques surviennent chez environ 30 à 50 % des patients et peuvent toucher tous les organes. Récemment, trois phénotypes distincts de patients ont été décrits à partir d’une analyse en clusters : (1) biologiquement actifs avec peu de symptômes (BALS), (2) forte activité systémique (HSA), (3) symptomatiques avec faible activité systémique (LSAHS). Nous avons cherché à évaluer si ces clusters étaient associés à des biomarqueurs distincts et à la valeur pronostique de la signature IFN. Patients et méthodes La cohorte ASSESS est une cohorte prospective de 20ans de patients atteints de SjD. Les biomarqueurs suivants ont été comparés : IFN-a2, IFN-b, CXCL10, CXCL13, BAFF, IL7, CCL19 et TNFRII. La signature IFN a été évaluée par analyse transcriptomique. Nous avons ensuite comparé l’évolution systémique et symptomatique, ainsi que le risque de nouvelle prescription d’immunosuppresseurs et de lymphome, en fonction de la signature IFN dans les trois clusters. Résultats Au total, 395 patients (94 % de femmes, âge médian 53 [43–63] ans) ont été inclus. Des niveaux plus élevés de CXCL-13, IL7 et TNF-RII ont été observés dans les clusters BALS et HSA par rapport au cluster LSAHS. Une signature IFN élevée a été principalement retrouvée dans le cluster BALS (57 %, contre 48 % et 38 % dans les clusters HSA et LSAHS, respectivement). Cette signature IFN était principalement due à l’IFN de type I, avec des niveaux plus élevés d’IFN-a2. Dans le cluster BALS, une signature IFN élevée était associée à un risque accru de traitement immunosuppresseur (HR 9,38 ; IC95 % 1,22–72,16). Tous les lymphomes du cluster BALS sont survenus chez des patients avec une signature IFN élevée. Conclusion Notre étude a démontré que notre stratification, définie par les symptômes, les signes cliniques systémiques et les données biologiques de routine, repose sur différents mécanismes physiopathologiques, en particulier l’activation des lymphocytes B et T et la voie de l’interféron alpha. L’activation de la voie interféron pourrait aider à prédire l’évolution du cluster BALS, un cluster biologique mais peu symptomatique, pour envisager une surveillance plus étroite et/ou des traitements précoces afin de prévenir les complications. Ces résultats plaident également pour une meilleure stratification des essais thérapeutiques et contribuent à la compréhension de l’hétérogénéité des patients atteints de maladie de Sjögren.

Patients et méthodes Sous l’égide du réseau F-CRIN, les médecins inscrits dans les réseaux CRI-IMIDIATE, CRISALIS (réseau national de recherche clinique sur l’asthme sévère) et FRADEN (réseau FRench de DErmatite atopique) ont été invités à déclarer les patients : i) diagnostiqués avec un RI/MIS ; ii) après l’introduction d’une biothérapie pour un asthme ou une maladie apparentée (asthme/MA). Résultats Quarante neufs patients ont été déclarés. Vingt-trois ont été exclus, le plus souvent car ils présentaient une pathologie rhumatologique non inflammatoire (n=19). Vingt-six patients atteints de RI/MIS ont été inclus (62 ans (extrêmes 25–84), sexe-ratio 12H/14F). Ils étaient traités par dupilumab (n=15), mépolizumab (n=9), benralizumab (n=1) et omalizumab (n=1) initié 11 mois (1–86) avant l’apparition des premiers signes de RI/MIS, pour un asthme (n=19), une dermatite atopique (n=4) ou une polypose nasosinusienne (n=3). Les diagnostics de RI/MIS retenus étaient : polyarthrite rhumatoïde (n=13, 50 % dont n=5 FR+ et n=6 CCP+), pseudo-polyarthrite rhizomélique (n=5, 19,2 %), spondyloarthrite (n=2, 7,7 %), rhumatisme psoriasique (n=2, 7,7 %), sarcoïdose (n=1, 3,9 %), RS3PE (n=1, 3,9 %) et RI aigu (n=2, 7,7 %). La biothérapie de l’asthme/MA a été suspendue chez 11 patients (42 %). Sept (63,6 %) ont présenté une rechute de l’asthme/MA (contre 1 [3,9 %] dans le groupe poursuite de la biothérapie, p=0,0033). La majorité des patients ayant rechuté à l’arrêt de la biothérapie présentait un asthme (n=4, 57 %). Au dernier suivi (8 mois, extrêmes 1–92), deux tiers des patients ayant suspendu la biothérapie de l’asthme/MA (n=7, 64 %) avaient de nouveau une biothérapie, réintroduite dans un délai de 2 mois (extrêmes 0–19) (même biothérapie de l’asthme/MA n=2, autre biothérapie n=6). Aucun patient n’a présenté une amélioration du RI/MIS pendant la période d’arrêt de la biothérapie sans traitement spécifique du RI/MIS. Un traitement pour le RI/MIS a été introduit chez tous les patients (csDMARDS : n=21, 80,8 %, le plus souvent méthotrexate : n=21, 80,8 % ; bDMARDS : n=4, 15,4 %). Les traitements reçus pour le RI/MIS et leur efficacité étaient similaires dans le groupe ayant poursuivi la biothérapie de l’asthme et celui l’ayant arrêtée. Parmi les 22 patients ayant reçu une biothérapie de l’asthme/MA et un traitement du RI/MIS (csDMARDS n=21 et/ou bDMARDS n=4) en combinaison, aucun effet secondaire grave n’a été rapporté. Conclusion Dans cette série nationale, la polyarthrite rhumatoïde était le RI/MIS le plus fréquent sous biothérapie de l’asthme/MA, survenant dans la première année de traitement, sous dupilumab et mépolizumab dans la majorité des cas (>90 %). L’arrêt de la biothérapie n’influençait pas le pronostic du RI/MIS. Son association avec les traitements du RI/MIS était efficace et bien tolérée. Ces données pourraient guider l’élaboration de recommandations pour le traitement des RI/MIS sous biothérapie de l’asthme/MA.

