Les rhumatismes inflammatoires chroniques (RIC), incluant la polyarthrite rhumatoïde, les spondyloarthrites et le rhumatisme psoriasique, sont des maladies inflammatoires systémiques nécessitant des traitements immunomodulateurs au long cours. Historiquement, la crainte d’une survenue ou d’une récidive tumorale a conduit à une utilisation restrictive des biothérapies chez les patients ayant un antécédent de cancer, entraînant parfois un contrôle insuffisant de la maladie. Les données récentes issues de registres et de méta-analyses soutiennent désormais une approche plus différenciée. Elles ne mettent pas en évidence de sur-risque de récidive avec les anti-TNF chez les patients avec antécédent de cancer solide en rémission, ou le rituximab chez les patients avec antécédent d’hémopathie maligne en rémission. Cependant une prudence reste recommandée avec les inhibiteurs de JAK et l’abatacept, en raison d’un excès de risque de cancer rapporté chez des patients sans antécédent de cancer. La stratégie thérapeutique doit être individualisée selon le type de cancer, le statut de rémission et les comorbidités, et nécessite une collaboration étroite entre rhumatologues et oncologues. En cas de cancer évolutif, la prise en charge reste personnalisée et repose sur une discussion multidisciplinaire. Les perspectives de recherche incluent le suivi prospectif des thérapies ciblées récentes et le développement d’outils de stratification personnalisée du risque oncologique.

OBJECTIVES:To characterize the longitudinal evolution of B-cell biomarkers in patients with primary Sjögren's disease (SjD) and analyse their association with the clinical disease course. METHODS:We analysed data from the French multicentre prospective ASSESS cohort. Patients fulfilling AECG criteria with ≥2 visits including both immunological assessments and ClinESSDAI scores over a 5 years follow-up were included. Baseline B-cell biomarkers included immunoglobulin levels, monoclonal component, cryoglobulinaemia, complement fractions, RF and β2-microglobulin. Disease activity was assessed using ClinESSDAI score. Associations between the number of abnormal B-cell markers and disease activity were analysed using ANOVA and Kruskal-Wallis tests. Changes in IgG were evaluated according to the biological domain of the STAR index, defined as a relative decrease ≥10%. RESULTS:Among the 395 ASSESS participants, 362 met inclusion criteria. Mean follow-up was 56.4 months (±10.6), with a mean of 5.3 visits per patient (±0.5). B-cell biomarkers remained stable in 80.5%. According to STAR criteria, 43.1% were classified as biological responders to the biological domain of STAR based on IgG decrease, occurring mostly within the first year, without correlation with changes in ClinESSDAI or ESSPRI. Although baseline ClinESSDAI did not differ by the number of B-cell abnormalities (P = 0.096), patients with multiple B-cell activity markers-particularly ≥5-had an increased risk of persistent or worsening disease (OR 4.6, 95% CI 1.2-17.8; P = 0.002). CONCLUSION:B-cell biomarkers profile in SjD is largely stable over time. However, a high baseline 'B-cell burden' identifies patients at risk of poorer outcomes, supporting their use for stratification and monitoring.

OBJECTIVES:This study aims to evaluate the safety, biological activity, and exploratory clinical effects of CD19-directed T-cell engagement with blinatumomab in patients with severe, treatment-refractory antitopoisomerase I-positive systemic sclerosis (SSc). METHODS:We conducted an exploratory case series of 5 patients with refractory SSc who received a 14-day continuous intravenous infusion of blinatumomab (9 µg/d for 7 days, escalated to 28 µg/d for 7 days) in 2 tertiary hospitals. Safety assessments included cytokine release syndrome (CRS), neurotoxicity, infections, and serum immunoglobulin levels. Exploratory efficacy outcomes comprised modified Rodnan skin score (mRSS), pulmonary function tests, and patient-reported outcomes. Immunologic endpoints included serial peripheral CD19⁺ B-cell counts, B-cell subset phenotyping, and a 6-gene type I interferon signature. Patients' follow-up was a median of 8 months (range: 6-12). RESULTS:Blinatumomab administration was generally well tolerated. Three patients experienced low-grade CRS (grade 1, n = 2; grade 2, n = 1), managed conservatively; no neurotoxicity or severe infections occurred. Rapid peripheral CD19⁺ B-cell depletion was achieved in all patients. B-cell repopulation occurred by 1 month in all but 1 patient and was dominated by naïve and transitional subsets. At 3 months, modest clinical improvements were observed, including a median mRSS change of -4 points (range: +1 to -8) from a baseline of 16 (range: 0-25) and a transient improvement in lung function and patient-reported outcomes. However, all patients experienced clinical relapse between months 3 and 6, leading to resumption of immunosuppressive therapy in most cases. CONCLUSIONS:CD19-directed T-cell engagement with blinatumomab induces rapid B-cell depletion and short-term clinical improvement in refractory SSc but lacks durability after a single treatment cycle.

