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.

OBJECTIVES:Ultrasound (US) is a valuable tool to detect inflammation in peripheral psoriatic arthritis (pPsA). This multicentre study assessed the intra- and inter-reader reliability of US-detected elementary lesions in peripheral psoriatic arthritis (pPsA) and evaluated the impact of standardized training on reliability, as a first step to guide multicentre assessment in the APACHE cohort. METHODS:A cross-sectional study was conducted to analyse the reliability of pPsA US lesions, as a first step in an ongoing predictive cohort (APACHE, NCT03768271) study. Three web-based reliability exercises were carried out between 2020 and 2024. Inter-rater and intra-rater reliability were assessed using Light's kappa (κ). During the third reliability exercise, a reference atlas of elementary US lesions in dactylitis was developed. RESULTS:Experienced and trainee sonographers from 30 recruiting centres participated into the study. In step 1, intra-reader kappas were moderate-to-good for synovitis (0.50-0.80), tenosynovitis (0.51-0.63), enthesitis (0.62-0.73), and poor for dactylitis (0.31-0.47); inter-reader kappas were lower for synovitis (0.32-0.70), tenosynovitis (0.40-0.49), enthesitis (0.47-0.60) and dactylitis (0.13-0.24). In Step 2, reliability improved notably in expert and trainees except for dactylitis [intra-reader: synovitis (0.81-0.90), tenosynovitis (0.66-0.83), enthesitis (0.61-0.81), dactylitis (0.37-0.47); inter-reader: synovitis c(0.72-0.84), tenosynovitis (0.55-0.76), enthesitis (0.37-0.59), dactylitis (0.12-0.30)]. Step 3 achieved moderate-to-good reliability for dactylitis (intra 0.69-0.80, inter 0.46-0.68). An atlas was produced based on expert consensus and lesion identification rates among sonographers. CONCLUSION:Standardized training was associated with a marked improvement in intra- and inter-reader reliability for the assessment of elementary pPsA lesions. The consensus-based US atlas provides practical guidance for identifying challenging dactylitis-related lesions in clinical and research settings.

OBJECTIVES:Calcinosis Cutis (CaC) represents one of the most frequent and disabling non-lethal manifestations in SSc. Our objectives were to evaluate (1) associations of CaC with SSc clinical characteristics and (2) identify risk factors for CaC development. METHODS:EUSTAR database-registered SSc patients with available information on their CaC status were included. We compared baseline patient characteristics (with vs without CaC at baseline) and investigated predictors of CaC development at 5 and 10 years (in those without baseline CaC) with logistic regression analyses. RESULTS:A total of 7114 SSc patients were included. At baseline, 11.9% had CaC. Among 1010 and 997 patients without baseline CaC, 40% and 46% developed CaC within 5 years and 10 years, respectively. Patients with CaC were more frequently female, had longer disease duration, higher modified Rodnan Skin Score, telangiectasia, digital ischaemia, late capillaroscopy patterns, joint contractures, tendon friction rubs, gastrointestinal involvement (all P < 0.001), pulmonary arterial hypertension (PAH) (P = 0.02), joint synovitis, and renal crisis (both P = 0.04). CaC patients had a higher frequency of ACA and anti-PM/Scl antibody positivity (P < 0.001; P = 0.03, respectively). Predictors for the development of CaC at 5 years included longer disease duration [odds ratio (OR) 1.04], cardiac involvement (OR 1.63), late capillaroscopy pattern (OR 1.70), telangiectasia (OR 1.92), digital ulcers (OR 2.60), and PAH (OR 2.10). Predictors at 10 years included longer disease duration (OR 1.03), dcSSc (OR 1.51), female gender (OR 1.85), telangiectasia (OR 1.92), and digital ulcers (OR 2.92). CONCLUSION:CaC is common and progressive; clinical risk factors may provide insights into the pathogenesis.

