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International audience; BACKGROUND: Use of a combination of targeted therapies (COMBIO) in patients with refractory/overlapping immune-mediated inflammatory diseases (IMIDs) has increased, but reported data remain scarce. We aimed to assess effectiveness and safety of COMBIO in patients with IMIDs. METHODS: We conducted a French ambispective multicenter cohort study from September 2020 to May 2021, including adults' patients with 1 or 2 IMIDs and treated at least 3-month with COMBIO. RESULTS: Overall, 143 patients were included. The most common IMIDs were Crohn's disease (63.6%), axial spondyloarthritis (37.7%), and ulcerative colitis (14%). Half of patients had only one IMID, of which 60% were Crohn's disease. Mean duration of COMBIO was 274.5±59.3 weeks, and COMBIO persistence at 104 weeks was estimated at 64.1%. The most frequent COMBIOs combined anti-TNF agents with vedolizumab (30%) or ustekinumab (28.7%). Overall, 50% of patients achieved significant and 27% mild-to-moderate improvement in patient-reported outcomes. Extended duration of COMBIO (aOR=1.09; 95% CI: 1.03-1.14; p=0.002) and diagnoses of two IMIDs (aOR=3.46; 95%CI: 1.29-9.26; p=0.013) were associated with significant improvement in patient-reported outcomes. Incidence of serious infection during COMBIO was 4.51 per 100 person-years (95% CI 2.20-8.27) and 5 COMBIOs were discontinued due to adverse events. CONCLUSIONS: COMBIO can be effective and safe in patients with refractory/overlapping IMIDs.

Objectives To characterize patients with positive anti-topoisomerase I (ATA) in lcSSc. Methods SSc patients enrolled in the EUSTAR cohort with a disease duration of ≤3 years at database entry were considered. We assessed the risk of major organ involvement in the following groups: ATA-lcSSc vs ACA-lcSSc and vs ANA without specificity (ANA)-lcSSc, and ATA-lcSSc vs ATA-dcSSc. Cox regression models with time-dependent covariates were performed with the following outcomes: new-onset interstitial lung disease (ILD), ILD progression [forced vital capacity (FVC) decline ≥10% and ≥5% vs values at ILD diagnosis), primary myocardial involvement (PMI), pulmonary hypertension (PH), any organ involvement and all-cause mortality. Results We included 1252 patients [194 ATA-lcSSc (15.5%)], with 7.7 years (s.d. 3.5) of follow-up. ILD risk was higher in ATA-lcSSc vs ACA- and ANA-lcSSc and similar to ATA-dcSSc, although with less frequent restrictive lung disease. The risk of FVC decline ≥10% (35% of ATA-lcSSc) was lower in ATA-lcSSc than in ATA-dcSSc, whereas FVC decline ≥5% occurs similarly between ATA-lcSSc (58% of patients) and other SSc subsets, including ATA-dcSSc. The risk of PMI was similar in ATA-lcSSc and ANA-lcSSc but lower than in ACA-lcSSc; no difference in PH and mortality risk was observed among lcSSc subsets. The risk of any organ involvement, PMI and PH was lower and the mortality tended to be lower in ATA-lcSSc vs ATA-dcSSc. Conclusion ATA-lcSSc patients have a high risk of ILD, albeit with a lower risk of progression compared with ATA-dcSSc, supporting careful screening for ILD in this subgroup.

Systemic sclerosis (SSc) is a debilitating autoimmune disease characterized by severe lung outcomes resulting in reduced life expectancy. Fra-2-transgenic mice offer the opportunity to decipher the relationships between the immune system and lung fibrosis. This study was undertaken to investigate whether the Fra-2-transgenic mouse lung phenotype may result from an imbalance between the effector and regulatory arms in the CD4+ T cell compartment.We first used multicolor flow cytometry to extensively characterize homeostasis and the phenotype of peripheral CD4+ T cells from Fra-2-transgenic mice and control mice. We then tested different treatments for their effectiveness in restoring CD4+ Treg cell homeostasis, including adoptive transfer of Treg cells and treatment with low-dose interleukin-2 (IL-2).Fra-2-transgenic mice demonstrated a marked decrease in the proportion and absolute number of peripheral Treg cells that preceded accumulation of activated, T helper cell type 2-polarized, CD4+ T cells. This defect in Treg cell homeostasis was derived from a combination of mechanisms including impaired generation of these cells in both the thymus and the periphery. The impaired ability of peripheral conventional CD4+ T cells to produce IL-2 may greatly contribute to Treg cell deficiency in Fra-2-transgenic mice. Notably, adoptive transfer of Treg cells, low-dose IL-2 therapy, or combination therapy changed the phenotype of Fra-2-transgenic mice, resulting in a significant reduction in pulmonary parenchymal fibrosis and vascular remodeling in the lungs.Immunotherapies for restoring Treg cell homeostasis could be relevant in SSc. An intervention based on low-dose IL-2 injections, as is already proposed in other autoimmune diseases, could be the most suitable treatment modality for restoring Treg cell homeostasis for future research.

