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As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4

Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD).In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine.From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% IC [30.4; 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines, and according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases.Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients.

Objectives Although dyslipidemia is a strong risk factor for thrombosis in antiphospholipid syndrome (APS), it has been poorly studied. This study aimed to assess lipids profile and risk factors for unachieved cholesterol levels in a real-life APS population. Methods Inclusion criteria were: APS diagnosis according to international classification criteria, referring to the out-patients clinic of our tertiary care center for their follow-up, and having a blood sample collection for lipids levels determination. Cholesterol level targets for each patient were defined according to 2019 ESC/EAS guidelines for the management of dyslipidemia. Results Between January 2020 and April 2021, 114 APS patients were included (male 37 (32.5%); mean age 49 ± 14 years). Among them, 40 (35.1%) had a history of dyslipidemia, 48 (42.1%) were under lipid-lowering therapies, and 59 (51.8%) had a history of cardiovascular disease (CVD). Mean levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride were, respectively, 110 ± 40 mg/dL, 60±20 mg/dL, and 120 (80–190) mg/dL. Unachieved LDL-C levels were found in 77 (67.5%) patients of whom 53 had history of CVD. Overall, 90 (78.9%) had protective HDL-C and 31 (27.2%) had hypertriglyceridemia. In the multivariate analysis, independent risk factors for unachieved LDL-C levels were older age and history of CVD; triple aPL negativity, defined as complete disappearance of aPL over time in APS patients who were previously positive in accordance to international criteria, was an independent protective factor for unachieved LDL-C. Conclusion Our finding suggested that dyslipidemia is frequent in APS patients and mainly insufficiently treated, especially in patients with history of CVD, who are at highest risk of future CV events.

Objectives To describe the effectiveness and safety of biologics for the treatment of relapsing and/or refractory polyarteritis nodosa (PAN). Methods A retrospective European collaborative study was conducted in patients with PAN who received biologics for relapsing and/or refractory disease. Results Forty-two patients with PAN received a total of 53 biologic courses, including TNF-α blockers in 15 cases, rituximab (RTX) in 18 cases, tocilizumab (TCZ) in 10 cases and other biologics in 10 cases. TNF-α blockers and TCZ were mainly used for refractory diseases whereas RTX was mainly initiated for relapsing disease. After a median follow-up of 29 (8–50) months, remission, partial response, treatment failure and treatment discontinuation due to severe adverse events occurred in, respectively, 40%, 13%, 40% and 7% of patients receiving TNF-α blockers, 50%, none, 30% and 20% of TCZ recipients, and 33%, 11%, 56% and none of the RTX recipients. No remission was noted in patients treated with other biologics. Severe adverse events were observed in 14 (28%) patients without significant differences between the three biologics, leading to early biologics discontinuation in only three cases. Conclusion These results suggest that TCZ may be effective in relapsing and/or refractory PAN. Our data warrant further study to confirm these findings.

Objectives Immunoglobulin A vasculitis (IgAV) is a small-vessel vasculitis most frequently benign in children while more severe in adults. We aimed to study the impact of age on presentation and outcome of adult IgAV. Methods We conducted a nationwide retrospective study including 260 IgAV patients. Patients were divided into four quartiles according to the age at IgAV diagnosis: Results Mean age at diagnosis was 50.1 (18) years and 63% were male. IgAV diagnosed in the lowest quartile of age was associated with more frequent joint (P 6 months, clinical response and relapse rates were similar between the four groups. Median follow-up was of 17.2 months (9.1–38.3 months). Renal failure at the end of follow-up was significantly more frequent in the highest quartile of age (P = 0.02), but the occurrence of end-stage renal disease was similar in all groups. Last, overall and IgAV-related deaths were associated with increase in age. Conclusion Aging negatively impacts the severity and outcome of IgAV in adults. Younger patients have more frequent joint and gastrointestinal involvement, while old patients display more frequent severe purpura and glomerulonephritis.

Introduction We aimed to evaluate the impact of an immersive simulation session on the experience of the beginning of residency. Methods The interventional group consisted of newly recruited residents in 2019, who participated in the workshop presenting four emergency scenarios frequently encountered during night shifts; the control group comprised residents who had begun their internship in 2018, without having participated in the simulation workshop. The level of psychological stress and self-confidence were self-estimated in the simulation group before and immediately after the workshop. During the second semester of residency, stress, self-efficacy and anxiety were evaluated in both groups with the Perceived Stress Scale (PSS), General Self-efficacy Scale (GSES), and Generalized Anxiety Disorder-7 (GAD-7) scale. Results In the second semester 2020, the PSS, GSES and GAD-7 were 20.71 ± 8.15 and 22.44 ± 5.68 (P = 0.40); 26.88 ± 6.30 and 27.11 ± 3.95 (P = 0.87); 6.94 ± 5.25 and 8.89 ± 4.78 (P = 0.22) for the simulation (n = 17, 89.5% of participation) and control (n = 9, 75%) groups, respectively. In the simulation group, the level of self-confidence had significantly improved from 1.82 ± 0.95 before the session to 2.29 ± 1.16 after the session (P = 0.05). Interestingly, this improvement in self-confidence was significantly correlated with GAD-7 (P = 0.014) and PSS (P = 0.05), and tended to be correlated with GSES (P = 0.09). Conclusion Our study showed a significant improvement in self-confidence between before and after the simulation session. Residents who experienced an improvement in self-confidence saw their stress and anxiety levels decrease during the second semester reevaluation, in favor of a prolonged benefit from the session.

Optimal management of systemic lupus erythematosus (SLE)‐associated pulmonary arterial hypertension (PAH) remains unclear. Our observation describes the case of a 31‐year‐old SLE patient presenting with cardiogenic shock revealing severe PAH, in which a therapeutic scheme combining immunosuppressants (pulse cyclophosphamide and corticosteroids) and PAH‐specific drugs (bosentan, tadalafil, and epoprostenol) led to a complete normalization of pulmonary haemodynamics and allowed a progressive weaning of PAH vasodilators. This case report supports the efficacy of immunosuppressants and use of PAH‐specific therapy as a bridge therapy in severe SLE‐PAH. Further studies on larger population are required to confirm these findings.

Background: Systemic sclerosis (SSc) is a fibrotic disease. Assessment of body image could be central in optimizing care. Yet, data are scarce. The main objective was to assess perception of aesthetic impairment using a visual aesthetic scale (AES) in patients with SSc compared to healthy subjects. Secondary objectives were to assess associations between perception of aesthetic impairment and standardized questionnaires for aesthetic impairment as well as clinical, psychological/quality of life, and functional parameters of SSc. Methods: This study evaluated and compared perception of aesthetic impairment in two populations: patients with SSc, in a referral center at Lille Hospital, France, and healthy controls. Results: This study included 88 patients (69 [78.4%] women) with a median age of 52 years and 88 controls (49 [55.7%] women) with a median age of 45 years. Perception of aesthetic impairment assessed using the AES was poorer in patients than in controls (3.7 ± 0.3 vs 2.8 ± 0.3, p=0.028), with statistical correlation with ASWAP. Patients with anxiety or depressive symptoms had significantly higher AES scores. Conclusion: The AES appears to be an ease of use tool to evaluate body image. Correlations found with psychological and quality of life parameters reflect the importance of these parameters for body image evaluation and its complex assessment.Trials registration: NCT03271320

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort. Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK). Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity). This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc., Early screening for pulmonary arterial hypertension in patients with systemic sclerosis improves patient outcome. This study identified a novel eight-protein biomarker panel that has the potential to assist early detection of PAH in this patient group. https://bit.ly/373BNkL

Objective: Systemic sclerosis mainly affects the microvascular network. However, macrovascular manifestations have been reported. We aimed to investigate the characteristics of systemic sclerosis patients with an amputation of a lower limb segment. Methods: We designed a retrospective, case–control, multicentric study on systemic sclerosis patients with amputation of a lower limb segment secondary to critical ischemia via the French Research Group on Systemic Sclerosis. For each case, a control (systemic sclerosis patient without lower limb symptom) was matched with sex, age (±5 years), and cutaneous subset of systemic sclerosis. Results: In total, 26 systemic sclerosis patients (mean age of 67.2 ± 10.9 years, 20 females, 21 limited cutaneous forms) with a lower limb amputation and 26 matched controls (mean age of 67.3 ± 11.2 years, 20 females, 22 limited cutaneous forms) were included. At the time of amputation, the mean disease duration was 12.8 (±8.6) years. In comparison to controls, systemic sclerosis patients with amputation had more digital ulcers (p = 0.048), history of digital ulcers (p = 0.026), and a higher prevalence of pulmonary arterial hypertension (p = 0.024). Systemic sclerosis patients with amputation were more often smokers (p = 0.008) and under corticosteroids (p = 0.015). In the multivariate model, pulmonary arterial hypertension, smoking status, and corticosteroids were independent markers associated with lower limb amputation in systemic sclerosis. In the follow-up, 10 patients (38.5%) had recurrent ischemia requiring a new limb amputation, and five patients (19.2%) had an amputation of the contralateral limb. Conclusion: This study identifies some markers associated with lower limb amputation in systemic sclerosis such as digital ulcers and pulmonary arterial hypertension and points out the high risk associated with tobacco consumption and corticosteroid use.