BACKGROUND:Prospective data on pregnancies in systemic sclerosis are scarce. We aimed to examine the frequency of adverse pregnancy outcomes and maternal disease progression in systemic sclerosis, as well as the factors that predict these events. METHODS:In this analysis, we studied pregnant women with systemic sclerosis (American College of Rheumatology-European League Against Rheumatism 2013 classification) or with Very Early Diagnosis of Systemic Sclerosis (VEDOSS criteria) included in the GR2 French prospective study. Frequency of composite adverse pregnancy outcomes (preterm birth at 34 weeks or less, placental insufficiency complications, small for gestational age, or fetal or neonatal death) and maternal disease course were the primary objectives. The secondary objectives were to assess other complications related to pregnancy (including delivery outcomes and postpartum complications) and compare these results with outcomes for age-matched controls from the French perinatal survey (ENP) 2016 (ie, general population), and to identify predictive factors associated with composite adverse pregnancy outcomes and maternal disease course using univariate analysis. FINDINGS:Between May 1, 2014, and Dec 27, 2020, we included 58 pregnancies (in 52 women), with 53 (91·4%) resulting in livebirths. Of the 53 ongoing pregnancies beyond 22 weeks of gestation, 14 (26·4%) had a composite adverse pregnancy outcome, including two (3·8%) preterm deliveries at 34 weeks of gestation or less, 12 (22·6%) placental insufficiency complications (pre-eclampsia or fetal growth restriction), and six (11·3%) small for gestational age. Among the 53 pregnancies, six (11·3%) severe postpartum haemorrhage events occurred. When compared with the 2016 ENP survey results, pre-eclampsia (seven [13·2%] of 53 vs 16 [3·0%] of 530, p=0·0010, preterm birth before 37 weeks of gestation (seven [13·2%] of 53 vs 31 [5·8%] of 530, p=0·047), birthweight of less than 2500 g (11 [21·1%] of 52 vs 23 [4·3%] of 530, p<0·0001), and severe postpartum haemorrhage (six [11·3%] of 53 vs seven [1·4%] of 516, p=0·0001) were more frequent than in the general population. No factors were significantly associated with the composite adverse pregnancy outcome in univariate analysis. Systemic sclerosis or VEDOSS worsened in 23 (39·7%) of 58 pregnancies, mainly during the postpartum period. In the univariate analysis, diffuse cutaneous systemic sclerosis (odds ratio 3·7 [95% CI 1·1-12·4]) and previous cutaneous vascular involvement (3·7 [1·2-11·5]) were associated with maternal disease progression, whereas the presence of anticentromere antibodies was inversely associated with stable disease (0·2 [0·1-0·8]). INTERPRETATION:Despite 53 (91·4%) of 58 livebirths, systemic sclerosis pregnancies were associated with higher rates of adverse pregnancy outcomes and severe postpartum haemorrhage. Disease worsened in 23 (39·7%) of 58 pregnancies, particularly during the postpartum period, especially in women with diffuse cutaneous systemic sclerosis, previous cutaneous vascular involvement, and antibodies other than anticentromere. FUNDING:Lupus France, Association des Sclérodermiques de France, Association Gougerot Sjögren, Association Francophone Contre la Polychondrite Chronique Atrophiante, AFM-Telethon, Société Nationale Française de Médecine Interne, Société Française de Rhumatologie, Cochin Hospital, French Health Ministry, Fondation for Research in Rheumatology, Association Prix Véronique Roualet, Union Chimique Belge.