We report the case of a patient followed for a mixed connective tissue disease with signs of systemic sclerosis and systemic lupus, who presented an acute renal failure with severe neurological symptoms (confusion, obnubilation) and hypertension. The distinction between scleroderma renal crisis and lupus nephritis was challenging and hence, the decision to use or not high dose of corticosteroids. Kidney biopsy was of major importance for the diagnosis and therapeutic strategy. The diagnosis of neurological symptoms was also made difficult given the clinical presentation and the results of imaging. Neurolupus, malignant hypertension, or posterior reversible encephalopathy syndrome were the evoked diagnosis.

Resume Objectif La sclerodermie systemique (ScS) est une maladie systemique auto-immune rare. Il s’agit d’une pathologie a distribution mondiale mais sous l’influence de facteurs geographiques et ethniques encore mal connus. Methodes Cette etude visait a comparer les caracteristiques demographiques et la frequence de l’atteinte des organes internes entre des patients de race noire et des sujets caucasiens atteints de ScS en France. Au total, 425 patients sclerodermiques ont ete recrutes dans les Services de Medecine Interne et de Rhumatologie de l’Hopital Cochin. Les donnees ont ete recueillies a la visite initiale et chaque patient noir a ete apparie a 2 ou 3 temoins d’origine caucasienne recrutes dans le meme service. Resultats 105 patients de peau noire et 320 sujets de peau blanche ont ete inclus. La comparaison des caracteristiques demographiques a mis en evidence l’âge plus avance des sujets blancs (48,6 ± 14,8 vs 39,5 ±10,7, p Conclusion Dans cette population de patients issus d’un centre de reference des maladies systemiques auto-immunes rares, les manifestations cutanees et pulmonaires etaient de forme plus severe chez les patients de race noire et s’accompagnaient d’une plus faible prevalence des ACA que chez les sujets caucasiens, ces observations suggerant un phenotype plus severe.

Objective To validate the predictive value of the DAS28-γGT for the occurrence of major cardiovascular (CV) events (MACE) in the ESPOIR cohort. Methods Analysis of 13-year outcome from the ESPOIR cohort. Rheumatoid arthritis (RA) patients with missing data for baseline γGT activity and those not followed-up to 1 year were excluded. Baseline DAS28-γGT was calculated using the following formula: 0.56*√TJ-28 + 0.28*√SJ-28 + 2*ln (γGT)+0.014*GH. Our primary outcome was the merit of the DAS28-γGT in predicting the occurrence of MACE. Results Among the 696 patients (536 women, mean age of 49 ± 12 years), 34 MACE were recorded, with a mean time to event of 71 ± 44 months. ROC curve analysis indicated that a DAS28-γGT > 9.4 had the best sensitivity and specificity for the diagnosis of MACE during the observation period. DAS28-γGT >9.4 was predictive of the occurrence of MACE, with a hazard ratio (HR) of 3.11 (95% CI 1.41–5.43). Multivariate Cox analyses confirmed higher DAS28-γGT (HR 2.44, 95% CI 1.05–5.64) together with age (HR 1.04, 95% CI 1.01–1.07) and diabetes mellitus (HR 4.12, 95% CI 1.55–10.95) as independent predictors of MACE. There was a dose effect of the DAS28-γGT for MACE-risk prediction, which was in line with the application of the Framingham risk score. Conclusion The DAS28-γGT was identified in this large prospective cohort as an independent predictor of MACE in patients with RA. The DAS28-γGT is a simple and useful tool to evaluate CV risk in routine and warn the clinician about the CV risk burden in patients with RA.