Background: Neurological manifestations can occur in up to half of patients with Sjögren disease (SjD) and the peripheral nervous system (PNS) is the most commonly involved (5-21%). Objectives: To analyze the frequency and phenotypic expression of PNS involvement at the time of SjD diagnosis Methods: The Big Data Project Consortium is an international, multicenter registry created in 2014. Baseline clinical information from leading centers on clinical research in SjD of the five continents was collected as a first step. The centers share a harmonized data architecture and conduct cooperative online efforts to refine collected data under the coordination of a big data statistical team. The inclusion criteria were the fulfillment of the 2002 or 2016 classification criteria. Results: By December 2023, the participant centers had included 16'703 patients from 28 countries (15'602 women, mean age at diagnosis of 51.66 years). PNS involvement at diagnosis, defined according to the ESSDAI classification, was reported in 869 (5.2%) patients. Among them, 518 (60%) showed mild active PNS involvement (pure sensory axonal polyneuropathy, V neuralgia, or proven small fibre neuropathy), 264 (30%) showed moderate involvement (axonal sensory–moto neuropathy, cryoglobulinemic pure sensory neuropathy, mild/moderate ganglionopathy, mild chronic inflammatory demyelinating polyneuropathy -CIDP-, or other cranial nerve involvements), and 87 (10%) showed highly active PNS involvement (severe motor axonal neuropathy, mononeuritis multiplex, severe ataxia due to ganglionopathy, or severe CIDP). Univariate analysis showed that patients with PNS involvement were more frequently men, diagnosed at an older age, white, had a higher frequency of activity in all the 12 ESSDAI domains and more commonly hypocomplementemia and cryoglobulinemia (all P-values <0.001). The multivariate logistic regression model adjusted for age, sex, ethnicity and the ESSDAI domains showed that systemic activity in the constitutional (OR = 1.95; 95% CI, 1.43–2.65), articular (OR = 1.35; 95% CI, 1.06–1.73), renal (OR = 1.92; 95% CI, 1.25–2.96), muscular (OR = 1.89; 95% CI, 1.11–3.24) and CNS (OR = 5.37; 95% CI, 3.18–9.06) ESSDAI domains, as well as low C3 (OR = 1.44; 95% CI, 1.05–1.98) and low C4 (OR = 1.74; 95% CI, 1.27–2.39), were independently associated with a diagnosis of PNS involvement at the time of diagnosis of SjD. Conclusion: Around 5% of patients had PNS involvement at the time of diagnosis of SjD. Patients with PNS involvement showed higher systemic activity in multiple domains (1.3-2 times higher frequency of constitutional, joint, renal, and muscular involvement), especially concerning concomitant CNS involvement (5-fold higher frequency). Hypocomplementemia was the key immunological marker independently associated with PNS involvement. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: The SEMAPHORE trial[1] was a randomized controlled prospective study to assess the safety and efficacy (success defined by PMR-AS≤10 and GC≤5mg or GC decrease ≥10mg/day) of intra venous (i.v.) tocilizumab (TCZ) in glucocorticoids (GC)-dependent polymyalgia rheumatica (PMR). Tocilizumab was shown to reduce GC while improving clinical and biological inflammatory parameters at 24 weeks. After the 24-week study, patients entered a double-blind extension. Objectives: In this study, we aimed to assess after the 24th week the relapse rate and markers of patients who received a 6-month TCZ treatment and achieved remission. Methods: Among 101 patients randomly 1:1 allocated to receive i.v. 8mg/kg TCZ or placebo for 24 weeks in the SEMAPHORE trial, 49 received TCZ and 33 of them succeed (Figure 1). All 33 patients but one stopped TCZ at week 24 and they visited at week 32, with optional follow-up visits every 8 weeks until week 48. The relapse was defined by the failure of the primary composite outcome during follow-up or the need for ≥1 TCZ infusion. Results are presented by proportion of patients achieving success at each visit and the outcome over time using a Kaplan Meier curve. Results: Among the 33 TCZ group patients in remission at week 24, 7 stopped follow-up before the 48th week, 5 of the other 26 subjects (19.2%) sustained remission in the 6 following months, 21 (80.8%) relapsed. Median time to relapse was 15 weeks (interquartile range: 8-25). 