Background: Systemic sclerosis encompasses a range of disorders characterized by vascular and connective tissue abnormalities. Although rare in pediatrics, juvenile systemic sclerosis (jSSc) is a severe and life-threatening condition that significantly impacts children's development. This study aimed to provide an overview of JSSc in France over the past decade. Methods: Patients with disease onset before the age of 16 were included following a request for observations sent via email to member practitioners of the SOFREMIP (French pediatric Rheumatology society). Results: Our study included 18 patients from 8 different French centers. While our cohort exhibited a balanced distribution between limited and diffuse subsets of the disease, we observed a higher prevalence of the diffuse subset in children above the age of 10. Skin induration was the most reported symptom, while Raynaud's phenomenon was present in 61% of the children at initial clinical evaluation. All children tested positive for antinuclear antibodies, with anti-Scl70 being the most common specificity, even among children with limited cutaneous subsets. Interestingly, we found a high sensitivity of the ACR / EULAR criteria for diagnosing jSSc in our cohort with 83% of patients meeting these criteria, except for 3 children who presented with overlap syndromes. Despite the frequent use of corticosteroids at the onset, no deaths or renal crises were reported. Three patients received treatment with biological agents, specifically Rituximab and Tocilizumab. Conclusion: JSSc is a rare but severe disease requiring rapid, specialized, and multidisciplinary care. Further studies are needed to validate proper diagnosis criteria including overlap syndromes and evaluate the use of biotherapies in children.

Methotrexate-induced osteopathy (MTX-IO) is a rare condition typically involving the lower limbs, especially tibia or foot fractures, among patients with well-controlled rheumatoid arthritis (RA) or psoriatic arthritis (PsA). This study aimed to identify the affected population, describe fracture characteristics and identify risk factors for poor clinical outcome. A multicentre retrospective study included patients with MTX-IO diagnosed by bone specialists or identified through French pharmacovigilance. The data collected included clinical presentation, imaging features, bone mineral density and biochemical markers. Between 2012 and 2024, 92 patients were included, predominantly postmenopausal women with seropositive RA. A history of major fractures was noted for 22% of the patients, and 56% presented osteoporosis at diagnosis. Fractures were most common in the tibial metaphysis (distal and proximal) (88%) and the foot bones (49%), with multiple fractures often present at diagnosis (76%), and frequently repeated fractures in the patients’ recent histories (63%). Diagnosis was conducted using MRI of the painful sites (84%), but bone scintigraphy was also used (41 patients, 45%). Management involved methotrexate discontinuation in 79% of the cases. Fracture healing and pain relief were achieved in 77% of the cases, with a significant difference in outcomes between those who discontinued methotrexate (91%) versus those who continued (29%) (p<0.001). MTX-IO is a rare but significant condition, especially among postmenopausal women with RA or PsA. Early diagnoses via MRI or bone scintigraphy and the discontinuation of methotrexate are critical, as stopping the drug significantly improves outcomes and prevents further fractures.

BACKGROUND:Total lung capacity (TLC) is seldom assessed in the prediction of systemic sclerosis (SSc) disease severity. OBJECTIVE:To describe and analyse TLC in SSc. METHODS:We performed a retrospective multicentre study of SSc patients enrolled in the French national SSc cohort with at least one TLC assessment, described patients based on baseline TLC measurements, modelized TLC trajectories in SSc, and associated TLC measures with disease prognosis. RESULTS:Two thousand three hundred and forty-seven patients were included in the study. Baseline TLC was associated with disease severity and survival, as well as with the occurrence of interstitial lung disease (ILD), lung fibrosis (LF), and pulmonary arterial hypertension (PAH). Individual TLC trajectories varied among patients. Different models of TLC trajectories were assessed using latent process mixed models. The best model showed that the vast majority of SSc patients had stable TLC trajectories and clustered patients into three groups predictive of SSc survival, ILD, LF, and PAH. Lastly, a 10 % decrease of TLC was found to be predictive of a 5 % decrease in forced vital capacity (FVC), a 10 % decrease in DLCO, and consequently an earlier predictive marker of ILD and LF than FVC. LIMITATIONS:Retrospective study. CONCLUSION:TLC is predictive of disease severity and survival in SSc and SSc-ILD. This work suggests TLC as an earlier risk factor for ILD and LF than FVC in SSc.

