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Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα signaling via NF-κB" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974

Epidermal necrolysis (EN, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)) is mostly induced by drugs. Prevalence of lupus erythematosus (LE) is higher in EN than in general population (1.2 to 2%).1,2 Furthermore, flares of LE may present as EN (TEN-like LE).3-5 We aimed to describe EN in patients with clinical or biological LE to better characterize the relation between both diseases.

Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with versus without auto-Abs.We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2, β and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with versus without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiOIn ICU patients, auto-Abs against type I IFNs were found in at least 10% of patients with critical COVID-19 pneumonia. They were not associated with day 28 mortality.

Rationale: Uncontrolled inflammatory innate response and impaired adaptive immune response are associated with clinical severity in patients with coronavirus disease (COVID-19). Objectives: To compare the immunopathology of COVID-19 acute respiratory distress syndrome (ARDS) with that of non–COVID-19 ARDS, and to identify biomarkers associated with mortality in patients with COVID-19 ARDS. Methods: Prospective observational monocenter study. Immunocompetent patients diagnosed with RT-PCR–confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and ARDS admitted between March 8 and March 30, 2020, were included and compared with patients with non–COVID-19 ARDS. The primary clinical endpoint of the study was mortality at Day 28. Flow cytometry analyses and serum cytokine measurements were performed at Days 1–2 and 4–6 of ICU admission. Measurements and Main Results: As compared with patients with non–COVID-19 ARDS (n = 36), those with COVID-19 (n = 38) were not significantly different regarding age, sex, and Sequential Organ Failure Assessment and Simplified Acute Physiology Score II scores but exhibited a higher Day-28 mortality (34% vs. 11%, P = 0.030). Patients with COVID-19 showed profound and sustained T CD4+ (P = 0.002), CD8+ (P

Background The observation that COPD is an independent risk factor for cardiovascular disease (CVDs) comes from comparisons between smokers with COPD and smokers without COPD. The mechanisms that explain increased risk of CVD in patients with COPD are still unclear. Objectives The goal of this study was to assess systemic arterial stiffness (a predictor of CVD mortality) and to evaluate its determinants in a group of patients with mild to moderate COPD secondary to organic dust exposure, tobacco smoking, or both. Methods Systemic arterial stiffness was assessed by using aortic pulse wave velocity (aPWV). Measurements were made in 142 patients with COPD and 155 healthy control subjects matched for age, sex, BMI, and tobacco smoking, exposed to tobacco smoking (n = 56/70 for COPD/control subjects, respectively), organic dusts (n = 44/48), or both (n = 42/37). Results aPWV was higher in COPD than in healthy controls in subjects exposed to tobacco smoking and to both organic dusts and tobacco smoking. By contrast, among never smokers exposed to organic dusts, patients with COPD and matched control subjects had similar aPWV. Multivariate analysis of the 142 patients with COPD (exposed to tobacco smoking and/or to organic dusts) showed that tobacco smoking was associated with high aPWV. Moreover, soluble suppression of tumorigenicity 2, a marker of major cardiovascular events, was correlated with aPWV in these patients. Conclusions Analysis of an unselected group of patients with COPD with different causes suggests that: (1) COPD by itself is not sufficient to explain increased aPWV; and (2) tobacco smoking is a risk factor for elevated aPWV in COPD.

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30-April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote "Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy." (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, there is no doubt that the desired renaissance of solid basic HS research is progressing with rapid steps and that HS has developed deep roots among inflammatory diseases in Dermatology and beyond, recognized as "the only inflammatory skin disease than can be healed". This anniversary article of 43 research-performing authors from all around the globe in the official journal of the European Hidradenitis Suppurativa Foundation e.V. (EHSF e.V.) and the Hidradenitis Suppurativa Foundation, Inc (HSF USA) summarizes the evidence of the intense HS clinical and experimental research during the last 15 years in all aspects of the disease and provides information of the developments to come in the near future., info:eu-repo/semantics/published