We report herein the case of a patient with low blood levels of different hormones during a systemic capillary leak syndrome (Clarkson’s disease) attack.

Resume L’hypertension pulmonaire (HTP) est une complication rare des connectivites, notamment de la sclerodermie systemique, du lupus erythemateux systemique et de la connectivite mixte. Elle se definit par une elevation de la pression arterielle pulmonaire moyenne ≥ 25 mmHg documentee par un catheterisme cardiaque droit. Du fait de leur nature systemique, les connectivites peuvent induire une HTP par differents mecanismes, parfois intriques : remodelage des petites arteres pulmonaires (groupe 1 de la classification de l’HTP) ou des petites veines (groupe 1′), cardiopathie gauche (groupe 2), maladie respiratoire chronique (groupe 3) ou maladie thromboembolique chronique (groupe 4). L’existence d’une HTP peut etre suspectee par l’echographie cardiaque (qui peut montrer une elevation de la vitesse de la fuite tricuspide et/ou une dilatation des cavites droites), et par une baisse isolee de la DLCO lors des epreuves fonctionnelles respiratoires, une elevation du NT-pro-BNP ou l’apparition de signes droits a l’electrocardiogramme. Son diagnostic necessite toujours une confirmation hemodynamique par catheterisme cardiaque droit. La prise en charge therapeutique de l’HTP depend du(es) mecanisme(s) en cause : traitement vasodilatateur en cas d’HTP de groupe 1 (avec discussion d’une immunosuppression en cas de lupus ou de connectivite mixte) ; traitement de la cardiopathie gauche en cas d’HTP de groupe 2 ; traitement de la maladie respiratoire chronique en cas d’HTP du groupe 3 ; anticoagulation, traitement vasodilatateur, endarteriectomie et angioplastie pulmonaire en cas d’HTP du groupe 4. Un suivi regulier est indispensable.

Introduction Les angioedemes bradykiniques (AEB) sous antagonistes des recepteurs de l’angiotensine II (ARAII) sont rares et peuvent mimer les angioedemes histaminiques (AEHi) qui sont plus frequents ce qui mene alors a tort a l’arret du medicament. L’objectif de cette etude etait alors d’evaluer les caracteristiques cliniques, therapeutiques et d’evolution d’une cohorte de patients suspects d’AEB secondaires aux ARAII. Materiel et methodes Cette etude multicentrique nationale, observationnelle et retrospective a inclus les cas consecutifs d’angioedemes acquis apparus chez des patients sous ARAII et suivi dans un centre de Reference associe sur les angioedemes a kinines (CReAk). Discussion Cinquante-cinq patients adresses dans les services specialises pour AE sous ARAII ont ete inclus. Le diagnostic final etait un AEB dans 30 (55 %) cas et un AEHi dans 25 (45 %) cas a la fin du suivi. Les caracteristiques cliniques des AE n’etaient pas significativement differentes dans les deux groupes. Le concentre de C1 inhibiteur etait significativement plus utilise dans le groupe AEB que AEHi, soit respectivement 30 % et 4% (p

Methods: Data on clinical characteristics, histologic features, and treatment response from 260 patients with IgAV included in a French multicenter retrospective survey were analyzed. Efficacy data were compared using different statistical models. Results: The mean ± SD age of the patients with IgAV at diagnosis was 50.1 ± 18 years, and 63% of patients were male. Baseline manifestations included purpura (100%), arthralgias/arthritis/myalgia (61%), glomerulonephritis (70%), and/or gastrointestinal involvement (53%). Thirty percent of patients showed renal failure at baseline. In univariate analysis, the response to therapy was 80% (64 of 80) in patients treated with corticosteroids (CS) alone, compared to 77% (23 of 30) in patients treated with CS plus cyclophosphamide (CYC) and 59% (10 of 17) in patients treated with colchicine (P = 0.17). Multivariable analysis showed that treatment with CS or CS plus CYC was more effective than colchicine in achieving a response. Efficacy differences were demonstrated using different statistical models: in the multivariable logistic regression model, odds ratio (OR) 3.68, 95% confidence interval (95% CI) 1.10–12.33 (P = 0.03); in the inverse probability weighting on propensity score model, OR 3.75, 95% CI 1.28–10.99 (P = 0.02). The efficacy of CS plus CYC as compared to CS alone was discordant according to the analytic method used. Analysis with the multivariable logistic regression model did not demonstrate a difference between CS plus CYC and CS alone (OR 0.88, 95% CI 0.29–2.67; P = 0.82). In contrast, inverse probability weighting on propensity score showed that CS plus CYC was more effective than CS alone (OR 1.79, 95% CI 1.00–3.20; P = 0.049). Conclusion: This series constitutes the largest series of adults with IgAV reported in the literature so far. It provides data on clinical and histologic presentation and therapeutic efficacy, suggesting that CS alone appears to be a reasonable first‐line therapy in patients with IgAV, while the benefit of adding CYC to CS remains uncertain.

Resume Introduction Aucune donnee n’est disponible concernant la tolerance du bevacizumab, anticorps anti- vascular endothelial growth factor-A (VEGF-A), chez le patient atteint d’hypertension arterielle pulmonaire (HTAP), pathologie dans laquelle le VEGF-A joue un role central et probablement protecteur. Observation Nous rapportons l’observation d’une patiente presentant une HTAP associee a une sclerodermie systemique, stable sous bosentan. La decouverte d’un carcinome epidermoide du col uterin metastatique a conduit a l’administration de deux lignes successives de chimiotherapie cytotoxique. Leur echec a motive l’initiation d’un traitement anti-angiogenique : trois injections de bevacizumab 15 mg/kg ont ainsi ete administrees. Tout au long du traitement, aucune modification clinique ni echographique de l’HTAP n’a ete constatee. Conclusion Cette observation suggere que, sous surveillance clinique et echographique rapprochee, le bevacizumab peut etre bien tolere en cas d’HTAP stable et moderee. La decision de traitement doit etre prise de maniere individuelle et adaptee au rapport benefice–risque, le risque d’aggravation de l’HTAP n’etant pas exclu.

International audience; BACKGROUND:As intravenous immunoglobulins (IVIG) exhibit immunomodulatory and antifibrotic properties, they may be a relevant treatment for systemic sclerosis (SSc). The objectives of this work were thus to report on the efficacy and safety of IVIG in a population of SSc patients and to review the available literature.METHODS:46 patients from 19 French centers were retrospectively recruited. They were included if they had a diagnosis of SSc and received at least 1 IVIG infusion at a dosage >1g/kg/cycle. Relevant data collected at IVIG discontinuation were compared to those collected at IVIG initiation. A comprehensive literature review was performed.RESULTS:We observed a significant improvement of muscle pain (74% vs. 20%, p

