Objective To investigate the prevalence and longitudinal evolution of anti‐carbamylated fibrinogen antibodies (ACa‐Fib) of IgG and IgA isotypes in early rheumatoid arthritis (RA), and determine whether these antibodies provide additional diagnostic and prognostic information beyond anti‐cyclic citrullinated peptide antibodies (anti‐CCP) and rheumatoid factors (RF). Methods ACa‐Fib IgG and IgA were quantified by in‐house ELISA at baseline (M0), 6 months (M6), and 24 months (M24) in 619 patients with available 2010 ACR/EULAR classification criteria, including 575 RA patients, from the French ESPOIR cohort. Clinical, biological, and radiographic data were collected. Multivariable models and appropriate statistical analyses were used to assess associations between ACa‐Fib levels and disease activity, therapeutic response, smoking exposure, CRP concentrations, and structural progression. Results At baseline, ACa‐Fib IgG and IgA were detected in 16.6% and 6.3% of anti‐CCP‐negative RA patients, respectively. Baseline ACa‐Fib levels were not associated with therapeutic response or remission. Over 24 months, ACa‐Fib IgG levels decreased whereas IgA levels remained stable. Higher ACa‐Fib IgA levels were associated with longer smoking duration (p=0.003) and cumulative smoking exposure (p=0.016). Patients in the highest quartile of ACa‐Fib IgG (≥20.29 AU) had an increased risk of rapid radiographic progression (global p=0.004). Despite its markedly lower prevalence, ACa‐Fib IgA (≥3.07 AU) was also associated with structural progression (OR=1.9, 95% CI 1.1–3.4, p=0.031). Conclusion The distinct longitudinal behaviour and prognostic associations of ACa‐Fib IgG and IgA highlight a previously underappreciated component of the anti‐CarP response and support their utility as complementary biomarkers for improved risk stratification in early RA. image

Les auto-anticorps occupent une place centrale dans le diagnostic et le pronostic de la polyarthrite rhumatoïde (PR). En pratique courante, les anticorps anti-protéines citrullinées (ACPA) et les facteurs rhumatoïdes (FR) d’isotype IgM, constituent les principaux biomarqueurs immunologiques. Les ACPA présentent une meilleure spécificité diagnostique que les FR, tandis que leur positivité conjointe rend le diagnostic quasi certain et identifie des formes de PR à évolution plus sévère. Des titres élevés sont également associés à la progression structurale et à certaines manifestations extra-articulaires, notamment pulmonaires. Cependant, une proportion importante de patients demeure étiquetée « polyarthrite immunonégative » avec les tests de routine, qui ne détectent qu’une partie du répertoire auto-immun. L’étude des autres isotypes de ces 2 auto-anticorps, notamment des IgA et des auto-anticorps dirigés contre des protéines modifiées (AMPA) pourrait améliorer la caractérisation des formes immunonégatives et affiner la stratification pronostique.

Abstract Background Spondyloarthritis (SpA) has specific features in women and may be triggered by parturition. The peripartum period is marked by musculoskeletal remodelling and IL-17 secreting cell activation to enable childbirth. We therefore hypothesized that peripartum SpA might predominantly involve the entheses and be less dependent on HLA-B27 and TNFα. Methods We conducted a retrospective, observational, case-control study using the Rouen University Hospital’s clinical data warehouse. Delivery dates and symptom onset were available for 154 women with SpA. Characteristics were compared between cases (with peripartum SpA) and controls. Results We identified 58 cases and 96 controls. HLA-B27 (37.3% vs. 52.3%, p-value: 0.04), anterior chest syndrome (74.1% vs. 54.7%, p-value: 0.012 and psoriasis (37.9% vs. 16.8%, p-value: 0.004 were significantly associated with peripartum SpA. Lower rates of biological inflammatory syndrome at TNFα inhibitor introduction, (22.2% vs. 48.1%, p-value: 0.003), of radiographic sacroiliac damage (4% vs. 18.6%, p-value: 0.012 and of MRI sacroiliitis (30.6% vs. 47.4%, p-value: 0.046 were observed in women with peripartum SpA. Also, a lower retention rate of TNFα inhibitors was observed in women with peripartum SpA, 45.6% at 12 months, versus 71.2% controls (Odd ratio: 2.56 [95% CI: 1.34–4.95]). Multivariate survival analysis found a hazard ratio for TNFα inhibitor discontinuation of 2.43 (95% CI: 1.62–3.65) within the first two years of treatment. Conclusions Our study highlights a distinct phenotype of peripartum SpA, and a lower retention rate of TNFα inhibitors suggesting a worse response to these class of bDMARD. Trial registration As we conducted a retrospective study without health care intervention, no prospective registration was done.