15 patients were considered in relapse because of PMR-AS≥10, 4 for isolated CRP elevation, 2 after the clinician’s decision. Among the 16 patients treated with TCZ but not in remission at 24th week, 4 of them (25%) achieved the primary outcome after continuing TCZ for 24 other weeks. Conclusion: Among patients with GC-dependent PMR, in remission after a 6-month TCZ treatment, only a quarter remained relapse-free after treatment discontinuation. This study suggests that a 6-month treatment is not enough to withdraw TCZ. Further studies assessing the required duration of anti-IL6-receptor treatment to limit PMR relapses are needed. REFERENCES: [1] Devauchelle-Pensec, V. et al. Effect of tocilizumab on Disease Activity in patients with active polymyalgia rheumatica receiving glucocorticoid therapy: A Randomized Clinical Trial. JAMA 328, 1053–1062 (2022). Acknowledgements: We thank the French rheumatologists, particularly those from the French University Hospital VICTOR HUGO (InnoVation en reCherche OsTeo-aRticulaire des Hôpitaux Universitaires du Grand Ouest) network (srouest.fr), and the general practitioners who referred their patients to this trial. We are grateful to the Clinical Investigations Center (CIC) 1412, Institut National de la Santé et de la Recherche Médicale (INSERM), Brest, France, for centralizing the trial data and to Audrey le Goff, MS; Adrien Clarysse, MS; and Valentine Guiton, MS, of the Brest University Hospital research board (DRCI) at the Brest University Hospital, who received no compensation for their role in the study. Disclosure of Interests: Baptiste Chevet Galapagos, I wrote congress review for a journal they own, I received support outside of this work from Amgen, Abbviie, Novartis, Santi, Sandoz, Souki Aghiles: None declared, Nowak Emmanuel Dr Nowak reported receiving nonfinancial support from Roche-Chugai Pharmaceutical, which donated the infusion form of tocilizumab during the conduct of the study., Dr Nowak reported receiving grants from the French National Program for Clinical Research, Guillermo Carvajal Alegria Dr Carvajal Alegria reported receiving personal fees from Chugai Pharmaceutical outside the submitted work., Emmanuelle Dernis Dr Dernis reported receiving personal fees from Novartis, Bristol Myers Squibb, UCB, AbbVie, Nordic Pharma, Amgen, and Janssen outside the submitted work., Christophe Richez Dr Richez reported receiving personal fees from Sanofi, personal fees from Lilly, and personal fees from Novartis outside the submitted work., Marie-Elise Truchetet: None declared, Daniel Wendling Dr Wendling reported personal fees from AbbVie, Bristol Myers Squibb, MSD, Pfizer, Chugai Pharmaceutical, Amgen, Nordic Pharma, UCB, Novartis, Janssen, Eli Lilly, Grunenthal, and Galapagos outside the submitted work, Eric Toussirot: None declared, Aleth Perdriger: None declared, Jacques-Eric Gottenberg Dr Gottenberg reported receiving personal fees from Roche-Chugai Pharmaceutical, Sanofi, Pfizer, Eli Lilly, Gilead, and Abbvie and grants from Bristol Myers Squibb outside the submitted work., Renaud Felten: None declared, Bruno Fautrel Dr Fautrel reported receiving personal fees from Roche Chugai Pharmaceutical during the conduct of the study., Anne Lohse: None declared, Laurent Chiche: None declared, Pascal Hilliquin: None declared, Catherine Le Henaff Bourhis: None declared, Dervieux Benjamin: None declared, Guillaume Direz Dr Direz reported receiving personal fees from Novartis and personal fees from Roche-Chugai Pharmaceutical outside the submitted work., Isabelle Chary-Valckenaere: None declared, Divi Cornec: None declared, Dewi Guellec: None declared, Thierry Marhadour: None declared, Alain Saraux Dr Saraux reported receiving grants from Roche-Chugai Pharmaceutical and grants from the French National Program for Clinical Research during the conduct of the study and personal fees from Nordic Galapagos, AbbVie, Eli Lilly, Nordic, and Roche-Chugai and grants from Eli Lilly outside the submitted work., Valerie Devauchelle-Pensec Dr Devauchelle reported receiving personal fees from Chugai Pharmaceutical and AbbVie a, Dr Devauchelle-Pensec reported grants and personal fees from Novartis during the conduct of the study and personal fees from Galapagos, Pfizer, Bristol Myers Squibb, Janssen, and AbbVie outside the submitted work.Figure 1Flow chart of the patients included in the SEMAPHORE trial, orientation of patients after the 24th week Figure 2Relapse-free survival among GC-dependant PMR patients in remission after a 6-month treatment of TocilizumabFootnotes: Remission was defined by PMR-AS<10, and GC≤5mg/j or daily GC dose decreased by ≥10mg. Day 0 was the visit at 24th week in the SEMAPHORE trialAbbreviations: PMR: Polymyalgia rheumatica; PMR-AS: Polymyalgia rheumatica activity score