Introduction L’objectif de ce travail est d’etudier les alterations du proteome serique des patients atteints d’hypertension arterielle pulmonaire (HTAP) associee a la clerodermie systemique (SSc), d’identifier les proteines correlees a la severite hemodynamique et determiner leur role potentiel dans la physiopathologie de la maladie. Patients et methodes Les patients eligibles ont ete recrutes dans les centres de reference SSc et/ou HTAP de Boston, Lille, Le Kremlin-Bicetre et Grenoble. Les patients etaient inclus s’ils remplissaient les criteres suivants : diagnostic de SSc selon les criteres ACR/EULAR 2013, forme cutanee limitee, pas de pneumopathie interstitielle diffuse (PID) etendue selon les criteres de Goh, et pas de traitement specifique de l’HTAP. Les patients etaient consideres comme des cas s’ils avaient un diagnostic d’HTAP confirme par catheterisme cardiaque droit (KTD) et un echantillon de serum preleve le meme jour que le KTD. Ils etaient consideres comme des temoins s’ils n’avaient aucun signe evocateur d’HTAP a l’echocardiographie. Resultats Dans une premiere etape exploratoire, l’expression serique de 1129 proteines a ete evaluee chez 15 cas et 16 temoins par analyse proteomique a haut debit (SOMAscan). Nous avons identifie 53 proteines exprimees differentiellement entre les 2 groupes. Parmi ces 53 candidats, seules 2 etaient significativement correlees avec les resistances vasculaires pulmonaires (RVP) : chemerine (p = 0,01, ρ = 0,62) et SET nuclear proto-oncogen (SET) (p = 0,01, ρ = 0,62). Pour valider ces resultats, les taux seriques de chemerine et SET ont ete mesures en ELISA chez 25 cas et 19 controles supplementaires. Les dosages de chemerine etaient de nouveau significativement plus eleves chez les cas (p = 0,01) et correles avec les RVP (p = 0,01, ρ=0,46) dans cette cohorte independante. Dans une deuxieme etape, pour etudier le role physiopathologique potentiel de la chemerine, nous avons realise des marquages en immunofluorescence confocale sur des poumons explantes de temoins sains, de patients SSc-PID sans HTAP et de patients SSc-HTAP. Le marquage du recepteur de chemerine, CMKLR1, etaient significativement augmente sur les cellules musculaires lisses d’artere pulmonaire (CML-AP) de patients SSc-PID et de patients SSc-HTAP. Nous avons ensuite teste l’effet de la chemerine sur la proliferation des CML-AP en stimulant les CML-AP de patients presentant une HTAP idiopathique (HTAPi) avec du serum de patients SSc avec et sans HTAP, en presence ou en l’absence d’un inhibiteur de CMKLR1. On confirmait que les CML-AP d’ HTAPi surexprimaient l’ARNm de CMKLR1 par rapport aux temoins sains (p = 0,03). Le serum des patients SSc-HTAP induisait une proliferation de CML-AP significativement plus elevee (p = 0,005) que le serum des temoins. Cette difference n’etait plus significative (p = 0,69) lors de l’ajout de l’inhibiteur CMKLR1 a-NETA. Conclusion La chemerine semble etre un biomarqueur de substitution valide des RVP dans l’HTAP-SSc. L’elevation de la chemerine circulante et la surexpression de son recepteur, CMKLR1, contribuent a la physiopathologie de l’HTAP-SSc en induisant la proliferation des CML-AP.

Introduction L’internat, et en particulier son debut, associe aux premieres gardes, est une periode source de stress et d’anxiete importante. La simulation en sante est un outil pedagogique reconnu comme efficace pour l’amelioration des competences techniques mais egalement non techniques dans de nombreux domaines. Cependant, elle est encore peu utilisee dans le co- Diplome d’Etudes Specialisees (DES) de Medecine Interne Immunologie Clinique, Maladies Infectieuses et Tropicales, et Allergologie (MIIC-MIT-A). Son utilisation a par ailleurs montre un benefice sur le stress, l’anxiete et le sentiment d’auto-efficacite chez les etudiants infirmiers. L’objectif de cette etude etait d’evaluer le benefice d’une seance de simulation immersive sur le vecu des premieres gardes des internes du co-DES de MIIC-MIT-A. Materiels et methodes Nous avons realise une etude prospective, controlee, multicentrique, dans laquelle deux groupes d’internes ont ete constitues. Le groupe simulation comprenait les internes qui ont beneficie de la seance de simulation immersive pour la preparation aux premieres gardes lors du premier semestre d’internat, comportant 4 scenarios mettant en jeu des situations critiques (choc hypovolemique sur hemorragie digestive, detresse respiratoire aigue avec arret cardiorespiratoire, choc septique sur pyelonephrite obstructive, choc anaphylactique). Il etait constitue des internes des DES de MIIC-MIT-A de Montpellier, Bordeaux et Nice, qui ont passe les Epreuves Classantes Nationales Informatisees (ECNi) en 2019. Le groupe controle, qui n’a pas beneficie des seances de simulation, etait constitue des internes du meme co-DES de Montpellier et Nice, qui ont passe les ECNi en 2018. L’objectif principal etait d’explorer l’impact de la seance de simulation immersive realisee au premier semestre d’internat, sur le stress, l’anxiete, et le sentiment d’auto efficacite lors des premieres gardes, evalues au second semestre. Les objectifs secondaires etaient la comparaison du stress et de la confiance en soi auto estimes entre le debut et la fin de la seance, et leur association avec le stress, l’anxiete, et l’auto-efficacite au second semestre. Le niveau de stress et de confiance en soi etaient evalues par autoquestionnaire anonymise en debut et fin de seance (echelles de Likert de 0 a 5). Au cours du second semestre, les niveaux de stress, d’anxiete et de sentiment d’auto-efficacite ont ete evalues dans les deux groupes d’internes, a l’aide d’echelles validees : Perceived Stress Scale (PSS), Generalized Anxiety Disorder -7 (GAD-7) scale et General Self-efficacy Scale (GSES). Nous avons enfin evalue la satisfaction des apprenants et leur avis concernant la pertinence de cet outil dans leur formation dans le cadre du co-DES de MIIC-MIT-A. Resultats Les groupes simulation et controle comprenaient respectivement 19 et 9 internes. Au second semestre, les scores PSS, GSES et GAD-7 etaient de 20.71 ± 8,15 et 22,44 ± 5,68 (p = 0,40) ; 26,88 ± 6,30 et 27,11 ± 3,95 (p = 0,87) ; 6,94 ± 5,25 et 8,89 ± 4,78 (p = 0,22) dans les groupes simulation et controle, respectivement. A noter qu’en utilisant le seuil de 8 pour le GAD-7, a partir duquel on considere que l’interroge est anxieux, on retrouve 35,3 % d’internes anxieux dans le groupe simulation contre 55,6 % dans le groupe controle (p = 0,32). Dans le groupe simulation, le niveau de confiance en soi s’est significativement ameliore apres la seance (1,82/5 avant versus 2,29/5 apres, p = 0,05). De maniere interessante, cette amelioration de la confiance en soi est significativement correlee au niveau d’anxiete (GAD-7 ; p = 0,014) et de stress (PSS ; p = 0,05) au second semestre, et tendait a l’etre avec le GSES (p = 0,09). Le niveau de satisfaction des internes concernant la seance etait excellent, ainsi que leur volonte d’integration de la simulation dans le co-DES (4,8/5 ± 0,5). Conclusion Notre etude a mis en evidence une amelioration significative de la confiance en soi entre avant et apres la seance de simulation. Les internes qui tirent un benefice immediat de la seance de simulation, avec une amelioration de leur confiance en eux, voient leur niveau de stress et d’anxiete diminuer a moyen terme au second semestre. A notre connaissance, il s’agit de la premiere etude controlee montrant l’interet de la simulation immersive sur le vecu du debut d’internat et des premieres gardes en MIIC-MIT-A. La simulation semble etre une methode d’interet pour l’amelioration des competences et du vecu des internes dans le co-DES de MIIC-MIT-A.

Objectives To describe the clinical presentation, treatments and prognosis of gastrointestinal (GI) involvement in adult IgA vasculitis (IgAV). Methods Data from 260 adults with IgAV included in a French multicentre retrospective survey were analysed. Presentation and outcomes of patients with (GI+) and without (GI-) GI involvement were compared. Results One hundred and thirty-seven (53%) patients had GI involvement. Initial manifestations were abdominal pain in 99%, intestinal bleeding in 31%, diarrhoea in 26% and acute surgical abdomen in only 4%. Abdominal imaging revealed thickening of intestinal wall in 61%, and endoscopies revealed abnormalities in 87%, mostly mucosal ulcerations. GI+ vs GI- patients were younger (46 ± 18 vs 54 ± 18 years; P = 0.0004), had more constitutional symptoms (43% vs 23%; P = 0.0005) and joint involvement (72 vs 50%; P = 0.0002), and higher CRP levels (3.7 vs 1.9 mg/dl; P = 0.001). Clinical response and relapse rates were comparable between groups, and all causes mortality (2 vs 4%) and IgAV-related mortality (1% vs 2%) as well. GI-related deaths were due to intestinal perforation and mesenteric ischaemia. Conclusion GI involvement is frequent in adult IgAV. GI involvement is frequent in adult IgAV. Mortality is not uncommon but does not seem to be specifically related to GI. Immunosuppressants should not be preferred as first-line therapy for GI+ patients but may be required in case of acute surgical abdomen.