Targeted therapies (TTs), including biologic and targeted synthetic DMARDs, have transformed the management of inflammatory arthritis (IA). However, their use in patients with a history of cancer raises concerns due to the role of immunity in tumor surveillance and the lack of randomized controlled trial data in this population. Recent observational studies and systematic reviews, including over 15,000 patient-years of follow-up, show no increased risk of new or recurrent malignancy with TNF inhibitors compared with csDMARDs. Rituximab appears safe in patients with prior lymphoma, while caution remains warranted for JAK inhibitors and abatacept given potential safety signals observed in other contexts. Importantly, TNF inhibitors initiated within five years of a cancer diagnosis were not associated with higher recurrence risk. The 2024 EULAR Points to Consider provide updated guidance, recommending individualized therapeutic strategies based on cancer type, remission status, and comorbidities, with close collaboration between rheumatologists and oncologists. While current evidence is reassuring for TNF inhibitors, data on other TTs remain limited. Future research should focus on long-term safety, inclusion of broader IA subtypes, and development of personalized cancer risk stratification tools.

Sjögren's disease (SjD) remains a major unmet medical challenge, characterised by biological complexity, patient heterogeneity, and the absence of curative treatments. To advance mechanistic understanding and support therapeutic discovery, we developed a comprehensive Molecular Interaction Map (MIM). Differential expression analyses were conducted on peripheral blood samples from SjD patients and healthy controls across three datasets (GSE51092, UKPSSR, PRECISESADS), identifying 1,625 differentially expressed genes (DEGs), of which 25 were shared across all datasets. Nine common DEGs were linked to interferon signalling, reinforcing its pivotal role in SjD pathogenesis. Pathway enrichment analysis revealed 137 pathways, 43 of which were integrated into the MIM alongside literature-derived knowledge. The resulting SjD Map, freely available at https://sjdmap.elixir-luxembourg.org/ , encompasses 829 molecular entities connected by 598 interactions by transcriptomic data and by curated evidence. This first comprehensive SjD Map provides an integrative framework for visualising pathways, overlaying omics data, and exploring therapeutic opportunities.

OBJECTIVES:Axial spondyloarthritis (axSpA) diagnoses are often delayed, which is associated with poorer patient outcomes. To improve understanding of diagnostic delay in France, we describe the time and patient journey to axSpA diagnosis in primary care. METHODS:This retrospective consecutive case series of adult axSpA patients in France (January 2000-August 2023) analysed primary care data from The Health Improvement Network® (THIN) database. Key study outcomes were time from earliest GP-recorded back pain diagnosis to axSpA diagnosis, and number and type of back pain episodes in this period. Other variables included axSpA symptoms and comorbidities at back pain and axSpA diagnosis, and healthcare resource utilization (HCRU). RESULTS:Of 7313 adult patients diagnosed with axSpA eligible for inclusion, 4402 had a prior back pain diagnosis. Mean time from earliest back pain to axSpA diagnosis was 6.3 years. Mean number of back pain episodes recorded prior to axSpA diagnosis was 6.1; 17.3% of patients experienced ≥10 episodes. Lower back pain was the most common (47.4% of diagnoses). The proportion of patients experiencing >1 axSpA symptom or comorbidity increased from 1.9% or 23.7% at earliest back pain diagnosis to 8.9% or 50.7% at axSpA diagnosis, respectively. HCRU was high; mean number of primary care consultations per patient per year between earliest back pain and axSpA diagnosis was 7.0. CONCLUSIONS:Patients in France wait over 6 years for an axSpA diagnosis. This research may raise awareness of the patient journey to axSpA diagnosis and support development of a primary care flagging strategy to identify patients with suspected axSpA earlier.