Endometriosis is a chronic hormono-dependent inflammatory gynecological disease. Endometriosis can be subdivided into three forms: superficial peritoneal implants, endometrioma, and deep infiltrating endometriosis (DIE). Inflammation is a typical feature of endometriosis with overproduction of prostaglandins, chemokines, and cytokines, like granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a hematopoietic growth factor and immune modulator which belongs to the group of cytokines that actively participate in inflammatory reactions. GM-CSF autoantibodies (Ab) are described in inflammatory diseases such as Crohn disease and ulcerative colitis where high concentrations of anti-GM-CSF Ab are correlated with severity, complications, and relapses. We have evaluated the presence of anti-GM-CSF Ab in the serum of 106 patients with endometriosis and 92 controls using a home-made enzyme-linked immunosorbent assay (ELISA) and correlated the results with the form and severity of the disease. We found that anti-GM-CSF Ab level is significantly increased in the sera of patients with endometriosis compared to controls and is associated with the severity of the disease especially in patients with deep endometriosis (p

We read with great interest the study by Bertin et al [1] exploring the involvement of antiphospholipid (aPL) antibodies in a cohort of SARS-COV 2 patients. The authors observed that the levels of IgG anticardiolipin were significantly associated with severe COVID-19 manifestations (odds ratio [OR] = 6.50; P = 0.009).

Background Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. Methods Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. Results Among 105 patients included, 35% had a reduced exercise capacity (VO2peak CO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. Conclusion Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.

Background Acute exanthemas (AEs) are frequently seen; they can be caused by drugs or viruses but often the cause is unknown. Objectives To describe the clinical, virological and histological aspects of AEs and explore their cytokinic and metagenomic profiles. Methods This prospective study examined 98 patients with AE, from February to July 2014. Clinical data were recorded in a standardized chart. Virological investigation and skin biopsies were performed. In addition, blood and skin samples were analysed for cytokines and then by a shotgun metagenomic approach. We identified five groups of patients: those with maculopapular exanthemas (MPEs) that were virally induced (group 1); those with drug-induced MPEs (group 2), those with MPEs that were both viral and drug induced (group 3), those with idiopathic MPEs (group 4) and those with pityriasis rosea (group 5). Results A virus was identified in 29 cases (human herpesvirus 6, 72%). Cytokinic analysis of the skin (n = 23 MPEs) showed higher levels of interferon-γ and interleukin-1 receptor-α in viral MPEs, higher interleukin-33 levels in idiopathic MPEs, and higher macrophage inflammatory protein 1α levels in drug-induced MPEs. By metagenomics analysis (n = 10 MPEs), viruses identified with routine practice methods were not found in group 1 (n = 4 MPEs). However, Enterovirus A was detected in two cases, especially in a group 1 patient for whom metagenomic analysis rectified the diagnosis of the culprit agent. Conclusions Human herpesvirus 6 was the virus most frequently identified, and histology did not discriminate MPEs. In addition, the level of interleukin-33 seen in idiopathic MPEs suggests that an environmental factor may be the trigger for these. The results bring into question the utility of routine polymerase chain reaction analysis and viral serology for determining cause in AE. What's already known about this topic? Acute exanthemas, especially maculopapular exanthemas, are a frequent reason for patients consulting emergency and dermatology departments. It is difficult to evaluate the aetiology of acute exanthema based on the clinical aspects. Few data are available on the investigations needed in routine practice, and no prospective series have been published. What does this study add? Our study provides a global and prospective description of acute exanthemas. Cytokine analysis could help to investigate the pathophysiology of idiopathic eruptions. Metagenomic analysis provides new insights about the value of routine practice virological investigations. We show for the first time the feasibility of metagenomics analysis in the skin, which results question the interest of routine PCR and viral serologies for the exploration of such acute exanthemas.

Background The mechanisms of organ failure during sepsis are not fully understood. The hypothesis of circulating factors has been suggested to explain septic myocardial dysfunction. We explored the biological coherence of a large panel of sepsis mediators and their clinical relevance in septic myocardial dysfunction and organ failures during human septic shock. Methods Plasma concentrations of 24 mediators were assessed on the first day of septic shock using a multi-analyte cytokine kit. Septic myocardial dysfunction and organ failures were assessed using left ventricle ejection fraction (LVEF) and the Sequential Organ Failure Assessment score, respectively. Results Seventy-four patients with septic shock (and without immunosuppression or chronic heart failure) were prospectively included. Twenty-four patients (32%) had septic myocardial dysfunction (as defined by LVEF

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role has been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including pre-existing cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late, remarkably stable, memory B cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection., Graphical abstract, The B cell response against SARS-CoV-2 shows a temporal shift from an extrafollicular reaction that includes memory B cells against seasonal coronaviruses toward a germinal center-dependent memory response encoding (spike-specific) neutralizing antibodies.