Background: Polyarteritis nodosa (PAN) is a rare systemic necrotizing vasculitis of medium- and small-sized arteries, not associated with antineutrophil cytoplasmic antibodies (ANCA). Conventional treatments include glucocorticoids (GCs) for non-severe disease and a combination of GCs and immunosuppressive agents for severe disease. Nevertheless, some patients have refractory and/or relapsing disease. Objectives: We examined the use of off-label biological therapy for relapsing/refractory PAN. Methods: This retrospective European collaborative study included patients with PAN meeting ACR criteria and/or Chapel Hill Consensus Conference 2012 definitions. Treatment efficacy and safety are recorded. Remission was defined as the absence of vasculitis manifestations (BVAS = 0) with a prednisone dose ≤5 mg/day. Partial response was defined as a BVAS = 0 with a prednisone dose between 6 and 10 mg/day. Results: Fifty-one patients (24 men, 27 women; median age 51 years) were included. Eighteen (35%) patients received TNF-alpha blockers, 16 (31%) received rituximab (RTX), 9 (18%) tocilizumab (TCZ), and 8 (16%) other biologics (including alemtuzumab in 3, anakinra in 2, interferon-alpha in 2 and abatacept in one). Previous treatments were: GCs in all cases, including methylprednisolone infusions (72%) and oral GCs (92%), cyclophosphamide (61%), azathioprine (53%), methotrexate (45%) and mycophenolate mofetil (47%). At inclusion, median BVAS was 5 (range 0-18), including 5 (2-12) in the TNF-alpha blockers group, 5 (2-12) in the RTX group and 4 (0-6) in the TCZ group. After median follow-up of 34.4 months (IQR 21.5-59.5), remissions, partial responses and treatment failure, respectively, were noted in 41%, 6% and 53% for TNF-alpha blockers recipients, 25%, 12% and 63% for RTX recipients, and 57%, 0% and 43% for TCZ recipients. No remission was noted in patients treated with anakinra, alemtuzumab and abatacept. Median BVAS dropped to 3 at 6 months, 0 at 12 months and 0 at last follow-up in the TNF-alpha blockers group, to 3.5, 0 and 2 in the RTX group, respectively, and 0, 0 and 0 in the TCZ group. A GC-sparing effect seemed more important with TNF-alpha blockers and TCZ. Median GCs dose decreased from the baseline 15 mg/day to 10 at 6 months, 5 at 12 months and 5 at last follow-up in the TNF-alpha blockers group, from 15 mg/day to 10 at 6 months, 5 at 12 months and 10 at last follow-up in the RTX group, and from 15 mg/day to 7 at 6 months, 5 at 12 months and 5 at last follow-up in the TCZ group. Four (22%) patients stopped TNF-alpha blockers because of allergic reaction in one and refractory disease in 3. Six (38%) stopped RTX because of refractory disease. Finally, 4 (44%) stopped TCZ because of adverse events in 2 (testicular abscess and worsening renal failure) and refractory disease in 2. Conclusion: The results of this study suggest that TNF-alpha blockers and TCZ may achieve higher rates of remission and GC-sparing in relapsing and/or refractory PAN than other biologics. Our data warrant further study to confirm or not these findings. Disclosure of Interests: Alice Canzian: None declared, Omer Karadag: None declared, Anne Contis: None declared, Francois Maurier: None declared, Silvia Sartorelli: None declared, Laure Denis: None declared, Sebastien Sanges: None declared, Claire De Moreuil: None declared, Cecile-Audrey Durel: None declared, Stephane Durupt: None declared, Marie Jachiet: None declared, Diane Rouzaud: None declared, Carlo Salvarani: None declared, Franco Schiavon: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Fabrice Bonnet: None declared, David Jayne Grant/research support from: David Jayne has received research grants from Chemocentryx, GSK, Roche/Genentech and Sanofi-Genzyme. He has received consultancy fees from Astra-Zeneca, Boehringer-Ingelheim, Chemocentryx, Chugai, GSK, Infla-RX, Insmed and Takeda, Loic Guillevin: None declared, Benjamin Terrier: None declared

Background Myositis is recognized as a manifestation of primary Sjogren’s syndrome (pSS). Grading muscle involvement using the EULAR Sjogren Syndrome Disease Activity index (ESSDAI) does not require biopsy-proven active myositis or extensive immunological investigations. However, several studies have reported that a high proportion of pSS-associated myositis is either inclusion body myositis (IBM) or an overlap with idiopathic inflammatory myopathies. Objectives The objective of our study was to investigate the nature of inflammatory muscle involvement in a large sample of patients with pSS and concurrent myositis. Methods We conducted a French nation-wide survey among reference centers known for their experience in the field of systemic auto-immune diseases. Patients with physician-based diagnosis of pSS and inflammatory muscle involvement were included. They were categorized and subsequently described and compared according to the identification of an associated condition likely to explain inflammatory muscle involvement. Results 60 cases of myositis in patients with pSS were identified. Patients were mostly female (52/60) and pSS classification criteria were met in 43/60. Muscle biopsy was performed in 50/60 patients and showed inflammatory lesions in 80% of cases. An associated condition likely to explain myositis was identified in 31 patients: typical dermatomyositis rash (n=8), MCTD-specific antibodies (n=11), myositis specific antibodies (n=10), and systemic lupus erythematosus, scleroderma or ANCA associated vasculitis specific antibodies in favor of an overlap syndrome (n=7). Among the 29 patients without associated condition likely to explain myositis, 17 had a biopsy proven inflammatory muscle disease, showing histopathologic features consistent with IBM in 5 cases. 4 of the 5 patients with IBM histological features received corticosteroids and/or other immunosuppressive agents to treat muscle disease. Worsening of muscular involvement despite treatment was reported in these 4 patients. Comparative analysis showed a lower ESSDAI (p = 0.001) among patients without identified associated condition likely to explain myositis. Conclusion In most cases of concurrent pSS and myositis, inflammatory muscle involvement is explained by a context of overlap syndrome or has a histological pattern consistent with IBM. Extensive immunological investigations and muscle biopsy appear to be necessary in pSS patients with suspected inflammatory muscle involvement, in order to avoid misclassification and/or overtreatment. Disclosure of Interests Camille Houssais: None declared, Jean-baptiste Noury: None declared, Yves Allenbach: None declared, Laure Gallay: None declared, Florence Assan: None declared, Olivier Benveniste: None declared, Jonathan Broner: None declared, Pierre Duffau: None declared, Alexandra Espitia-Thibault: None declared, Anne Grasland: None declared, Sebastien SANGES: None declared, Gilles Hayem: None declared, Veronique LE GUERN: None declared, Nihal Martis: None declared, Kuberaka Marianpillai: None declared, Denis Mulleman Speakers bureau: Pfizer, Novartis, Grifols, Gaetane Nocturne: None declared, alain meyer: None declared, Valerie Devauchelle-Pensec Grant/research support from: Roche-Chugai, Speakers bureau: MSD, BMS, UCB, Roche, Divi Cornec: None declared, Dewi Guellec: None declared

Introduction Les services de Medecine Interne menent une importante activite de recours expert et de recherche, grevee par plusieurs obstacles. L’activite d’avis specialises est chronophage, non valorisee, et limitee par l’impossibilite d’echanger simplement les elements du dossier medical. L’activite de recherche clinique est limitee par la frequence des visites protocolaires. L’objectif de ce travail est de determiner si la telemedecine (TLM) peut contribuer a resoudre ces difficultes. Patients et methodes Concernant l’activite de recours, nous avons demande aux medecins de declarer les avis donnes a l’aide d’un formulaire standardise, afin de determiner s’ils validaient les criteres de teleconsultation (TLC) ou de tele-expertise (TLE). Concernant l’activite de recherche, nous avons remis aux investigateurs et a 50 patients un questionnaire sur l’acceptabilite de TLC protocolaires. Resultats Concernant l’activite de recours, on denombrait 120 avis (soit 21 h) hebdomadaires, dont 29 % aux patients et 69 % a des medecins. Soixante et un pour cent des avis aux patients validaient les criteres de TLC ; 18 % des avis aux medecins ceux de TLE. Concernant l’activite de recherche, 70 % des investigateurs consideraient la frequence des visites comme limitant les inclusions ; pres de la moitie des patients serait favorable au recours a des TLC a la place (40 %) ou en plus (56 %) des visites presentielles. En termes de facturation, la TLM represente un revenu potentiel de 300 € hebdomadaires pour le TLE et 616€ hebdomadaires pour le TLC. Conclusion Si le recours a la TLM comme procedure degradee au presentiel s’est democratise avec la pandemie, les solutions qu’elle apporte aux difficultes rencontrees dans les activites d’avis et de recherche peuvent contribuer a integrer pleinement son usage dans le suivi standard des patients. Si tel etait le cas, on pourrait tout a fait imaginer avec ce budget (47 632 €/an) pouvoir financer un praticien hospitalier supplementaire a temps partiel.