Background/Aims Filgotinib (FIL) is a preferential Janus kinase 1 inhibitor, approved in Europe for the treatment of Rheumatoid arthritis (RA). A phase 4 European study of FIL (FILOSOPHY; NCT04871919) in patients with RA is ongoing. We report baseline characteristics and 1-month efficacy data from the first 200 patients. Methods The prospective, observational study will enroll approximately 1500 patients aged ≥18 years with moderate-severe active RA, prescribed FIL for the first time in accordance with the product label. We report baseline demographics, disease characteristics, comorbidities, prior treatments, reasons for starting FIL, and mean change from baseline (CFB) in pain severity (measured using a 10-cm visual analog scale [VAS]) and Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue score (range 0-52) via electronic PRO data collection at Week 1 and Month 1, and mean CFB in Clinical Disease Activity Index (CDAI; range 0-76) score at Month 1. The proportion of patients with clinically meaningful CFB in FACIT-fatigue (increase of ≥ 4) and VAS pain (reduction of ≥ 10) from Week 1 to Month 1 was reported. Patients included in analysis were enrolled May 2021-February 2022. Results 206 patients were enrolled from Germany (n = 134), UK (n = 40), Netherlands (n = 27), Belgium (n = 4), and Italy (n = 1); nearly 75% were female, mean (standard deviation [SD]) age 56.8 (10.6) years, and mean (SD) RA duration 10.0 (9.5) years. Approximately 40% of treated patients had comorbidities, most common: hypertension (28.3%), dyslipidemia (9.1%), type 2 diabetes mellitus (5.3%). FIL was started due to inadequate response (43.3%), loss of response (40.6%), or intolerance (non-allergic) to previous treatment (5.9%), or for other reasons (10.2%). Of treated patients, 167 (89.3%) received FIL 200 mg and 20 (10.7%) received FIL 100 mg (study drug information was pending for 19 patients). FIL monotherapy was taken by 55.6% of patients (19.3% with glucocorticoids), while 37.4% received FIL in combination with MTX (13.4% with glucocorticoids). Mean (SD) and median (range) daily dose of oral glucocorticoids at baseline was 7.5 (6.0) mg and 5.0 (1.0-30.0) mg. At Week 1 and Month 1, respectively, mean (SD) CFB in FACIT-fatigue score was 3.7 (6.9) and 6.8 (8.6), and mean (SD) CFB in VAS pain score was -11.9 (18.0) and -22.2 (27.8). At Month 1, mean (SD) CFB in CDAI score was -13.7 (17.1). Conclusion These are the first international real-world data to be reported from a cohort of RA patients treated with FIL. At baseline, patients generally had moderate disease activity. Initial interim data indicate rapid improvements in disease measures with FIL treatment (given as combination therapy or monotherapy, with/without glucocorticoids), which could be observed as early as Week 1 for VAS pain and FACIT-fatigue scores. Long-term follow-up is needed to further evaluate effectiveness and safety. Disclosure J. Galloway: Other; AbbVie, AstraZeneca, Biogen, Celgene, Galapagos, Gilead, Janssen, Medicago, Lilly, Novartis, Novavax, Pfizer, Roche, UCB. K. Bevers: None. P. Verschueren: Other; AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Pfizer, Roularta, Sidekick Health. R. Caporali: Other; AbbVie, Celltrion, Fresenius-Kabi, Galapagos, Janssen, Pfizer, Roche, UCB, Eli Lilly, Gilead, Sanofi. S. Romero Yuste: Other; Pfizer, Lilly, AbbVie, Biogen, Sanofi. J. Avouac: Other; Galapagos, AbbVie, Lilly, Pfizer, Bristol Myers Squibb, Novartis, Fresenius-Kabi, Sanofi, Sandoz, Nordic Pharma, Biogen, Medac, Janssen, Roche-Chugai. E. Gvozdenovic: Other; Galapagos. K. Harris: Other; Galapagos. M. Zignani: Other; Galapagos. G. Burmester: Other; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc.

Objectives To compare the features of difficult-to-treat rheumatoid arthritis (D2TRA) patients using two different definitions according to the previous failure of targeted therapies. Methods We stratified consecutive RA patients treated at Cochin Hospital into two groups, a D2TRA group and a non-D2TRA group, according to two definitions of D2TRA. Both definitions defined D2TRA as RAs failing at least two targeted therapies, with a different mechanism of action for the EULAR-D2TRA definition or without prejudging the mechanism of action and for the Alternative D2TRA definition. Results We included 320 consecutive RA patients. We identified 76 EULAR-D2TRA and 244 non-DTRA patients, and 120 Alternative D2TRA and 200 non-DTRA patients. Compared with non-D2TRA, D2TRA patients from both definitions were more likely to have lower socioeconomic level, positive rheumatoid factor, interstitial lung disease, higher DAS28-CRP and were more likely to respond to rituximab and Janus kinase inhibitors. Although EULAR and Alternative D2TRA patients displayed similar clinical and biological features, they were characterized by different therapeutic profiles. We observed fewer patients receiving methotrexate in the Alternative D2TRA group (53% vs 64%, P = 0.046). Patients with Alternative D2TRA not fulfilling the EULAR definition (n = 44) had all received two successive first-line TNF inhibitors, a monoclonal antibody and a soluble receptor, and were comparable to EULAR-D2TRA patients with regards to all other characteristics. Conclusion Low socioeconomic status, diabetes, interstitial lung disease and absence of combination with methotrexate allow identification of D2TRA. In addition, the inclusion as ‘early-D2TRA’ of patients failing two TNF inhibitors in the EULAR definition of D2TRA would facilitate the rapid identification of D2TRA patients.