Background Biomarkers of disease severity might help individualizing the management of patients with the acute respiratory distress syndrome (ARDS). Whether the alveolar compartmentalization of biomarkers has a clinical significance in patients with pneumonia-related ARDS is unknown. This study aimed at assessing the interrelation of ARDS/sepsis biomarkers in the alveolar and blood compartments and explored their association with clinical outcomes. Methods Immunocompetent patients with pneumonia-related ARDS admitted between 2014 and 2018 were included in a prospective monocentric study. Bronchoalveolar lavage (BAL) fluid and blood samples were obtained within 48 h of admission. Twenty-two biomarkers were quantified in BAL fluid and serum. HLA-DR+ monocytes and CD8+ PD-1+ lymphocytes were quantified using flow cytometry. The primary clinical endpoint of the study was hospital mortality. Patients undergoing a bronchoscopy as part of routine care were included as controls. Results Seventy ARDS patients were included. Hospital mortality was 21.4%. The BAL fluid-to-serum ratio of IL-8 was 20 times higher in ARDS patients than in controls (p p = 0.026), IL-6 (p = 0.002), IP-10/CXCL10 (p = 0.024) and IL-10 (p = 0.023) than others. The BAL fluid-to-serum ratio of IL-1Ra was more elevated in hospital survivors than decedents (p = 0.006), even after adjusting for SOFA and driving pressure (p = 0.036). There was no significant association between alveolar or alveolar/blood monocytic HLA-DR or CD8+ lymphocytes PD-1 expression and hospital mortality. Conclusions IL-8 was the most compartmentalized cytokine and lower BAL fluid-to-serum concentration ratios of IL-1Ra were associated with hospital mortality in patients with pneumonia-associated ARDS.

International audience; Background: Most cases of Stevens-Johnson syndrome and toxic epidermal necrolysis are drug-induced. A small subset of cases remain with unknown aetiology (idiopathic epidermal necrolysis [IEN]).Objective: We sought to better describe adult IEN and understand the aetiology.Methods: This retrospective study was conducted in 4 centres of the French national reference centre for epidermal necrolysis. Clinical data were collected for the 19 adults hospitalized for IEN between January 2015 and December 2019. Wide toxicology analysis of blood samples was performed. Histology of IEN cases was compared with blinding to skin biopsies of drug-induced EN (DIEN, 'controls'). Available baseline skin biopsies were analysed by shotgun metagenomics and transcriptomics and compared to controls.Results: IEN cases represented 15.6% of all EN cases in these centres. The median age of patients was 38 (range 16-51) years; 68.4% were women. Overall, 63.2% (n = 12) of cases required intensive care unit admission and 15.8% (n = 3) died at the acute phase. Histology showed the same patterns of early- to late-stage EN with no difference between DIEN and IEN cases. One toxicology analysis showed unexpected traces of carbamazepine; results for other cases were negative. Metagenomics analysis revealed no unexpected pathological microorganism. Transcriptomic analysis highlighted a different pro-apoptotic pathway in IEN compared to DIEN, with an overexpression of apoptosis effectors TWEAK/TRAIL.Conclusions: IEN affects young people and is a severe form of EN. A large toxicologic investigation is warranted. Different pathways seem involved in IEN and DIEN, leading to the same apoptotic effect, but the primary trigger remains unknown.

International audience

Memory B cells play a fundamental role in host defenses against viruses, but to date, their role have been relatively unsettled in the context of SARS-CoV-2. We report here a longitudinal single-cell and repertoire profiling of the B cell response up to 6 months in mild and severe COVID-19 patients. Distinct SARS-CoV-2 Spike-specific activated B cell clones fueled an early antibody-secreting cell burst as well as a durable synchronous germinal center response. While highly mutated memory B cells, including preexisting cross-reactive seasonal Betacoronavirus-specific clones, were recruited early in the response, neutralizing SARS-CoV-2 RBD-specific clones accumulated with time and largely contributed to the late remarkably stable memory B-cell pool. Highlighting germinal center maturation, these cells displayed clear accumulation of somatic mutations in their variable region genes over time. Overall, these findings demonstrate that an antigen-driven activation persisted and matured up to 6 months after SARS-CoV-2 infection and may provide long-term protection.