Resume Introduction L’angiœdeme hereditaire (AOH) est caracterise par des poussees recidivantes d’œdemes de localisations et de severite variables. Une alteration de la qualite de vie des patients atteints d’AOH est decrite par plusieurs etudes. Nous avons etudie l’impact global de la maladie chez les patients suivis pour un AOH de type I, notamment son retentissement sur les activites de la vie quotidienne, la sphere emotionnelle et la qualite de vie. Methodes Un questionnaire a ete distribue aux patients consultant pour un AOH de type I, recueillant les caracteristiques demographiques, les caracteristiques de la maladie, le retentissement sur la vie professionnelle, le score Hospital Anxiety And Depression (HAD), le score SF-36 et le questionnaire de handicap prioritaire McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR). Resultats Les 33 patients inclus rapportaient en moyenne de 5,17 crises sur l’annee precedente. Le stress etait le principal facteur declenchant. Un traitement de fond etait rapporte par 58 % des patients, 72 % recevaient un traitement specifique en cas de crise severe. Un absenteisme pendant leurs etudes etait rapporte 33 % des patients, et pendant leur travail par 34 %. Un patient souffrait de symptomes depressifs et dix autres de symptomes anxieux d’apres le questionnaire HAD. Les domaines les plus impactes sur le score SF-36 etaient la perception generale de la sante et de la vitalite. Le score moyen pour le MACTAR etait faible. Conclusion L’AOH a un retentissement encore important dans la vie quotidienne et affective des patients, malgre la disponibilite de traitements preventifs et curatifs des crises.

Background:Systemic sclerosis (SSc) is a fibrotic autoimmune disease characterized by dermatological involvement. Skin involvement can alter appearance, which can have a psychological impact(1). Assessment of body image could be central in optimizing care. Yet, data are scarce(2).Objectives:The main objective of our study was to assess aesthetic impairment measured on a visual aesthetic scale (AES) (3) in patients with SSc compared to a group of healthy subjects. Secondary objectives were to assess associations between aesthetic impairment and standardized questionnaires for aesthetic impairment as well as clinical, biological, psychological/quality of life, and functional parameters of SSc.Methods:The “Sclero-esthet” study is a descriptive single-center study of two populations: patients with SSc, included in a referral center for systemic and autoimmune diseases at Lille Hospital, France, and healthy controls.Results:This study, from January 2017 to October 2017, included 88 patients (69 [78.4%] women) with a median age of 52 years (range: 43 to 59) and 88 controls (49 [55.7%] women) with a median age of 45 years (range: 32 to 55). Perception of physical changes assessed using the AES was greater in cases than in controls (3.7 ± 0.3 vs 2.8 ± 0.3, p=0.028), with statistical correlation with ASWAP. SSc patients with anxiety or depressive symptoms had significantly higher AES scores. Cases presented poorer quality of life than controls.Conclusion:The AES appears to be a good tool to evaluate aesthetic impairment. Correlations found with psychological and quality of life parameters support the need to improve patient management in this field.References:[1]Cash TF. Body image: past, present, and future. Body Image 2004;1(1):1–5.[2]Benrud-Larson LM, Heinberg LJ, Boling C, Reed J, White B, Wigley FM. Body image dissatisfaction among women with scleroderma: extent and relationship to psychosocial function. Health Psychol mars. 2003;22(2):130–9.[3]Nguyen C, Ranque B, Baubet T, Bérezné A, Mestre-Stanislas C, Rannou F, et al. Clinical, Functional and Health-Related Quality of Life Correlates of Clinically Significant Symptoms of Anxiety and Depression in Patients with Systemic Sclerosis: A Cross-Sectional Survey. PLoS ONE 2014;9(2).[4]Heinberg LJ, Kudel I, White B, Kwan A, Medley K, Wigley F. Assessing body image in patients with systemic sclerosis (scleroderma): Validation of the Adapted Satisfaction with Appearance Scale. Body Image 2007;4(1):79–86.Disclosure of Interests:None declared

Background:Systemic autoimmune diseases are mostly taught through theoretical lectures, which do not allow for the acquisition of physical examination skills and semiologic confrontation.Objectives:We report herein the results of a pilot experiment using role-play to teach how to manage patients with Raynaud phenomenon (RP).Methods:We developed a workshop that consisted of two 30-minute OSCE (Objective and Structured Clinical Examination) stations. Students were divided into groups of 4 to 5 persons. On each station, 2 students were actors and 2 were observers. After a short briefing, students played a 15-minute scenario and then had a 15-minute debriefing.The first station simulated the case of a 26-year old woman referred for suspected RP. Students were instructed to perform clinical history taking and physical examination of the patient, formulated relevant diagnosis hypotheses and prescribe any additional necessary exams. Students had to suspect the diagnosis of idiopathic RP. The simulated patient was played by a trained facilitator with expertise on RP.The second station simulated the case of a 56-year-old woman referred for RP complicated by digital ulcers. Students received the same instructions as before. They had to suspect the diagnosis of systemic sclerosis. The patient role was held by a real patient with systemic sclerosis, followed by the physician who was supervising the station, who had received prior training and who agreed to participate in this training.At the end of the workshop, the students had to complete a satisfaction questionnaire.Results:A total of 21 students participated in the workshop and 17 completed the survey. The students were “very satisfied” (Likert 4/4) of this training in 94%. They considered this workshop “not very stressful” (Likert 2/4) and “very formative” (Likert 4/4) in 71%, but “a little short” (Likert 2/4) in 88%. After taking this training, all students felt “a little” (Likert 3/4, 24%) or “much more comfortable” (Likert 4/4, 76%) to manage patients with idiopathic RP; and “a little” (Likert 3/4, 65%) or “much more comfortable” (Likert 4/4, 35%) to manage patients with systemic sclerosis. All would recommend this workshop to other students.When asked about the strengths of this training, the students mentioned the benefits of being put in an immersive situation, which allowed for a better acquisition of practical skills (especially physical examination) and a more interactive exchange with teachers; as well as the confrontation with a real patient, which allowed for a better retention of semiologic findings and associated a relational component to this experience. The main weak points reported were its short duration and the stress induced by being observed during the simulation.Conclusion:This workshop suggests the interest and feasibility on a small group of students of a rare diseases awareness workshop using role-play. The evaluation of its pedagogical efficiency and its generalization on large student promotions are being considered.Acknowledgments:NoneDisclosure of Interests:Sebastien SANGES: None declared, Sandrine Morell-Dubois: None declared, Meryem-Maud Farhat: None declared, Morgane Assaraf: None declared, Marc Lambert: None declared, Vincent Sobanski: None declared, David Launay Grant/research support from: Dr. Launay reports personal fees from Actelion, grants and personal fees from Takeda, grants and personal fees from CSL Behring, outside the submitted work., Eric Hachlla: None declared