Nipocalimab is a neonatal Fc receptor (FcRn)-blocking monoclonal antibody approved for the treatment of generalized myasthenia gravis (gMG) and is being evaluated for other immunoglobulin G (IgG) autoantibody- or alloantibody-mediated diseases. Nipocalimab binds to FcRn with high specificity and affinity, eliciting increased clearance of IgG antibodies without affecting IgG production or other immune functions. However, nipocalimab's impact on vaccine responses in patients has not been previously reported. The effect of nipocalimab on pre-existing antibodies against tetanus toxoid (TT) and herpes zoster virus (HZV) vaccines as well as humoral responses to TT vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines, and SARS-CoV-2 infections was examined in post hoc analyses of data from three randomized, placebo-controlled trials in participants with gMG, rheumatoid arthritis, and Sjögren's disease. The levels of pre-existing anti-TT and anti-HZV IgG followed the kinetics of total IgG during nipocalimab treatment (60%-65% and 53%-68% IgG reduction, respectively) and returned to baseline after discontinuation. Nevertheless, the majority of nipocalimab-treated participants maintained pre-existing anti-HZV (66/90, 73.3% above ≥100 IU/L reference threshold) and anti-TT IgG levels (62/81, 76.5% ≥0.16 IU/mL protective threshold) throughout the study period. Participants treated with nipocalimab elicited positive IgG responses to TT and SARS-CoV-2 vaccination, similar to placebo-treated participants. SARS-CoV-2 infections during the studies were mild to moderate in severity with no complications. These results suggest that nipocalimab does not impair the development of humoral responses to vaccines or viral infections in patients with IgG autoantibody-mediated diseases.Trial registration number: NCT04951622, NCT04991753, NCT04968912.

Objectives B-cell activating factor (BAFF) of the Tumors Necrosis Factor (TNF) family is involved in the pathogenesis of Sjögren’s disease (SjD). A functional variant (BAFF variant [BAFF-var]) of the BAFF gene (TNFSF13B), leading to increased levels of BAFF, has been described. The aim of this study was to investigate the association between BAFF-var and clinical phenotype and risk of SjD. Methods A case-control study including cases from Paris Saclay and the Assessment of Systemic Signs and Evolution in Sjögren's syndrome (ASSESS) cohort and controls (blood donors from Etablissement Français du Sang [EFS]) was conducted. Genetic association analyses included only patients with European ancestry assessed by a principal component analysis using 24 ancestry-informative markers. Results We included 770 cases (420 from Paris Saclay and 350 from ASSESS) and 786 controls from EFS. Among them, 666 cases and 721 controls were found of European ancestry. We found that BAFF-var was significantly associated with higher soluble BAFF (sBAFF) level (1392.7 vs 1107.0 pg/mL, P < .001), and with increased occurrence of lymphoma (13% in patients with SjD with BAFF-var vs 5.8% in patients with SjD with BAFF-WT (wild-type), P = .013). BAFF-var remained independently associated with lymphoma after adjustment for rheumatoid factor, sex, and cumulative European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (odds ratio [OR] 2.60, 95% CI: 1.14-5.47).By comparison with ancestry-matched controls, BAFF-var was also associated with SjD itself with a minor allele frequency of 0.061 in cases and 0.035 in controls (OR = 1.77, P = .0017). Conclusions We found an association between BAFF-var and sBAFF levels, occurrence of lymphoma as well as occurrence of SjD itself. This variant could be a new biomarker for lymphoma risk in SjD.

OBJECTIVE:Patients with primary Sjögren disease (pSD) are prone to develop non-Hodgkin lymphoma (NHL), but relevant biomarkers are lacking. We aimed to determine new biomarkers predictive of NHL in patients with pSD. METHODS:Two hundred six patients with pSD fulfilling American College of Rheumatology/EULAR 2016 criteria were included and divided into three groups: pSD, lymphoproliferative pSD (Arl-pSD), and NHL-pSD. Deep flow cytometry immunophenotyping of B and T cell compartments as well as serum interferon-α (IFNα) quantification were coupled to clinical, biologic, and histopathologic data analysis. RESULTS:We identified CD11c+ FcRL5+ tissue-like memory B cells and IFNγ+ TNFα+ conventional T cells as significantly associated with NHL in pSD. These clusters showed progressive enrichment in Arl-pSD and NHL-pSD as compared to pSD. The combination of these two population abundances discriminates patients with NHL-pSD with a sensitivity of 78.9% and a specificity of 76.8%, thus overcoming alone the performance of the sum of conventional clinical and biologic markers such as cryoglobulinemia vasculitis, parotid enlargement, adapted clinical EULAR Sjögren's Syndrome Disease Activity Index, rheumatoid factor antibodies, low C4 and elevated serum IFNα levels (68.4% and 78.0%, respectively). CD11c+ FcRL5+ tissue-like memory B cells were associated with occurrence of mucosa-associated lymphoid tissue (MALT) marginal-zone NHL, whereas IFNγ+ TNFα+ conventional T cells were more indicative of non-MALT B cell NHL. CONCLUSION:We unveil novel biomarkers of NHL in pSD based on an integrative analysis coupling deep immunophenotyping and clinical, biologic, and histopathologic data. Furthermore, these markers allow distinguishing B cell NHL subtypes in pSD.