International audience; Background - Although farming is often considered a risk factor for COPD, data regarding the burden and characteristics of COPD in dairy farmers are sparse and conflicting. Objectives - To characterize COPD in dairy farmers. Methods - 4788 subjects entered two parallel COPD screening programs, one in agricultural workers and one in general practice from 2011 to 2015. Subjects with COPD were invited to participate in the characterization phase of the study. Those who accepted were included in two subgroups: dairy farmers with COPD (DF-COPD) (n = 101) and non-farmers with COPD (NF-COPD) (n = 85). Patients with COPD were frequency-matched with subjects with normal spirometry for age, sex and tobacco smoking (pack-years and status) (DF-controls n = 98, NF-controls n = 89). All subjects from these four groups underwent lung function and exercise testing, questionnaires and blood analysis. Results - The frequency of COPD in dairy farmers was 8.0% using the GOLD criterion and 6.2% using the lower limit of normal criterion and was similar in non-farming subjects (7.3% and 5.2%, respectively) although dairy farmers had lower tobacco consumption (screening phase). DF-COPD had better pulmonary function, exercise capacity and quality of life, fewer symptoms and comorbidities than NF-COPD, and higher levels of some Th2 biomarkers (MCP-2, periostin) (characterization phase). In farmers, COPD was not related to occupational exposure factors, supporting the role of host factors. Conclusion - COPD secondary to organic dust exposure (dairy farming) appears less severe and associated with fewer comorbidities than COPD secondary to tobacco smoking.

Hidradenitis suppurativa (HS) is a chronic, relapsing, inflammatory skin disease. HS appears to be a primary abnormality in the pilosebaceous-apocrine unit. In this work, we characterized hair follicle stem cells (HFSCs) isolated from HS patients and more precisely the outer root sheath cells (ORSCs). We showed that hair follicle cells from HS patients had an increased number of proliferating progenitor cells and lost quiescent stem cells. Remarkably, we also showed that the progression of replication forks was altered in ORSCs from hair follicles of HS patients, leading to activation of the ATR/CHK1 pathway. These alterations were associated with an increased number of micronuclei and with the presence of cytoplasmic ssDNA, leading to the activation of the IFI16/STING pathway and the production of type I IFNs. This mechanistic analysis of the etiology of HS in the HFSC compartment establishes a formal link between genetic predisposition and skin inflammation observed in HS.

Background In kidney transplant recipients, anticardiolipin (ACL) antibodies without antiphospholipid syndrome (APS) are found in up to 38% of patients and could be associated with thrombotic events (TEs). However, the prognostic role of ACL regarding kidney transplant and patients outcomes have still not been well defined. Methods We conducted an observational, monocentric, retrospective cohort study including 446 kidney transplant recipients and standardized follow-up: 36-month allograft and patient survival, 12-month estimated glomerular filtration rate (eGFR) and 3- and 12-month screening biopsies. Results ACL tests were run on 247 patients, 101 were positive (ACL+ group, 41%) and 146 were negative (ACL- group, 59%). Allografts and patient survival within 36 months as TE were similar between both groups [hazard ratio (HR) = 1.18 and HR = 0.98, respectively]. The 12-month eGFR was significantly lower in the ACL+ group [median (95% confidence interval) 48.5 (35.1-60.3) versus 51.9 (39.1-65.0) mL/min/1.73 m2, P= 0.042]. ACL+ was independently associated with eGFR decrease (P = 0.04). In 12-month screening biopsies, tubular atrophy was significantly more severe in the ACL+ group compared with the ACL- group (P = 0.02). Conclusions ACL without APS before kidney transplantation is an independent risk factor of eGFR decline within the first year post-transplant without over-incidence of TEs. Specific immunosuppressive therapy including mammalian target of rapamycin inhibitors should be discussed in the future.