Resume Les patients atteints de rhumatisme inflammatoire chronique peuvent presenter des risques d’infection osteoarticulaire en rapport avec leur âge, la presence de comorbidites, la realisation de gestes locaux intra-articulaires ou d’actes chirurgicaux ou par l’utilisation de certains traitements immunosuppresseurs dont les corticoides ou les traitements cibles. Les donnees relatives au risque d’infection osteoarticulaire restent pour l’instant peu nombreuses et limites aux anti-TNF-α. Bien qu’un surrisque d’infection osteoarticulaire sur articulation native ou sur prothese articulaire sous traitement biologique cible soit rapporte dans differents registres, celui-ci apparait comme modere, inferieur aux infections respiratoires, cutanees et urinaires. Ce risque d’infection osteoarticulaire est egalement stable au cours du temps, similaire a celui decrit avant l’ere des biotherapies. Par ailleurs, ce surrisque doit etre mis en balance avec celui des corticoides, souvent necessaires pour controler les poussees induites par la suspension de l’agent biologique. Le Staphylococcus aureus reste le microorganisme le plus frequemment retrouve, mais certaines especes, habituellement rarement mises en cause dans les infections articulaires peuvent etre impliquees et doivent etre evoquees chez ces patients. L’absence de signes generaux et/ou de syndrome inflammatoire biologique ne doit pas faire eliminer l’infection chez ces patients sous traitements cibles, et peuvent conduire a proposer certains examens comme une biopsie synoviale. Plusieurs questions restent pour l’instant sans reponse, notamment le poids du traitement cible dans le surrisque d’infection osteoarticulaire par rapport aux autres facteurs de risques, notamment l’âge, la maladie articulaire sous-jacente ou la corticotherapie.

Resume La sclerodermie systemique (ScS) est une maladie auto-immune caracterisee par une grande heterogeneite clinique et une evolution variable. C’est une affection multifactorielle dans laquelle plusieurs voies pathogeniques liees a l’inflammation, la vasculopathie et la fibrose interagissent et favorisent des atteintes d’organes. Les progres faits ces dernieres annees dans la comprehension de sa pathogenese ont permis d’identifier des cibles therapeutiques pertinentes. Des essais cliniques interessants ont ete publies et des avancees considerables ont ete realisees dans le developpement d’options therapeutiques efficaces. Les resultats positifs de l’essai SENSCIS (Safety and Efficacy of Nintedanib in Systemic SclerosIS) ont conduit a l’homologation du premier medicament pour le traitement de la pneumopathie interstitielle diffuse associee a la ScS (PID-ScS). La majorite des essais cliniques, toutefois, etaient axes sur des therapies immunosuppressives. Un benefice semble se dessiner, mais les resultats obtenus ne sont pas spectaculaires et a ce jour, aucun agent immunosuppresseur n’a ete approuve dans la ScS. Les criteres d’inclusion des essais cliniques ont evolue en vue d’elargir le recrutement aux patients presentant une maladie progressive. Les criteres d’evaluation ont egalement ete revises afin de mieux couvrir et de la capacite fonctionnelle des patients. Enfin, un traitement de fond par immunosuppresseurs synthetiques a ete autorise dans certains essais evaluant des therapies ciblees, ouvrant la voie aux traitements combines. Nous faisons ici un tour d’horizon des principaux essais cliniques menes ces dernieres annees dans la prise en charge de la ScS.

Resume La therapie par cellules T autologues genetiquement modifiees exprimant un recepteur antigene chimerique ou cellule CAR-T est basee sur un ciblage specifique de l’antigene tumoral conduisant a la lyse et a la destruction des cellules tumorales. Les cellules CAR-T ont demontre une efficacite significative dans le traitement des hemopathies B. De nouvelles constructions derivees de cellules CAR-T ont ensuite ete developpees permettant d’eradiquer les cellules B pathogenes ou de restaurer la tolerance. L’objectif de cette revue est d’examiner et de discuter de la maniere dont les connaissances et la technologie generees par l’utilisation des cellules CAR-T en onco-hematologie pourraient etre integrees dans les strategies therapeutiques des maladies auto-immunes rhumatismales. Cette revue se propose de presenter la technologie des cellules CAR-T, de decrire les resultats principaux obtenus avec les cellules CAR-T en onco-hematologie et de discuter des donnees preliminaires des cellules CAR-T et leurs constructions derivatives dans des modeles experimentaux de maladies auto-immunes. Un point specifique traitera de l’integration potentielle des cellules CAR-T dans le traitement de trois maladies auto-immunes rhumatismales : la polyarthrite rhumatoide, le lupus systemique et la sclerodermie systemique.