Objectives:To investigate alterations in the serum proteome of patients with systemic sclerosis (SSc)-associated pulmonary hypertension (PAH), to identify proteins that correlated with hemodynamic severity and to determine their possible pathogenic role.Methods:Patients were included if they fulfilled the following criteria: diagnosis of limited cutaneous SSc, no extensive interstitial lung disease (ILD), and no treatment with PAH-specific therapy. Patients were classified as cases if they had a definitive diagnosis of PAH confirmed by right heart catheterization (RHC) and a serum sample collected on the same day as RHC. They were classified as controls if they had no sign suggestive of PAH on echocardiography.Results:In a first exploratory step, serum expression of 1129 proteins was assessed in 15 cases and 16 controls by a high-throughput proteomic assay (SOMAscan). We identified 53 proteins differentially expressed between the 2 groups. Among these 53 candidates, only 2 correlated significantly with pulmonary vascular resistance (PVR): chemerin (p=0.01,ρ=0.62) and SET nuclear proto-oncogen (SET) (p=0.01,ρ=0.62).To validate these results, serum levels of chemerin and SET were measured by ELISA assay in 25 additional cases and 19 additional controls. Chemerin levels were confirmed to be significantly higher in cases (p=0.01) and correlated with PVR (p=0.01,ρ=0.46).In a second step, to study the potential pathophysiological role of chemerin, we performed confocal immunofluorescence analyses on explanted lungs of healthy controls, SSc-ILD without PAH and SSc-PAH patients. Chemerin receptor, CMKLR1, was significantly increased on SSc-ILD and SSc-PAH pulmonary artery smooth muscle cells (PA-SMC).We then tested the effect of chemerin on PA-SMC proliferation by stimulating PA-SMCs from idiopathic pulmonary arterial hypertension (iPAH) patients with serum from SSc patients with and without PH, in the presence or absence of a CMKLR1 inhibitor. PA-SMCs from iPAH were confirmed to have higher mRNA expression of CMKLR1 than controls (p=0.03). Serum from SSc-PH patients induced a significantly higher PA-SMC proliferation (p=0.005) than serum from controls. This difference was no longer significant (p=0.69) when adding the CMKLR1 inhibitor α–NETA.Conclusion:Chemerin is a surrogate biomarker for PVR in SSc-PAH. Increased chemerin and its receptor, CMKLR1, contribute to the SSc-PAH pathogenesis by inducing PA-SMC proliferation.Acknowledgments:NoneDisclosure of Interests:Sebastien SANGES: None declared, Lisa Rice: None declared, Ly Tu: None declared, Jean-Luc Cracowski Grant/research support from: JL Cracowski received grants from United Therapeutic, Bioprojet and Topadur, David Montani Grant/research support from: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work, Julio Mantero: None declared, Camille Ternynck: None declared, Guillemette Marot: None declared, Eric Hachlla: None declared, David Launay Grant/research support from: Dr. Launay reports personal fees from Actelion, grants and personal fees from Takeda, grants and personal fees from CSL Behring, outside the submitted work., Marc Humbert Grant/research support from: Dr. Humbert reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, from United Therapeutics, personal fees from Acceleron, outside the submitted work., Christophe Guignabert: None declared, Robert Lafyatis Grant/research support from: RL holds research grants from Formation, Elpidera and Kiniksa., Consultant of: R.L. has served as a consultant for Bristol Myers Squibb, Boehringer-Mannheim, Merck, Magenta and Genentech/Roche

Background Systemic sclerosis (SSc) is an autoimmune disease characterised by an extensive multi-organs fibrosis. Immunosuppressants are effective in some extent but their incomplete efficacy is hampered by a higher infection risk. Intravenous immunoglobulins (IVIG) have a good safety profile, exhibit immunomodulatory and antifibrotic properties and hence could be a relevant treatment for SSc. Objectives The purpose of this study was to investigate the effects of IVIG in an experimental model of SSc. Methods SSc was induced in 6 weeks old Balb/c mice by subcutaneous injections of HOCl five days a week during six weeks (n=20), whereas control mice received subcutaneous injections of PBS (n=20). Human IVIG was administrated intravenously by single retro-orbital injection at a dose of 2 g/kg the first day of HOCl administration (n=20). A control group received an injection of 2% Maltose (n=20). Skin thickness was assessed during the protocol until the sacrifice (day 42). Skin tissues were collected in 4% PFA and processed for histological analysis. Dermal thickness was measured by performing a May-Grunwald–Giemsa staining of 4 µm skin sections; collagen deposition was assessed by performing a Picrosirius red-staining and quantified by using a colour deconvolution method. In addition, immunostaining of skin sections was performed in order to evaluate the α-smooth muscle actin (α-SMA) expression. Frozen skin tissues were analysed to also assess the mRNA expression of main inflammatory and pro-fibrotic genes (by quantitative reverse transcription polymerase chain reaction). Collagen deposition was also evaluated by measuring the content of hydroxyproline in 10 mg of frozen tissue. Results Mice exposed to HOCl developed a diffuse cutaneous SSc with higher dermal thickness compared to the PBS group. IVIG significantly reduced dermal thickness and collagen deposition in HOCl-receiving mice. The amount of α-SMA positive cells evaluated by immunofluorescence was reduced in the HOCl treated mice receiving IVIG. mRNA expression profile of various markers of fibrosis (fibronectin, TGFβ) or inflammation (TNFα, IL-1β, IL-6) were also significantly decreased in the skin of HOCl mice treated with IVIG compared to HOCl-treated mice receiving 2% maltose. Conclusions These results demonstrate the efficacy of IVIG in preventing experimental fibrosis in a HOCl murine model of SSc. Disclosure of Interest None declared

Introduction Bien que la sclerodermie systemique (ScS) soit une maladie du reseau microvasculaire, certains patients presentent des complications macrovasculaires graves : coronaropathie, accident vasculaire cerebral et arteriopathie obliterante des membres inferieurs (AOMI). L’occlusion de l’artere ulnaire est decrite chez les patients ScS, alors que l’atteinte macrovasculaire des membres inferieurs est beaucoup moins rapportee. Elle peut conduire a une ischemie critique avec des echecs de revascularisation et une amputation. L’objectif de ce travail etait d’evaluer les caracteristiques de patients atteints de ScS souffrant d’une amputation d’un segment de membre inferieur, afin d’identifier des facteurs de risque associes. Materiels et methodes Nous avons realise une etude retrospective, cas-temoins, multicentrique au sein du GFRS. Chaque patient atteint de ScS ayant subi une amputation d’un segment d’un membre inferieur secondaire a une ischemie critique etait apparie sur le sexe, l’âge (±5 ans) et la forme cutanee a un autre patient ScS sans atteinte macrovasculaire clinique des membres inferieurs. Resultats Vingt-six patients ScS avec amputation d’un segment de membre inferieur ont ete inclus. L’âge moyen etait de 67,2 ans (± 10,9), 20 femmes et 5 formes cutanee diffuse. Le groupe temoin comportait 26 patients ScS sans atteinte macrovasculaire. Les patients ScS avec amputation avaient une duree d’evolution de la maladie plus elevee (15,8 ± 9,4 vs 7,4 ± 5,9 ans), plus d’UD (p = 0,048), et plus d’antecedents d’UD (p = 0,026) que le groupe temoin. Ils avaient egalement un score de Medsger plus eleve, sans tenir compte de l’item « vasculaire » (p = 0,02), du fait d’une prevalence plus elevee de l’hypertension pulmonaire (HTP) (p Conclusion Il s’agit de la plus grande serie de patients ScS avec amputation d’un segment d’un membre inferieur et la premiere comportant un groupe temoin. L’amputation est une complication plutot tardive de la maladie. En comparaison au groupe temoin, l’HTP, le tabac et l’utilisation de corticoides apparaissent comme des marqueurs independants associes a l’amputation. Il est important de detecter et corriger les FRCV des patients ScS, particulierement le tabac, et de ne jamais negliger un trouble trophique du membre inferieur. La place du depistage de la macroangiopathie par echoDoppler arteriel des membres inferieurs devra etre evaluee dans le suivi de la ScS.