Introduction Les maladies immunologiques (lupus, dermatomyosite) sont des facteurs de risque de necrolyse epidermique (NE) medicamenteuse. D’autre part, en poussee aigue, elles peuvent mimer une NE. Cependant, le cadre nosologique des NEs avec auto-immunite peut etre difficile a statuer. Materiel et methodes Cette etude retrospective multicentrique a inclus les adultes avec NE de 07/2014 a 03/2020, avec antecedent de connectivite et/ou auto-anticorps (Ac) decouverts au moment de la NE (AAN, anti-DNA, anti-ECT, dot-myosite), qu’il y ait ou non un medicament (mdt) suspect. Les histologies ont ete relues en aveugle. Resultats Dix-huit patients ont ete inclus (17 F, âge median 47 ans), dont 4 avec lupus connu, 2 avec syndrome de Sjogren primaire, 2 avec photosensibilite. Sept (39 %) ont ete vus au printemps/ete. Onze (61 %) avaient un mdt suspect (ALDEN entre 3, possible et 6, certain). Le decollement median etait de 28 % (2-60 %). Une atteinte cephalique nette etait notee dans 12 cas. L’atteinte muqueuse etait constante. Trois patients sont decedes, 5 ont eu des sequelles severes. Trois situations ont ete observees : – Dans 5 cas : lesions annulaires, necrotiques, franche predominance cephalique, rare atteinte oculaire, connectivite connue, pas de mdt suspect. Les Ac etaient des AAN (n = 3, titre median 1/640), anti-ADN (n = 2), anti-SSA (n = 5), anti-MDA5 (n = 1). Ils ont recu un traitement specifique de la connectivite en phase aigue de la NE ; – Dans 10 cas : NE sans particularite clinique, frequente atteinte oculaire, mdt suspect dans 8 cas (80 %, ALDEN 4 a 6). Les Ac etaient des AAN (n = 8 titre median 1/800), anti-ADN (n = 1), anti-SSA (n = 6), anti-RNP (n = 1), anti-TIFF1γ (n = 1). Aucun n’a recu de traitement specifique en phase aigue. A distance, les Ac ont persiste sans manifestation clinique ; – Pour 3 patientes : NE sans particularite, au cours d’une poussee de lupus, avec mdt suspect : cotrimoxazole (n = 2, ALDEN 6), AINS (ALDEN 3). La nosologie a ete difficile a trancher. Au plan histologique, il n’y avait pas de difference significative entre les groupes, meme si une tendance a une mucinose dermique et moins de lesions lichenoides pilaires a ete observee dans le groupe 1. Un patient (groupe 1) avait une bande lupique en IFD. Discussion La presence d’une auto-immunite au cours d’une NE fait discuter 3 situations : – une NE immunologique, « non toxique », sur connectivite connue ou non (« lupus-Lyell »), melant au decollement des lesions annulaires, necrotiques, peu d’atteinte oculaire, justifiant un traitement specifique de la connectivite ; – une NE medicamenteuse, ou les Ac semblent fortuits (precessifs ? epitope spreading ?), n’imposant pas de traitement specifique de connectivite ; – une situation difficile a trancher (« lupus-Lyell » ou NE medicamenteuse favorisee par le lupus) chez des patients severes. L’indication d’un traitement immunomodulateur d’une NE avec auto-immunite doit etre pesee selon le cadre nosologique.

Introduction En 2009, nous avions conduit un audit de pratiques pour etudier le profil et le traitement (ttt) des patients atteints de pemphigoide bulleuse (PB) dans notre centre. Nous avons renouvele cet audit dix ans plus tard afin d’etudier l’evolution de l’epidemiologie de la maladie et des pratiques de prise en charge. Materiel et methodes Cette etude monocentrique retrospective a inclus toutes les nouvelles PB diagnostiquees entre le 01,01.2015 et le 21,12.2018 (issues de la base d’anatomopathologie, codage IFD IgG-C3) et suivies plus de 3 mois. Les donnees epidemiologiques, cliniques et therapeutiques ont ete recueillies dans les dossiers puis comparees aux donnees disponibles de l’etude de 2009 qui avait inclus 96 patients. Resultats 137 patients ont ete inclus (F 61 %, âge moyen 81 ans, forme bulleuse 91 %, dont multi bulleuse 71 %). En comparaison avec l’etude de 2009, les patients de l’etude de 2020 etaient un peu plus jeunes (moyenne 81 vs 84 ans) et avaient globalement autant de comorbidites neurologiques (47 % vs 54 %, p = 0,33). La prise en charge comprenait un recours plus frequent aux ttt systemiques (39 % vs 29 % dans les 6 premiers mois, p = 0,05) qui etait plus souvent le methotrexate (MTX), a visee d’epargne. La duree totale mediane de ttt etait plus longue de 2,5 mois en 2020 (11,5 vs 9 mois). Le taux de deces a 12 mois du diagnostic etait moindre dans l’etude actuelle (8 % vs 38 %, p Discussion Dans notre pratique, les patients pris en charge actuellement pour PB sont un peu plus jeunes qu’il y a 10 ans, et presentent autant de comorbidites neurologiques. L’etude actuelle montre cependant des differences significatives de prise en charge therapeutique, avec un recours actuel plus frequent aux immunosuppresseurs, essentiellement le MTX. Les experiences positives du MTX en France depuis 10 ans, en epargne ou 1ere ligne (etude PB3) ont sans doute encourage cette pratique pour limiter les effets indesirables de la corticotherapie locale prolongee. La duree actuellement plus longue du ttt reflete probablement une decision d’arret basee sur l’attente de resultats favorables de tests immunologiques (ELISA BP180 83 ans) etant un facteur pronostique majeur de mortalite dans la PB, et/ou par une meilleure prise en charge globale de la maladie et des comorbidites.