Summary Background Preliminary criteria for the very early diagnosis of systemic sclerosis (VEDOSS) have been previously proposed to identify signs and symptoms in patients with Raynaud's phenomenon. Patients with all signs or symptoms of the VEDOSS criteria already fulfil the 2013 American College of Rheumatology–European League Against Rheumatism (ACR–EULAR) classification criteria for systemic sclerosis. However, prospective data for the evolution to fulfilling these criteria do not exist. We therefore aimed to determine the clinical value of the VEDOSS criteria to identify patients with Raynaud's phenomenon who progress to systemic sclerosis within 5 years. Methods The VEDOSS project was a multicentre, longitudinal registry study done in 42 European Scleroderma Trial and Research group centres located in 20 countries in Europe, North America, and South America. Patients with Raynaud's phenomenon were eligible for enrolment. Those who had fulfilled the 1980 ACR or the 2013 ACR–EULAR classification criteria for systemic sclerosis, as well as of any other ACR or EULAR classification criteria for other definite connective tissue diseases at enrolment were excluded. Data were recorded each year during follow-up visits and included the four VEDOSS criteria (ie, positivity for antinuclear antibodies [ANAs], puffy fingers, systemic sclerosis-specific autoantibodies, and abnormal nailfold capillaroscopy). The primary endpoint was the fulfilment of the 2013 ACR–EULAR classification criteria for systemic sclerosis (ie, progression from enrolment to follow-up). Proportion of progressors and VEDOSS criteria interaction were reported descriptively. Predictors of progression of the distinct VEDOSS criteria interactions were determined based on the point prevalence at 5 years. To investigate the intermediate course of progression of the distinct VEDOSS criteria and their combinations, Kaplan-Meier analysis was done. Results Between March 1, 2010, and Oct 4, 2018, we enrolled 1150 patients with Raynaud's phenomenon in the VEDOSS database. 764 (66·4%) of 1150 patients met the VEDOSS criteria for study inclusion. Of the 764 patients, 553 (72·4%) had at least one available follow-up visit and the median duration of follow-up was 3·6 years (IQR 1·7–5·8). The mean age was 45·9 years (SD 15·0), 507 (91·7%) of 553 participants were female, and the median time since the onset of Raynaud's phenomenon was 4·0 years (IQR 1·7–10·0). At baseline, 401 (73·7%) of 544 patients with Raynaud's phenomenon had detectable ANA, with 208 (39·5%) of 527 patients positive for systemic sclerosis-specific autoantibodies. Nailfold capillaroscopy abnormalities were present in 182 (36·0%) of 505 patients and puffy fingers were detected in 96 (17·8%) of 540 at baseline. 1885 follow-up visits were recorded. 254 (45·9%) of 553 patients completed the study with progression or a 5-year follow-up; of whom, 133 reached the primary endpoint, resulting in an overall progression rate of 52·4%. The absence of ANA at baseline was the factor most strongly associated with a lack of progression within 5 years, with only four (10·8%) of 37 ANA-negative patients progressing. Conversely, positivity at baseline for systemic sclerosis-specific autoantibodies and puffy fingers was the combination having the highest risk of progression (16 [94·1%] of 17). Interpretation Our results from the VEDOSS project offers a useful tool for a stratified risk approach to patients with Raynaud's phenomenon. The absence of ANA is a strong protective factor that identifies patients with very low risk of developing systemic sclerosis whereas the presence of one or two VEDOSS criteria in patients with Raynaud's phenomenon confers a progressively higher risk for systemic sclerosis over time. This stratification tool can be used both for clinical management and to inform early interventional trials. Funding European Scleroderma Trial And Research and World Scleroderma Foundation.

Objective To identify which factors influence humoral response to coronavirus disease 2019 (COVID-19) vaccination in rituximab (RTX)-treated patients. Methods This was an observational, prospective, usual care study including consecutive patients with inflammatory rheumatic diseases in maintenance therapy with RTX. All patients received a two-dose regimen COVID-19 vaccination. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured at the time of the new RTX infusion. Results From the recruited patients, 16/45 (36%) produced antibodies reaching the assay cut-off value of 15 AU/ml and 29/45 (64%) had a negative serology. Within RTX-treated patients, 25 (56%) had undetectable B cells. Negative serology was associated with undetectable B cells (24/25 vs 5/20, P Conclusions B cell depletion is the main independent contributing factor of antibody response to SARS-CoV-2 vaccination in RTX-treated patients. Monitoring CD19 may be of interest to identify the most appropriate period to perform vaccination.