Introduction Du fait de la rarete des pathologies propres a notre specialite, les etudiants en medecine beneficient souvent d’un enseignement purement theorique de la medecine interne. Cette modalite d’apprentissage n’est cependant pas la plus adaptee pour l’acquisition de competences d’examen physique d’une part, et pour la confrontation clinique aux pathologies de medecine interne d’autre part. Nous rapportons ici les resultats d’une experimentation pilote utilisant une formation originale basee sur le jeu de role pour l’enseignement de la demarche diagnostique face a un phenomene de Raynaud. Materiels et methodes L’atelier se composait de 2 stations au format ECOS (examen clinique objectif et structure) durant chacune 30 minutes. Les etudiants de DFASM-1 inscrits a l’enseignement optionnel “Maladies Systemiques” etaient repartis par groupes de 4–5 personnes. Tous avaient beneficie au prealable d’un cours theorique sur le phenomene de Raynaud et la sclerodermie systemique. Sur chaque station, 2 etudiants etaient acteurs (l’un jouant le role de l’interne, l’autre celui de l’externe) et 2 etaient observateurs. Apres un briefing succinct, les etudiants jouaient le scenario pendant 15 minutes, puis beneficiait d’un debriefing de 15 minutes. Lors de la premiere station, les etudiants recevaient en consultation une femme de 26 ans, adressee par son medecin traitant pour suspicion de phenomene de Raynaud. La consigne donnee aux etudiants etait de mener l’interrogatoire et l’examen physique de la patiente, de formuler une hypothese diagnostique et de prescrire les eventuels examens complementaires necessaires. Les etudiants devaient aboutir au diagnostic de probable phenomene de Raynaud idiopathique. Le role de la patiente etait joue par une facilitatrice medecin beneficiant d’une expertise sur le phenomene de Raynaud et prealablement formee au role propose. Lors de la deuxieme station, les etudiants recevaient en consultation une femme de 56 ans, adressee par son medecin traitant pour un phenomene de Raynaud complique d’ulceration digitale. La consigne donnee aux etudiants etait identique a la premiere station. Les etudiants devaient aboutir au diagnostic de probable sclerodermie systemique. Le role de la patiente etait tenu par une patiente presentant une sclerodermie systemique, suivie par l’un des enseignants animant l’atelier, ayant beneficie d’une formation prealable et ayant donne son accord pour participer a cet enseignement. Chaque station etait animee par des enseignants formes au jeu de role et au debriefing. Au decours de l’atelier, les etudiants devaient remplir un questionnaire de satisfaction. Resultats Au total, 21 etudiants ont participe a l’atelier et 17 ont rempli le questionnaire de satisfaction. Les etudiants se montraient « tres satisfaits » (Likert 4/4) de cette formation dans 94 % des cas. Ils consideraient cet atelier « peu stressant » (Likert 2/4) et « tres formateur » (Likert 4/4) dans 71 % des cas, mais « un peu trop court » (Likert 2/4) dans 88 % des cas. A l’issue de cette formation, l’ensemble des etudiants s’estimaient « un peu » (Likert 3/4, 24 %) ou « beaucoup plus a l’aise » (Likert 4/4, 76 %) pour prendre en charge un patient atteint de phenomene de Raynaud idiopathique ; et « un peu » (Likert 3/4, 65 %) ou « beaucoup plus a l’aise » (Likert 4/4, 35 %) pour prendre en charge un patient atteint de sclerodermie systemique. Tous la recommanderaient aux etudiants ne l’ayant pas suivi. Interroges en texte libre sur les principaux points forts de cette formation, les etudiants soulignaient surtout les avantages procures par : – la mise en situation reelle en petits groupes, permettant une meilleure acquisition des competences pratiques (notamment d’examen physique) et un echange plus interactif avec l’enseignant ; – la confrontation avec un vrai patient, permettant une meilleure retention de la semiologie et l’integration d’une dimension relationnelle et humaine a l’apprentissage de la pathologie. Les principaux points faibles rapportes etaient une duree trop courte, l’illustration pratique de seulement 2 causes de phenomene de Raynaud (au detriment des autres) et le caractere potentiellement biaisant et stressant d’etre observe lors de la mise en situation. Conclusion Cette experimentation originale suggere l’interet et la faisabilite sur un petit groupe d’etudiants d’ateliers de jeu de role portant sur l’enseignement des maladies rares a partir de situations frequentes et la promotion de la “culture du doute”. L’evaluation de son efficacite pedagogique et sa generalisation sur de larges promotions d’etudiants, sur la base de l’Axe 9 du Plan Maladies Rares 3, sont en cours de reflexion au sein de la commission de reforme de la formation initiale de la Conference des Doyens.

Introduction La periarterite noueuse (PAN) est une vascularite necrosante touchant les vaisseaux de moyen ou petit calibre, sans glomerulonephrite ou vascularite des arterioles, capillaires ou veinules, et non-associee aux ANCA. Le traitement standard repose sur les glucocorticoides (GCs) associees ou non a des immunosuppresseurs conventionnels selon la presence ou non de facteurs de mauvais pronostic. Cependant, certains patients ont une maladie refractaire ou des rechutes. Nous avons etudie l’utilisation hors-AMM des biotherapies pour le traitement de PAN refractaires ou en rechute. Patients et methodes Etude retrospective, multicentrique europeenne, ayant inclut les patients atteints de PAN repondant aux criteres ACR et/ou a la definition de la Conference de consensus de Chapel Hill. L’efficacite et la tolerance des medicaments ont ete analysees. La remission etait definie par l’absence des manifestations actives de vascularite (BVAS = 0) et une dose de prednisone ≤ 5 mg/jour. La reponse partielle est definie par un score BVAS = 0 et une dose de GCs > 5 et ≤ 10 mg/jour. Resultats Cinquante et un patients ont ete inclus (24 hommes, âge moyen 51 ans). Dix-huit (35 %) patients ont recu un anti-TNF-α, 16 (31 %) du rituximab (RTX), 9 (18 %) du tocilizumab (TCZ), et 8 (16 %) d’autres biotherapies (alemtuzumab chez 3, anakinra chez 2, interferon-achez 2 et abatacept chez un). Les traitements precedemment recus etaient : GCs chez tous les patients, dont bolus de methylprednisolone (72 %) et GCs oraux (92 %), cyclophosphamide (61 %), azathioprine (53 %), methotrexate (45 %) et mycophenolate mofetil (47 %). A la mise sous biotherapies, le BVAS median etait 5 (extremes 0-18), dont 5 (2-12) dans le groupe traite par anti-TNF-α, 5 (2-12) dans le groupe traite par RTX et 4 (0-6) dans le groupe traite par TCZ. Apres un suivi median de 34,4 mois (IQR 21,5-59,5), les remissions, les reponses partielles et les echecs etaient observes dans 41 %, 6 % et 53 % dans le groupe traite par anti-TNF-α, respectivement, 25 %, 12 % et 63 % dans le groupe traite par RTX, et 57 %, 0 % et 43 % dans le groupe traite par TCZ. Il n’etait pas observe de remission chez les patients traites paranakinra, alemtuzumab et abatacept. Le BVAS median baissait de 5 a 3 a 6 mois, 0 a 12 mois et 0 au dernier suivi dans le groupe anti-TNF-α, de 5 a 3.5, 0 et 2 dans le groupe RTX, respectivement, et de 4 a 0, 0 et 0 dans le groupe TCZ. L’effet d’epargne cortisonique semblait plus important dans les groupes traites par anti-TNF-α et TCZ. La dose mediane de GCs baissait de 15 mg/j a 10 a 6 mois, 5 a 12 mois et 5 au dernier suivi dans le groupe anti-TNF-α, de 15 mg/j a 10 a 6 mois, 5 a 12 mois et 10 au dernier suivi dans le groupe RTX, et de 15 mg/j a 7 a 6 mois, 5 a 12 mois et 5 au dernier suivi dans le groupe TCZ. Quatre (22 %) patients ont arrete les anti-TNF-α en raison d’une reaction allergique chez un patient et d’un echec chez 3 patients. Six (38 %) patients ont arrete le RTX en raison d’un echec. Enfin, quatre (44 %) patients ont arrete le TCZ en raison d’effets indesirables chez 2 patients et d’un echec chez 2. Conclusion Les resultats de cette etude montrent que les anti-TNF-α et le TCZ sont associes a des taux remissions plus importants et un meilleur effet d’epargne cortisonique en cas de maladie refractaire ou en rechute que les autres biotherapies. D’autres etudes seront necessaires afin de confirmer ou infirmer ces conclusions.

Background There is an ongoing debate regarding the relevance of the 6-minute walking distance (6MWD) in systemic sclerosis (SSc) assessment, widely used as a usual test in these patients as well as an outcome measure in clinical trials. In this work, we aimed to assess the associations between the 6MWD and various disease parameters in patients with SSc. Methods Consecutive patients followed in our SSc National Reference Centre were included in this cross-sectional study if they fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc. Data were systematically collected during a comprehensive standardized evaluation that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores (European Scleroderma Study Group Activity Index, Medsger severity score, Health Assessment Questionnaire–Disability Index (HAQ-DI)) and treatments. Associations of the 6MWD with various disease parameters were assessed by linear regression in univariate and multivariate analyses. Results The study population comprised 298 patients (females 81%; mean age 58.2 ± 13.3 years; limited cutaneous SSc 82%; interstitial lung disease (ILD) 42%; pulmonary arterial hypertension (PAH) 6%). The 6MWD was significantly and independently associated with gender, age, body mass index, baseline heart rate (HR), HR variation during the test, PAH, history of arterial thrombosis and C-reactive protein levels, as well as with the HAQ-DI score in a sensitivity analysis. Muscle involvement, joint involvement and ILD were not independently associated with the 6MWD. Conclusions During SSc, the 6MWD is independently associated with initial HR and HR variation; with PAH but not ILD, suggesting that pulmonary vasculopathy may have a greater impact than parenchymal involvement on functional limitation; and with global markers of disease activity and patient disability. These results give clinicians further insight into how to interpret the 6MWD in the context of SSc. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1489-4) contains supplementary material, which is available to authorized users.