Introduction L’atteinte pulmonaire precoce de la necrolyse epidermique (NE, syndromes de Stevens–Johnson et necrolyse epidermique toxique) est liee a une atteinte specifique tracheobronchique de la maladie et peut necessiter le recours a la ventilation mecanique (VM). En dehors des constatations endoscopiques revelant un decollement de la muqueuse tracheobronchique, la physiopathologie de cette atteinte specifique a la phase aigue n’a ete que peu etudiee. Nous avons explore les caracteristiques de patients necessitant le recours a la VM a la phase aigue de la NE. Materiel et methodes Dans cette etude retrospective monocentrique, nous avons analyse les caracteristiques cliniques et du liquide bronchoalveolaire (LBA) de 15 patients admis en reanimation et mis sous VM pour NE en les comparant a 15 patients « temoins » apparies en âge et sexe, mis sous VM pour un syndrome de detresse respiratoire aigue (SDRA) d’origine infectieuse. Le dosage des cytokines (TNFα, IFNγ, IP10, IL8, IL10, IL6, IL13, GM-CSF, RAGE) dans le LBA a ete realise par technique Luminex (Human Magnetic Luminex assay, RD p = 0,7). Cependant, la composition du LBA etait differente : macrophagique chez les patients atteints de NE (mediane 74 % [50–80 %] vs 34 % [18–53] ; p = 0,001), neutrophilique chez les patients SDRA (mediane 53 % [40–75] vs 18 % [6–46] ; p = 0,002). Le pourcentage de lymphocytes n’etait pas different. Les concentrations alveolaires d’IL-13 etaient significativement superieures (p = 0,0056) et celles d’IL-6, d’IL-10 et de RAGE significativement inferieures (respectivement p = 0,0002 ; p = 0,047 ; p = 0,004) chez les patients NE comparativement aux SDRA. Les cytokines de type TH1 (TNFα, IFNγ, IP10, IL8, GM-CSF) n’etaient pas differentes. Les concentrations des cytokines dans le LBA des NE ne differaient pas selon la presence ou non d’un decollement bronchique macroscopique. Discussion Cette etude exploratoire met en evidence que, outre le phenomene de decollement tracheobronchique, il existe une inflammation pulmonaire au cours de la NE en phase aigue. Le profil inflammatoire des NE se distingue du SDRA par : – une agression tissulaire moins importante (moindre production IL6 et de RAGE) ; – la predominance d’infiltration macrophagique ; – une production accrue d’IL-13 en faveur d’un profil plus Th2. Cette inflammation alveolaire pourrait d’une part participer a la gravite du tableau initial, et d’autre part faire le lit des sequelles tardives observees a type de trouble de diffusion.