Purpose:In France, the integration of biosimilars into medical practice in rheumatology and gastroenterology is well established. Despite a high penetration rate in hospitals, the adoption of biosimilars varies depending on the molecules. This adoption differs between new patients, for whom biosimilars are prescribed as initial biologic treatment, and those receiving these medications as part of a treatment switch from reference biologics. The objective of the COMPRENDRE study was to identify and understand the obstacles to switching from reference biologic products to their biosimilars by examining prescription practices and patient decisions. This study proposes recommendations to overcome these barriers. Patients and Methods:A total of twelve rheumatology and gastroenterology prescribers and fourteen patients with rheumatologic and gastrointestinal disorders were interviewed for qualitative insights. Subsequently, one hundred prescribing physicians and one hundred ninety patients responded to a quantitative survey to validate and explore these findings. The study was supervised by a multidisciplinary expert committee. Results:The results from the quantitative and qualitative surveys show similarities in the outcomes. In the qualitative study, 71% (10/14) of patients accepted the switch to a biosimilar. For half of them (7/14), trust in the physician-patient relationship was the main reason for acceptance. Key barriers identified by prescribers included the limited time available during consultations and patient anxiety due to their illness, both of which negatively impacted willingness to switch. In the quantitative study, 89% (89/100) prescribers reported prescribing biosimilars through switching from the reference biologic. However, only 33% (29/89) indicated that they systematically switch eligible patients. Overall, 55% (104/190) of the patients surveyed had never been offered a switch to a biosimilar. Conclusion:Switching from a reference biologic to biosimilars is hampered by several factors, including the lack of systemic proposals in the practice of prescribers as well as the lack of information given to patients.

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.

Objective: To describe the joint manifestations associated with clonal haematopoiesis and to compare patients with and without VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Methods: Patients screened for UBA1 mutations between December 2019 and January 2023 in 7 Normandie (France) hospitals were recruited retrospectively. Results: Thirty patients with a haematological disorder associated with dysimmune manifestations were included: 17 (57%) without UBA1 mutations (non-VEXAS) and 13 (43%) with UBA1 mutations (VEXAS). Thirteen (77%) non-VEXAS patients had joint involvement (arthralgia/arthritis), compared with 4 (31%) VEXAS patients (p value: 0.016). Unsupervised clustering using hierarchical clustering identified two clusters. Cluster 1 (14 patients) had more joint involvement (93% vs 25%, p value: 0.001), less UBA1 mutation (14% vs 69%, p value: 0.008), pulmonary involvement (7% vs 50%, p value: 0.017), chondritis (0% vs 50%, p value: 0.003) and unprovoked venous thrombosis (7% vs 43%, p value: 0.039) than cluster 2 (16 patients). Cluster 1 had more ASXL1 mutations (21% vs 0%). Conclusion: Joint involvement was more frequent in patients with clonal haematopoiesis and dysimmune manifestations unrelated to VEXAS syndrome.

OBJECTIVES:Abatacept (ABA) is used for its ability to dampen T cell co-stimulation and because it could act on antigen-presenting cells in an indoleamine 2,3-dioxygenase (IDO)-dependent manner. The objective of this study was to identify biomarkers of ABA response in rheumatoid arthritis (RA) patients and to determine the involvement of IDO. METHODS:RA patients' samples were collected before and after ABA treatment. Clinical response was assessed after 6 months, macrophage phenotype was assessed by flow cytometry. IDO transcript expression were quantified in blood cells by RT-qPCR. In vitro assay: GM-CSF or M-CSF monocyte-derived macrophages from healthy donors were polarised with LPS, with or without IFN-g, and co-cultured with T cells in the presence of anti-CD3, with or without ABA. Macrophage phenotype and T cell proliferation were assessed. RESULTS:In RA patients, the frequency of CD16- CD64+ CD86high macrophages pre-treatment was increase in ABA good responders compared to non-responders. ABA seemed to increase IDO production. In vitro, ABA reduced the proliferation of T cells activated by anti-CD3 and macrophages differentiated and polarised with GM-CSF+LPS+IFN-γ. This inhibitory effect of ABA was abolished by blockade of IDO. CONCLUSIONS:ABA response in RA patients is associated with a particular pro-inflammatory macrophage phenotype pre-treatment and IDO is required for ABA effect. These findings reveal predictive markers of ABA response and the involvement of the IDO pathway.

Objective Despite significant savings with biosimilars, their negative perception can lead to the occurrence of a nocebo effect (NE), therefore we aimed to quantify the NE in inflammatory rheumatism after switching from adalimumab or etanercept originators to biosimilars. Methods This retrospective study was conducted in 4 hospitals in Normandy, France between January 2018 and July 2022. The study included patients with rheumatoid arthritis or spondyloarthritis in remission under adalimumab or etanercept originators before switching to biosimilars. The occurrence of a NE was considered in patients who did not maintain biosimilars at 12 months and who presented a subjective adverse event (AE). A comparative analysis of the quantitative data collected before and after switching was performed. The AE that led to biosimilar discontinuation was identified. Additional analyses were performed to identify potential risk factors for the occurrence of a NE. Results Among 183 patients included,13.1% presented a NE. Objective AEs were observed, including rheumatism reactivation (15.3%), intolerance (8.2%), infection (1.6%) and allergic reactions (0.5%). Morning stiffness duration was significantly different before and after the switch in the spondyloarthritis group (p=0.01). No risk factors were associated with the occurrence of a NE within the limits of the studied parameters. Conclusion The occurrence of a NE after switching to a biosimilar remains acceptable. It appears less frequent when the switch is supervised by the practitioner rather than being systematic (up to 33% in some countries). A shared medical decision seems to be essential in a subset of patients, which remains to be defined.

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.