OBJECTIVES:Mycophenolate mofetil (MMF) and rituximab (RTX) are recommended as first-line therapies for skin and interstitial lung disease (ILD) involvement in systemic sclerosis (SSc). However, data on their combined use remain limited. This study evaluated the efficacy and safety of MMF/RTX combination therapy compared to each drug alone. METHODS:We conducted a retrospective multicenter French study including SSc patients treated with MMF, RTX, or MMF/RTX combination for ≥12-months. Primary outcomes were changes in modified Rodnan skin score (mRSS) and predicted forced vital capacity (FVC) at 12 months. Secondary outcomes included factors associated with improvement in skin or ILD and adverse events. RESULTS:Forty-seven patients received MMF/RTX combination, 30 received RTX, and 50 received MMF. At 12 months, intra-group analyses showed significant mRSS improvement with MMF/RTX combination and MMF (p = 0.002 and p = 0.04, respectively). FVC increased significantly only with combination group (p = 0.003). In multivariate inter-group analysis, MMF/RTX combination was independently associated with greater mRSS improvement versus RTX (OR 0.07, 95 % CI [0.007-0.67], p = 0.02) and greater skin and/or lung improvement compared to RTX (OR 0.27 [0.08-0.89], p = 0.03) or MMF (OR 0.24 [0.07-0.81], p = 0.02). Adverse events were not significantly increased with MMF/RTX combination. In subgroup analyses restricted to MMF/RTX combination group, patients with upfront initiation significantly improved their FVC compared to patients with sequential introduction. Upfront initiation of MMF/RTX was associated with ILD improvement in multivariate analysis. CONCLUSION:In SSc, MMF/RTX combination is well-tolerated and improves skin and ILD involvement, particularly when MMF and RTX are introduced simultaneously.

Introduction Le lupus systémique (LS) est une maladie auto-immune rare dont la prise en charge diagnostique et thérapeutique implique de nombreux défis. Le délai diagnostique médian est de deux ans et l’absence de parcours de soin bien défini entraîne un retard diagnostique péjoratif et un vécu négatif par les patients. L’objectif de ce travail était d’évaluer de manière systématique les difficultés et freins rencontrés par les patients diagnostiqués d’un LS en Alsace afin d’y répondre par la création d’un parcours LS Alsace. Patients et méthodes Un groupe de travail pluriprofessionnel comprenant des médecins (rhumatologues, internistes, dermatologues, biologistes, médecins du travail) hospitaliers et libéraux, des pharmaciens, des paramédicaux (infirmiers), ainsi que des patients et représentants d’association de patients ont participé à ce travail. Chaque étape du parcours patient a été étudiée afin d’évaluer les freins et les leviers d’amélioration potentiels. Des solutions ont été discutées au sein du groupe et implémentées en vie réelle afin d’améliorer le parcours des patients. Résultats Trois axes principaux ont été identifiés par le groupe de travail : 1/ les délais et difficultés diagnostiques : une sensibilisation des médecins libéraux au LS a été réalisée par le biais de réunions de formations médicales continues et par la diffusion d’une fiche de symptômes/plaintes devant faire évoquer un LS (Fig. 1). Afin d’améliorer l’identification précoce des patients, une fiche d’aide à la prescription du bilan immunologique regroupant symptomatologie et explorations adaptées a été diffusée (Fig. 2). Le rendu des résultats immunologiques a été harmonisé à l’échelle de l’Alsace avec des commentaires permettant au prescripteur d’orienter au mieux le patient. Une ligne de télé-expertise OMNIDOC a été mise en place afin d’accompagner les libéraux dans l’orientation et l’aide à la prise en charge des patients. Enfin, une fois le diagnostic posé, une proposition de verbatim a été élaborée avec médecins et patients afin que l’annonce diagnostique soit la mieux vécue possible ; 2/ la prise en charge thérapeutique : un document formalisant un projet personnalisé de soin (PPS) a été élaboré pour permettre au patient d’avoir une vision globale de sa prise en charge (Fig. 3). En outre, une réunion de concertation pluridisciplinaire présentielle ou à distance a été renforcée afin de discuter des dossiers complexes (i.e., LS réfractaire, grossesse) ; 3/ prise en charge globale : une hospitalisation de jour modulaire est maintenant mise en place, proposant de manière personnalisée des entretiens médicaux, pharmaceutiques, kinésithérapiques, diététiques, d’activité physique adaptée, d’ergothérapie ou de médecine du travail. La prise en charge des comorbidités (ostéoporose, cardiovasculaire) et de la vaccination est également proposée. Enfin, le programme LS développé par l’équipe d’éducation thérapeutique (ETP) vient renforcer l’offre de prise en charge. Discussion L’impact de chaque élément du parcours lupus sera évalué par le biais de mesures quantitative et qualitative. Conclusion Ce parcours intégratif vise à améliorer et à faciliter le diagnostic précoce et la prise en charge globale des patients atteints de LS en Alsace. Ce type de parcours pourrait être étendu à d’autres régions et d’autres pathologies afin de renforcer les parcours de soin.