OBJECTIVE To study the potential role of semaphorins in the pathogenesis of rheumatoid arthritis (RA). METHODS Microarray experiments were performed on Affymetrix GeneChip Human Exon 1.0 ST arrays in RA endothelial cells (ECs) and control ECs derived from circulating progenitors. Expression of class 3 and class 4 semaphorins and their receptors in the serum of RA patients and healthy controls was assessed by immunohistochemical analysis in synovial tissue and by enzyme-linked immunosorbent assay. RESULTS Microarray analysis revealed differential expression of class 3 and class 4 semaphorins and their receptors in RA ECs. Semaphorin 4A (SEMA4A), plexin D1, and neuropilin 1 messenger RNA (mRNA) levels were markedly increased in RA ECs by 1.75-, 2.21-, and 1.68-fold, respectively. Stimulation with tumor necrosis factor (TNF) led to a 2-fold increase in SEMA4A mRNA levels in RA ECs, and deficient SEMA4A expression modified RA EC angiogenic properties. Class 3 and class 4 semaphorins as well as their receptors were overexpressed in RA synovial tissue. A respective 1.30-fold increase and 1.54-fold increase in SEMA4A and SEMA3E, as well as a 24% decrease in SEMA3A, was observed in the serum of RA patients. Serum levels of SEMA4A, SEMA4D, and SEMA3A correlated with levels of inflammation and proangiogenic markers. In 2 independent cohorts of patients with low disease activity or with RA in remission, the presence of SEMA4A identified patients with residual disease activity. CONCLUSION Gene expression profiling of ECs identified class 3 and class 4 semaphorins as potential biomarkers and therapeutic candidates in RA, with confirmed overexpression in ECs, synovial vessels, and serum, and correlation with validated markers of inflammation and angiogenesis. Thus, semaphorins might be novel and appealing EC-derived inflammatory and proangiogenic targets in RA.

JAK-inhibitors (JAK-i) might be associated with venous (VTE) and arterial thromboembolic events (ATE). To evaluate the association between JAK-i and the risk of VTE and ATE.A self-controlled case series was performed using data from the nationwide French healthcare insurance system database SNDS. We included all patients treated with JAK-i (baricitinib or tofacitinib), and having presented at least one VTE or ATE between November 1, 2017 and June 30, 2019. Associations were estimated using the incident rate ratio (IRR). Two post-exposure periods (until day 30 and until day 60) were individualized.Among 5870 patients with JAK-i dispensing, 92 had an incident VTE or ATE within the study period. Their median age at JAK-i initiation was 65.7 years [IQR: 56.1-75.8] and 65.2% were female (n = 60). Before event incidence, 65.2% (n = 60) received baricitinib, 32.6% (n = 30) tofacitinib and 2.2% (n = 2) had both medications. Moreover, 41.3% (n = 38) presented a VTE and 58.7% (n = 54) an ATE. The median time-to-onset after JAK-i initiation was 4.6 months [IQR: 2.5-9.2] for VTE and 6.1 months [IQR: 3.0-8.5] for ATE. An IRR of 8.27 (95% CI 3.41-20.04) for VTE was detected during JAK-i treatment and remained increased over the 30-day period of post-exposure (6.52 [2.02-21.11]). An IRR of 9.27 (3.68-23.34) was also found for ATE, which remained increased over the 30-day period of post-exposure (10.12 [3.27-31.37]). No increased risk was detected during long-term post-exposure for either VTE or ATE.This study shows evidence of an increased risk of VTE and ATE associated with the use of baricitinib and tofacitinib.

Background: The lack of validated tools to predict rheumatoid arthritis (RA) disease course warrants the development of new reliable biomarkers. We have previously detected increased semaphorin 4A (SEMA4A) expression in endothelial cells, synovial tissue, and serum of patients with RA. In addition, SEMA4A serum levels correlated with multiple clinical, biological, and power doppler ultrasound markers of disease activity. Our aim was to evaluate circulating SEMA4A for the prediction of outcomes in patients with RA.Methods: A first cohort included between May 2016 and February 2018 101 consecutive RA patients followed up on an annual basis until August 2021. Baseline SEMA4A concentrations were analyzed according to disease progression defined for the purpose of this study by the occurrence of patient-reported flares and initiation or change of targeted therapy. A second cohort included 40 consecutive RA patients who initiated new therapy because of insufficient disease control. The course of SEMA4A levels was studied between baseline and month 3 according to treatment response. Results: During a follow-up period of 41±15 months, disease progression occurred in 26/101 patients in the first cohort. Increased baseline SEMA4A levels were identified as an independent predictor of disease progression (hazard ratio, HR: 2.71, 95%CI 1.14-6.43). The highest predictive value of disease progression was obtained with the combination of increased circulating SEMA4A and/or DAS28-CRP>3.2 and/or synovial hyperemia on doppler ultrasound (HR: 10.42, 95%CI 1.41-76.94). SEMA4A was also predictive of disease progression in patients with a DAS28 Conclusion: circulating SEMA4A appears as an appealing biomarker in RA with ability to predict disease progression, and with association with response to therapy.