Sjögren’s disease (SjD) is often characterized by the presence of anti-SSA/Ro and anti-SSB/La autoantibodies. The Clinical European Alliance of Associations for Rheumatology (EULAR) Sjögren’s Syndrome Disease Activity Index (ClinESSDAI) and Patient-Reported Index (ESSPRI) assess disease activity and patient-reported symptomatology; however, their association with patient-reported outcome measures (PROMs) remains unclear. We aimed to describe systemic disease activity in seropositive and seronegative SjD patients and evaluate the association between proxy ClinESSDAI and ESSPRI scores with PROMs. Data were drawn from the Adelphi Real World SjD Disease Specific Programme™, a cross-sectional survey conducted in France, Germany, Italy, Spain and the United States between June and October 2018. Physicians reported patient demographics and clinical characteristics. Patients completed the EQ-5D-3L and Visual Analogue Scale (EQ-VAS), and the Functional Assessment of Chronic Illness Therapy—Fatigue Scale (FACIT-F). Proxy ClinESSDAI and ESSPRI scores were calculated using physician-reported organ activity and averaged patient ratings of dryness, pain, and fatigue, respectively. Associations between ClinESSDAI, ESSPRI, physician-reported disease severity, and PROMs were determined using linear and logistic regression modeling. Statistical significance was p < 0.05 for all tests. Overall, 319 rheumatologists provided data on 1879 patients with SjD. Mean (standard deviation) patient age was 53.2 (12.2) years, 89

ObjectiveTo examine the course of interstitial lung disease associated with rheumatoid arthritis (RA-ILD) in France on treatment with Janus kinase inhibitors (JAKis) using the MAJIK-SFR registry.MethodsProspective national multicentre observational study identifying patients with RA-ILD from the MAJIK-SFR registry. Pulmonary assessment data were collected at JAKi initiation and follow-up visits (6 months, 12 months and a median of 21 months postinclusion), including chest high-resolution CT (HRCT), pulmonary function tests (forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO)), acute exacerbations of ILD, respiratory infections and lung cancers.ResultsWe enrolled 42 patients (26 women, 62%) with RA-ILD with a mean age of 61±13 years and a mean disease duration of 16±10 years. Compared with the 778 RA patients without ILD from the MAJIK registry, RA-ILD patients were older, displayed more severe and active disease and had more prevalent comorbidities. Non-specific interstitial pneumonia and usual interstitial pneumonia accounted for 46% and 43% of the chest HRCT ILD patterns, respectively. No significant changes in FVC and DLCO were observed during the follow-up period. Chest HRCT lesions remained stable in 69% of patients. Progressive ILD was identified in 8 patients (19%). 16 (38%) respiratory tract infections were observed. Only one acute regressive exacerbation of ILD was noted, and no lung cancer was diagnosed. No deaths occurred. JAKi was discontinued in 17 patients including 8 for inefficacy on joint involvement and 5 for intolerance.ConclusionThe analysis indicates stability of RA-ILD in patients treated with JAKi. The tolerance profile of JAKi in this higher risk population did not reveal new safety signal.

Nomenclature for the disease widely known as Sjögren syndrome has proven unsatisfactory. Patients have perceived ‘syndrome’ as indicative of a vague collection of symptoms, prompting the Sjögren’s Foundation to abandon the term. Furthermore, the traditional distinction between ‘primary’ and ‘secondary’ forms fails to account for the complex interplay between overlapping autoimmune diseases. Following a bibliometric analysis, systematic literature review and a Delphi consensus process with equal involvement of professional and patient representatives, five recommendations are now issued. First, the term ‘Sjögren disease’ should replace ‘Sjögren syndrome’. Second, the acronym ‘SjD’ should be used as an abbreviation for ‘Sjögren disease’. Third, the descriptor ‘associated’ should be used in lieu of ‘secondary’ for Sjögren disease occurring in association with a second systemic autoimmune disease for which classification criteria are fulfilled. Fourth, Sjögren disease is the preferred terminology in common parlance and in clinical diagnosis, without differentiation as to primary and associated forms. Fifth, the differentiation between primary and associated Sjögren is recommended for scientific studies to define a homogeneous population. In conclusion, the consensus endorses ‘Sjögren disease’ as the official nomenclature to acknowledge the distinct pathogenesis of this disorder and to improve clarity in both clinical practice and research. In this Consensus Statement, an international group of experts and patient representatives validates and endorses the transition from the term ‘Sjögren syndrome’ to ‘Sjögren disease’, and issue several additional recommendations regarding the nomenclature of this disorder.