Background: Rheumatoid arthritis (RA) regularly affects women of childbearing age1. A higher obstetric morbidity in women with RA is suggested in the literature in several countries, but no comparison between patients with RA and women in the general population is available for France. Objectives: The aim of the study was to compare adverse fetal, maternal and pregnancy outcomes in women with RA with matched controls from the French general population. Methods: We conducted a matched comparative study of RA patients included in the GR2 (Groupe de Recherche sur la Grossesse et les Maladies Rares) national multicentre cohort from 2014 to June 2021 and controls from the French general population included in the French national perinatal surveys (Enquête Nationale Périnatale)2. The latter is a national survey carried out for one week every 5 years and recording around 13 000 births. As births before 22 gestational week (GW) and birth weights < 500 grams were excluded from the French national perinatal survey, the same exclusion criteria were applied to women with RA from the GR2 cohort. Each pregnancy in patients with RA was matched to 4 pregnancies in controls on age group (≤ 29, 30-34, 35-39, or ≥ 40 years), parity, area of residence, and gemellity. These matching variables were chosen according to their association with adverse pregnancy outcomes (potential confounders). Births in the GR2 cohort between 2015 and 2018 were matched to births in the 2016 survey and those between 2019 and 2021 were matched to births in the 2021 survey. RStudio's MatchIt package was used to match RA patients to controls. The frequency of each adverse pregnancy outcome was compared between the two groups using Fisher's exact test or Chi-2. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated for each variable. Results: Of the 92 patients with RA included in the GR2 cohort, 83 (including one twin pregnancy) were retained after excluding births before 22 GW and/or birth weight < 500 grams. They were matched with 332 control pregnancies from the French national perinatal survey (180 pregnancies from the 2016 survey and 152 from the 2021 survey). The mean age of RA patients was 33.7 (± 5.06) years and 53% were nulliparous. Preterm birth was significantly higher in newborns of RA patients than in newborns of controls (16.9% versus 6.3%, p < 0.01). Among the cases of preterm birth, only one case of extreme prematurity (at 30 GW) and no case of very extreme prematurity were found in the GR2 cohort. However, there was no significant difference for gestational diabetes nor macrosomia (despite the use of corticosteroids at least once during pregnancy in 42.1% of RA patients), gestational hypertension, low birth weight, severe postpartum hemorrhage, maternal or neonatal transfer to intensive care unit or congenital malformation between the two populations (Table 1). Conclusion: This study found an increased risk of preterm delivery in RA patients compared with control women in the French general population, which is consistent with an increased risk observed in other countries. These results raise the need for particular attention to obstetrical follow-up in these patients and providing useful insights for physician-patient dialogue. Table 1. Matched comparative analysis of adverse fetal, maternal and pregnancy outcomes in RA patients (GR2 cohort) and control women of the French general population (2016 and 2021 French national perinatal surveys). REFERENCES: [1] Van den Brandt S. Arthritis Res Ther. 2017;19(1):64. [2] https://enp.inserm.fr/ Acknowledgements: The GR2 Cohort is supported by the French Society of Rheumatology, the French Internal Medicine Society, and unrestricted grants from UCB. Disclosure of Interests: None declared.