There is an increasing body of evidence suggesting a direct pathophysiological role of anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA), and immunological remission could be a target for treatment. However, data related to the ability of biologics to reduce ACPA titres are contradictory.We aimed to evaluate the changes in ACPA titres after treatment with different biologics in patients with RA.As a first step, a systematic review of the literature available on 3 biologics (TNFi, abatacept and rituximab) and ACPA in patients with RA was performed in Pubmed and Cochrane. As a second step, a retrospective study was performed: all RA patients treated with the 3 above-mentioned biologics were identified. To be included in the analysis, patients had to have at least two titres of ACPA (one before and one after biologic treatment) available. ACPA titres were compared before and after treatment in each of the treatment groups.As a result of the literature review, 24 articles were retained confirming that the data on change in ACPA under biologics is contradictory, particularly for abatacept and TNFi. 144 RA patients (79.3% female, mean age: 56 years) were included in the retrospective analysis: 59 patients had received rituximab, 31 abatacept, 55 TNFi. ACPA titres decreased significantly with rituximab but not with abatacept nor TNFi. Modelling of ACPA titres over follow-up confirmed the significant decrease of ACPA over time rituximab.In this real-life study, ACPA titres only significantly decreased after treatment with rituximab.

Resume La sclerodermie systemique (ScS) est une maladie du tissu conjonctif caracterisee par une microangiopathie diffuse et un dereglement immunitaire qui aboutissent, a terme, a une fibrose generalisee touchant la peau et les organes internes. Si les criteres de 2013 de l’EULAR/ACR ont effectivement ameliore la sensibilite pour le diagnostic de la ScS, il s’avere que la sous-classification traditionnelle en formes cutanees limitee et diffuse ne suffit pas a couvrir l’ensemble des phenotypes du spectre de la sclerodermie. A cet egard, une vaste etude recente fondee sur des analyses typologiques et d’autres projets en cours tentent d’affiner la stratification des patients atteints de ScS car l’evolution de cette maladie est a ce jour encore tres difficile a prevoir. Des etudes precliniques et des essais comparatifs randomises recents ont obtenu des resultats encourageants avec de nouveaux medicaments ciblant les voies de signalisation inflammatoires/immunologiques et fibrotiques. L’un des principaux besoins non satisfaits dans la ScS est l’identification precoce des patients a haut risque de mortalite, pour lesquels il convient de definir et de nuancer l’agressivite des traitements en fonction du pronostic. Par ailleurs, l’option de transplantation pulmonaire et cardiaque peut egalement etre envisagee pour certains patients soigneusement selectionnes. Bien que le pronostic de la ScS reste mediocre, une meilleure stratification des patients, associee aux avancees therapeutiques recentes et en cours, pourrait influencer considerablement l’evolution de la maladie dans un avenir proche. Enfin, la necessite de developper des therapies combinees devrait s’intensifier prochainement dans le but de combattre plus efficacement cette maladie complexe. Dans cette revue, nous presentons de nouvelles informations relatives aux atteintes d’organes et aux options therapeutiques.

Objectives We aimed to clarify the definition, distribution, clinical association and outcomes of large calcinosis in patients with systemic sclerosis (SSc). Methods We conducted a systematic literature review (SLR) focusing on SSc-related large calcified masses. Upon updating the terminology and definition, all cases of “pseudotumoral” calcinosis seen at the Cochin and Padova University Hospitals were reviewed. Results The SLR yielded 30 SSc cases, with large calcified masses mainly defined as “tumoral” or “pseudotumoral”. Among the 629 SSc cases included in the Cochin and Padova cohorts, 19 (3%) living and 7 deceased patients were affected by pseudotumoral calcinosis; among these, the great majority had a severe vascular phenotype. The mean age in the whole population (56 cases) was 59 ± 11.4 years with a median disease duration at calcinosis onset of 7 (5–10) years. Twenty-five out of 56 patients (44.6%) had the diffuse cutaneous form of SSc. Anti-topisomerase I and anticentromere were found equally. Pseudotumoral calcinosis were commonly symmetrical and the size ranged from 2 to 15.5 cm. Most patients had multiple site involvement: 52% hand/wrist, 29% shoulders and elbows, 20% hips and 25% spinal calcinosis. Fistulization/ulceration and infections were reported in 32% and 23% of cases, respectively; nerve compression was found in 40% of spinal calcinosis and in one patient with limb calcinosis. There was no clear evidence of clinical and radiological improvement with any treatment. A partial improvement was seen in 7 patients that underwent surgery. Conclusion Pseudotumoral calcinosis may occur in about 3% of SSc patients, commonly symmetrical and in multiple sites without differences regarding the cutaneous subtypes but often in those with a severe vascular phenotype. Medical treatment seems ineffective, whereas a surgical approach may be considered.