Aim Long-term high-fat diet (HFD) induces both cardiac remodelling and myocardial dysfunction in murine models. The aim was to assess the time course and mechanisms of metabolic and cardiac modifications induced by short-term HFD in wild-type (WT) mice. Methods and results Thirty-three WT mice were subjected to HFD (60% fat, n = 16) and chow diet (CD, 13% fat, n = 17). Metabolic and echocardiographic data were collected at baseline and every 5 weeks for 20 weeks. Invasive haemodynamic data and myocardial samples were collected at 5 and 20 weeks. Echocardiographic data included left ventricular (LV) diameters and thickness, and systolic function using radial strain rate (SR). Histological assessment of cardiomyocyte and adipocyte sizes, interstitial fibrosis, and apoptosis index were performed. During follow-up, body weight, and glycaemia levels were higher in HFD than in CD mice, in association with an early adipose tissue remodelling. Despite no difference between both groups in blood pressure and LV mass at 5 weeks, an early LV dysfunction was observed in HFD mice as assessed by radial SR (21 ± 0.8 vs. 27 ± 0.8 unit/s, P

Introduction Dans les necrolyses epidermiques (syndromes de Stevens-Johnson ou Lyell, NE), les mecanismes d’activation des lymphocytes cytotoxiques T CD8+ ne sont pas completement elucides. Le role de l’immunite innee est suspecte. L’IL-33 est une cytokine liberee par le noyau des cellules epitheliales en cas de dommage tissulaire comme signal de danger. Ses taux sont normalement regules par sST2, recepteur soluble, qui bloque son action. Une etude preliminaire (JDP 2017) avait mis en evidence des niveaux differents de sST2 dans le serum des patients atteints de NE et ceux atteints de PEAG. Ces resultats suggerant une activation de la voie de l’IL-33 dans les NE, nous avons etudie son role potentiel dans les NE. Materiel et methodes Nous avons dose par Luminex l’IL-33 dans le liquide de bulle (n = 11) et le serum (n = 24) de patients avec NE en phase aigue, et les avons compares aux dosages seriques de 25 patients avec exanthemes maculopapuleux (EMP) et 11 donneurs sains. Un marquage de l’IL-33 en immunohistochimie (IHC) sur biopsies cutanees en paraffine de NE (n = 4), EMP (n = 4) et donneurs sains (n = 3) a ete realise. Nous avons realise des marquages en cytometrie de flux sur cellules mononucleees circulantes (PBMC, n = 8) et liquides de bulles (n = 8) de NE pour identifier les cellules exprimant le recepteur transmembranaire (ST2L) de l’IL-33. (etude financee par la bourse de Master 2 SFD). Resultats Les taux d’IL-33 etaient tres eleves dans les liquides de bulles par rapport aux serums des NE. La concentration d’IL-33 etait significativement augmentee dans le serum des NE par rapport aux EMP et aux donneurs sains ( Fig. 1 ). En IHC, un marquage nucleaire de l’IL-33 sur les keratinocytes etait observe dans la peau saine. Dans les EMP, ce marquage etait plus ou moins diminue ; en revanche dans les NE, il etait toujours minime voire absent ( Fig. 2 ). L’etude en cytometrie en flux a mis en evidence dans les liquides de bulles et les PBMC de NE deux populations exprimant ST2L : (i) des lymphocytes T CD8+ cytotoxiques et (ii) des cellules Natural Killer (NK) cytotoxiques. Discussion Nos resultats montrent des taux eleves d’IL-33 dans le liquide de bulles de NE. L’IL-33 est liberee par les keratinocytes necrotiques, comme en temoignent les IHC : marquage nucleaire en peau saine et disparition de ce marquage dans la NE. L’IL-33 se fixe sur les lymphocytes T CD8+ et NK et augmenterait ainsi leur pouvoir cytotoxique. Une boucle amplificatrice se mettrait en place : l’IL-33 liberee par la mort des keratinocytes augmenterait la capacite cytotoxique des T CD8+ ce qui entretiendrait le relargage d’IL-33. Des medicaments bloquant l’IL-33 sont en cours de developpement dans certaines pathologies comme l’asthme, et pourraient presenter un interet majeur dans le traitement des NE. Conclusion La voie de l’IL-33 est activee dans les NE et amplifierait la reaction cytotoxique. Il pourrait s’agir d’une piste therapeutique interessante, ciblant les cellules cytotoxiques.