Pulmonary hypertension can occur in GATA2 deficiency-associated pulmonary alveolar proteinosis and fibrosis http://ow.ly/aHv430aAZct

Introduction On designe par enteropathie exsudative (EE) toute pathologie conduisant a une perte anormale de serum dans la lumiere digestive, comme les maladies inflammatoires chroniques intestinales (MICI), la maladie caeliaque (MC), l’hypertension portale et la maladie de Waldmann. Ainsi, les EE sont responsables d’hypogammaglobulinemie et de lymphopenie, qui peuvent mimer un deficit de l’immunite humorale. D’autre part, le deficit immunitaire commun variable (DICV) peut se compliquer de manifestations digestives, dont certaines sont des causes classiques d’EE (pseudo-MICI, pseudo-MC, giardiase, granulomatose). Les objectifs de cette etude sont donc de determiner si : – le DICV peut se compliquer d’EE ; – l’EE s’associe a des anomalies immunologiques specifiques permettant de la differencier du DICV. Patients et methodes Les patients eligibles ont ete identifies au sein de 3 centres francais : service d’immunologie clinique (hopital Huriez, Lille, France), service des maladies digestives (hopital Huriez, Lille, France), service de lymphologie (hopital Cognacq-Jay, Paris, France). Ils etaient inclus s’ils presentaient une EE (diagnostiquee par la clairance fecale de la α1-antitrypsine ou le test de Gordon-Waldmann) et/ou un DICV (diagnostique selon les criteres de classification de l’ESID). Les donnees cliniques et biologiques pertinentes ont ete collectees de facon retrospective. L’index d’efficacite de la substitution en IgG a ete calcule selon la formule du groupe DEFI (Clin Exp Immunol 2013 ;171(2) :186–194). Resultats Les patients ont ete repartis en 3 groupes : DICV+ EE+ (n = 5), DICV+ EE− (n = 21), EE+ DICV− (n = 12). La plupart des patients DICV+ EE+ presentaient plusieurs causes d’EE : pseudo-MICI (3/5), hyperplasie regenerative nodulaire (2/5), atrophie villeuse (1/5), giardiase (2/5). Comparativement au groupe DICV+ EE−, les patients DICV+ EE+ presentaient des taux d’IgM (0,04 ± 0,01 vs 0,53 ± 1,5 g/L, p Comparativement au groupe DICV+ EE−, les patients EE+ DICV− ne developpaient pas de complications infectieuses. Ils presentaient des taux plus eleves d’IgA (1,24 ± 0,66 vs 0,13 ± 0,12 g/L, p Conclusion La survenue d’une EE est possible au cours du DICV, et necessite alors une majoration des doses de traitement substitutif. L’EE peut aussi induire des anomalies immunologiques proches du DICV mais celles-ci sont plus modestes, avec notamment un taux d’IgA normal ou moderement diminue.

Introduction Nous rapportons l’observation d’un patient de 75 ans adresse dans notre service pour bilan d’adenopathies cervicales. Une biologie preoperatoire systematique a mis en evidence une elevation asymptomatique du TCA avec effondrement des taux de facteur VIII et presence d’anticorps anti-VIII, conduisant au diagnostic d’hemophilie A acquise (HAA). L’analyse histologique d’une adenopathie cervicale a revele une hyperplasie folliculaire benigne avec infiltration de plasmocytes IgG4 ; et le dosage des sous-classes d’immunoglobulines G (IgG) retrouvait une elevation majeure des taux seriques d’IgG4, compatibles avec une maladie liee aux IgG4 (MAG4). On retenait donc le diagnostic d’HAA associee a une MAG4 et traitee avec succes par corticotherapie systemique pendant 9 mois. Neuf mois apres l’arret de la prednisone, la survenue d’une rechute a motive l’introduction d’un traitement par rituximab. Partant de cette observation, nous avons voulu etudier la possibilite d’un lien physiopathologique potentiel entre les deux maladies en determinant l’isotype des auto-anticorps anti-VIII. Materiels et methodes En utilisant une approche ELISA modifiee, nous avons mesure les taux circulants d’IgG4 et IgG1 anti-facteur VIII (les isotypes les plus frequents des inhibiteurs du facteur VIII) dans le serum de notre patient et dans un groupe temoin de 7 patients presentant une HAA mais sans diagnostic connu de MAG4. Resultats Chez notre patient presentant l’association HAA-MAG4, l’inhibiteur du facteur VIII etait principalement de l’isotype IgG4, avec un rapport IgG4/IgG1 anti-VIII a 42 lors du diagnostic et a 268 lors de la rechute. Ce ratio semblait inferieur dans le groupe temoin (mediane [min–max] : 8,1 [0,4 ; 56]) ; cependant, les temoins n°1 et n°C2 presentaient une elevation du rapport IgG4/IgG1 anti-VIII dans des proportions similaires a celui de notre patient au moment du diagnostic (56 et 41, respectivement). Aucun des controles n’avait un rapport IgG4/IgG1 anti-VIII proche de la valeur de la rechute de notre patient. Globalement, ces resultats suggerent une production preferentielle d’anticorps anti-VIII d’isotype IgG4 chez notre patient, bien qu’elle soit egalement observee en cas d’HAA non associee a une MAG4. Les IgG4 anti-VIII ne representaient qu’une faible proportion des IgG4 totales de notre patient, avec un ratio de 2,7,10–3 au diagnostic et de 1,0,10–3 au moment de la rechute. Ces valeurs semblaient plus elevees dans le groupe temoin (mediane [min–max] : 4,6,10–2 [4,4,10–3 ; 1,79,10–1]). Ceci suggere que la production d’IgG4 anti-VIII ne rend pas compte de l’augmentation des taux seriques d’IgG4 observee chez notre patient, ce qui conforte le caractere polyspecifique de la proliferation plasmocytaire dans la MAG4. Conclusion Nous rapportons ici un cas d’un patient presentant a la fois une HAA et une MAG4, association inhabituelle de deux maladies immunologiques rares, et suggerons que ses anticorps anti-facteur VIII sont principalement de l’isotype IgG4, en particulier lors de la rechute. Ceci pourrait plaider en faveur d’un lien physiopathologique entre les deux pathologies, bien que la presence d’IgG4 anti-VIII soit egalement constatee en cas d’HAA non associee a une MAG4.

Introduction During systemic sclerosis (SSc), peripheral B cells display alterations in subset homeostasis and functional properties and are a promising therapeutic target. However, there is only few data regarding whether these anomalies are accurately reproduced in animal models of SSc. Objective In this work, we assessed the B cell homeostasis modifications in an experimental model of SSc [hypochlorous acid (HOCl)-induced mouse], both at a phenotypic and functional level, during the course of the disease. Methods Balb/c mice underwent daily intradermal injections of HOCl (or phosphate-buffered saline) and were then sacrificed at day 21 (early inflammatory stage) or day 42 (late fibrotic stage). For phenotypic studies, the distribution of the main spleen cell subsets (B cells, T CD4 and CD8 cells, NK cells, macrophages) and splenic B cell subsets (immature, mature naïve, germinal center, antibody-secreting, memory, B1) was assessed by flow cytometry. For functional studies, splenic B cells were immediately MACS-sorted. Production of interleukin (IL)-6, CCL3, IL-10, and transforming growth factor (TGF)-β was assessed ex vivo by RT-PCR and after 48 h of culture by ELISA. Regulatory B cell (Breg) counts were quantified by flow cytometry. Results Phenotypic analyses showed an early expansion of transitional B cells, followed by a late expansion of the mature naive subset and decrease in plasmablasts and memory B cells. These anomalies are similar to those encountered in SSc patients. Functional analyses revealed a B-cell overproduction of pro-inflammatory cytokines (IL-6 and CCL3) and an impairment of their anti-inflammatory capacities (decreased production of IL-10 and TGF-β, reduced levels of Bregs) at the early inflammatory stage; and an overproduction of pro-fibrotic cytokines (TGF-β and IL-6) at the late fibrotic stage. These results approximate the anomalies observed in human SSc. Conclusion This work reports the existence of anomalies in B cell homeostasis and functional properties in an animal model of SSc that approximate those displayed by SSc patients. These anomalies vary over the course of the disease, which pleads for their participation in inflammatory and fibrotic events. This makes the HOCl mouse a relevant experimental model for the study of B cells, and therefore, B-cell-targeted therapies in SSc.