ObjectivesTo decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA).MethodsRA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis.ResultsRA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis.ConclusionsThese results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.

Immunocompromised patients have an increased risk of a severe form of COVID-19. The clinical efficacy of the tixagevimab/cilgavimab monoclonal antibody combination as pre-exposure prophylaxis against BA.1 and BA.2 SARS-CoV-2 Omicron sublineages is unknown. We aimed to describe the incidence and outcomes of COVID-19 among immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis during the Omicron wave in France.This was an observational multicentre cohort study of immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis between December 28, 2021 and March 31, 2022. Patients received tixagevimab/cilgavimab 150/150 mg intramuscularly if they had impaired vaccine response and a high risk of severe form of COVID-19.Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median (range) follow-up of 63 (49-73) days, COVID-19 was confirmed in 49/1112 (4.4%) ≥5 days after treatment. During the study period, mean weekly incidence rate was 1669 in 100 000 inhabitants in Ile-de-France and 530 in 100 000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to-moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19.Our study reported a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients.

Polyarticular juvenile idiopathic arthritis (pJIA) is a subset of juvenile idiopathic arthritis (JIA), divided into two subtypes according to the presence of rheumatoid factor: pJIA without rheumatoid factor (pJIA RF-) and pJIA with positive rheumatoid factor (pJIA RF+), this latter is characterised with more structural damage. Anti-citrullinated peptide antibodies (ACPA) are often associated with RF. The respective performance of ACPA versus RF in structural outcome in pJIA, and in particular in adulthood pJIA remains unknown. Therefore, the aim of this study was to determine whether ACPA could be of value to assess structural damage in pJIA persisting in adulthood.Patients with pJIA and available data for ACPA, RF and X-ray were included retrospectively. Structural damage was assessed by two independent blinded investigators using Sharp Van Der Heijde scores.56 pJIA adult patients were included: 62% (35/56) had pJIA RF+ and 38% (21/56) pJIA RF-. ACPA positivity in pJIA was significantly associated with presence of RF (96% vs 26%, P0.001). RF positivity was significantly associated with higher Sharp van Der Heijde erosion and total scores (respectively P0.01 and P0.05). There were higher Sharp Van Der Heijde erosion, joint space narrowing and total scores in the pJIA ACPA+ subgroup than in the pJIA ACPA- subgroup, although there was no statistical significance. However, when adjusted on disease duration, pJIA ACPA+ patients had significantly higher erosion and total scores than pJIA ACPA- patients (P0.05), and pJIA ACPA+ patients required more bDMARDs than pJIA ACPA- patients (P0.05). Moreover, pJIA patients with high Sharp van Der Heijde joint space narrowing and total scores had significantly higher ACPA levels (P0.01). A correlation was identified between ACPA levels and Sharp van Der Heijde total score (r=0.54, P0.05). In the pJIA RF+ subgroup the presence of ACPA was associated with additional structural damage compared to no ACPA: sharp Van Der Heijde erosion, joint space narrowing and total scores were higher in the pJIA RF+ ACPA+ subgroup than in the pJIA RF+ ACPA- subgroup although these results did not reach significance.Our results suggest that pJIA RF+ ACPA+ adult patients may have a more severe articular phenotype than pJIA RF+ ACPA- patients. ACPA could bring an additional value to RF for pJIA patients regarding structural damage. Altogether our results show that RF and ACPA are associated with structural damage measured by Sharp Van Der Heijde score in pJIA persisting in adulthood.

Objectives Vascular disease in SSc is associated with significant morbidity and mortality. Preliminary data may lead to the suggestion of a modifiable unified-vascular endophenotype. Our aim was to determine whether the prevalence, mortality and severity of SSc-vascular disease have changed over time. Methods We performed a systematic review and meta-analysis of the literature in PubMed 1950–2019 related to SSc-digital ulcers (DUs), pulmonary artery hypertension (PAH) and scleroderma renal crisis (SRC). We included full-text articles and extracted study characteristics and assessed risk of bias/quality. We examined the prevalence, mortality and surrogate measures of SSc-associated vascular disease severity. Results We included 55 studies in our meta-analysis. The pooled prevalence of DUs (41.0%), PAH (9.5%) and SRC (4.9%) remained largely stable over time. There was significant improvement in PAH 1-year (P = 0.001) and SRC mortality (P Conclusion Despite the heterogeneity and scarcity of the disease, there have been major improvements obtained in the various vascular complications in SSc leading to benefit in survival. This is supported by a trend towards improvement in several surrogate markers and demonstrates that progress in vascular management translates into major patient benefit.