International audience; Objective: Anti-transcription intermediary factor 1γ (anti-TIF1γ) antibodies are the main predictors of cancer in dermatomyositis (DM). Yet, a substantial proportion of anti-TIF1γ-positive DM patients do not develop cancer. This study was undertaken to identify biomarkers to better evaluate the risk of cancer and mortality in DM.Methods: This multicenter study was conducted in adult anti-TIF1γ-positive DM patients from August 2013 to August 2017. Anti-TIF1γ autoantibody levels and IgG subclasses were identified using a newly developed quantitative immunoassay. Age, sex, DM signs and activity, malignancy, and creatine kinase (CK) level were recorded. Risk factors were determined by univariate and multivariate analysis according to a Cox proportional hazards regression model.Results: Among the 51 adult patients enrolled (mean ± SD age 61 ± 17 years; ratio of men to women 0.65), 40 (78%) had cancer and 21 (41%) died, with a mean ± SD survival time of 10 ± 6 months. Detection of anti-TIF1γ IgG2 was significantly associated with mortality (P = 0.0011) and occurrence of cancer during follow-up (P < 0.0001), with a 100% positive predictive value for cancer when the mean fluorescence intensity of anti-TIF1γ IgG2 was >385. None of the patients developed cancer after 24 months of follow-up. Univariate survival analyses showed that mortality was also associated with age >60 years (P = 0.0003), active DM (P = 0.0042), cancer (P = 0.0031), male sex (P = 0.011), and CK level >1,084 units/liter (P = 0.005). Multivariate analysis revealed that age >60 years (P = 0.015) and the presence of anti-TIF1γ IgG2 (P = 0.048) were independently associated with mortality.Conclusion: Our findings indicate that anti-TIF1γ IgG2 is a potential new biomarker of cancer that should be helpful in identifying the risk of mortality in anti-TIF1γ-positive DM patients.

The observation that COPD is an independent risk factor for cardiovascular disease (CVDs) comes from comparisons between smokers with COPD and smokers without COPD. The mechanisms that explain increased risk of CVD in patients with COPD are still unclear.The goal of this study was to assess systemic arterial stiffness (a predictor of CVD mortality) and to evaluate its determinants in a group of patients with mild to moderate COPD secondary to organic dust exposure, tobacco smoking, or both.Systemic arterial stiffness was assessed by using aortic pulse wave velocity (aPWV). Measurements were made in 142 patients with COPD and 155 healthy control subjects matched for age, sex, BMI, and tobacco smoking, exposed to tobacco smoking (n = 56/70 for COPD/control subjects, respectively), organic dusts (n = 44/48), or both (n = 42/37).aPWV was higher in COPD than in healthy controls in subjects exposed to tobacco smoking and to both organic dusts and tobacco smoking. By contrast, among never smokers exposed to organic dusts, patients with COPD and matched control subjects had similar aPWV. Multivariate analysis of the 142 patients with COPD (exposed to tobacco smoking and/or to organic dusts) showed that tobacco smoking was associated with high aPWV. Moreover, soluble suppression of tumorigenicity 2, a marker of major cardiovascular events, was correlated with aPWV in these patients.Analysis of an unselected group of patients with COPD with different causes suggests that: (1) COPD by itself is not sufficient to explain increased aPWV; and (2) tobacco smoking is a risk factor for elevated aPWV in COPD.

Pisetsky et al recently reported substantial variability between two antinuclear antibodies (ANA) indirect immunofluorescence (IIF) assays as well as one solid-phase assay (SPA) from different manufacturers in a study of a cross-sectional cohort of systemic lupus erythematosus (SLE) patients.1 This publication triggered several responses related to the performance of IIF for ANA detection.2–6 Bizzaro questioned whether ANA testing by IIF can be replaced by SPAs for the diagnosis of ANA-associated rheumatic disorders (AARD).7 On the basis of his experience and a literature review, he concluded that (1) overall screening by SPAs yields results that are at least comparable to the sensitivity of ANA-IIF results, (2) the performance of the assays depends on the disease being investigated and (3) the best diagnostic strategy seems to be the concomitant use of the two methods,7 which is in accord with previous suggestions.8 We hereby further illustrate that combining SPA with IIF adds value based on the data from a recently published study of 480 patients with AARD [SLE (n=119), primary Sjogren’s syndrome (SjS, n=65), systemic sclerosis (SSc, n=220), idiopathic inflammatory myopathies (IIM, n=50) and mixed connective tissue disease (n=56)] and 767 diseased controls.9 ANA detection was performed by automated IIF (NOVA View, Inova Diagnostics, San Diego, CA, …