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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.

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 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.

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

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.

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.

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

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.

In an effort to find naturally occurring substances that reduce cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins were first discovered by Endo in 1972. With the widespread prescription and use of statins to decrease morbidity from myocardial infarction and stroke, it was noted that approximately 5% of all statin users experienced muscle pain and weakness during treatment. In a smaller proportion of patients, the myopathy progressed to severe morbidity marked by proximal weakness and severe muscle wasting. Remarkably, Mammen and colleagues were the first to discover that the molecular target of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is an autoantibody target in patients that develop an immune-mediated necrotizing myopathy (IMNM). These observations have been confirmed in a number of studies but, until today, a multi-center, international study of IMNM, related idiopathic inflammatory myopathies (IIM), other auto-inflammatory conditions and controls has not been published. Accordingly, an international, multi-center study investigated the utility of anti-HMGCR antibodies in the diagnosis of statin-associated IMNM in comparison to different forms of IIM and controls. This study included samples from patients with different forms of IIM (n=1250) and patients with other diseases (n=656) that were collected from twelve sites and tested for anti-HMGCR antibodies by ELISA. This study confirmed that anti-HMGCR autoantibodies, when found in conjunction with statin use, characterize a subset of IIM who are older and have necrosis on muscle biopsy. Taken together, the data to date indicates that testing for anti-HMGCR antibodies is important in the differential diagnosis of IIM and might be considered for future classification criteria.

International audience; We report here the case of a 50-years-old man treated for mixed ă connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein ă (U1RNP) antibodies who secondarily developed a granulomatosis with ă polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil ă cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of ă the association between anti-U1RNP and anti-PR3-ANCA antibodies by a ă systematic retrospective study in ten European hospitals. Overall, out ă of 11,921 samples analyzed for both auto-antibodies, 18 cases of ă anti-U1RNP and anti-PR3-ANCA double positivity were found and only one ă patient presented with both MCTD and GPA symptoms. Our retrospective ă analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double ă positivity is infrequent and very rarely associated with both MTCD and ă GPA. Our observation describes for the first time the coexistence of ă MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP ă and ANCA antibodies was rarely reported in the literature. Eleven cases ă of MCTD and ANCA vasculitis have been reported to date, with only two ă cases with anti-PR3-ANCA association, and only one vasculitis. The seven ă other cases reported in the literature presented with an association of ă MCTD and microscopic polyangiitis which appears to be a more frequent ă presentation than MTCD associated with GPA.

Summary Background There is no evidence that therapeutic drug monitoring is helpful in patients with inflammatory bowel disease patients in clinical remission with infliximab therapy. Methods Eighty consecutive inflammatory bowel disease patients in clinical remission on infliximab maintenance therapy were included and followed-up for at least one year. Infliximab trough level and antibody to infliximab concentration were measured prior to enrollment. At the time of enrollment, physicians in charge were free to alleviate infliximab therapy. Discrepancies between blind and therapeutic drug monitoring-based adjustments were assessed at the end of the follow-up period. Relapse-free survival was analyzed using univariate and multivariate analyses. Results The mean infliximab trough level was 3.1 μg/mL. Antibody to infliximab was found in 15 (19%) patients. At the end of the follow-up period, 18 (22.5%) patients experienced a relapse. The 3, 6, 9 and 12-month relapse-free rates were 98%, 87%, 86% and 80%, respectively. In our multivariate analysis, relapse-free survival was negatively associated with discrepancies between therapeutic drug monitoring-based and blind adjustments of infliximab therapy, absence of concomitant immunomodulator, the absence of mucosal healing, prior use of infliximab, infliximab therapy duration > 2 years and C-reactive protein levels > 5 mg/L at the time of enrollment. Conclusion In patients with inflammatory bowel disease in clinical remission on infliximab therapy, de-escalation of infliximab therapy should be considered based on therapeutic drug monitoring rather than according to symptoms and CRP.

Solid phase assays (SPAs) and automated microscope systems are increasingly used to screen for antinuclear antibodies (ANAs). The goal of this study was to evaluate the performance of three automated ANA screening assays; NOVA Lite HEp-2 using NOVA View® (NV, Inova Diagnostics), an automated indirect immunofluorescence method, EliA™ CTD Screen (Fluorescence Enzyme Immunoassay, FEIA; Thermo Fisher) and QUANTA Flash® CTD Screen Plus (Chemiluminescence immunoassay, CIA; Inova Diagnostics). The assays were performed on 480 diagnostic samples from patients with an ANA-associated rheumatic disease (AARD; systemic lupus erythematosus, primary Sjögren's syndrome, systemic sclerosis, inflammatory myopathy, mixed connective tissue disease) and on 767 samples from diseased and healthy controls. Using cut-offs proposed by the manufacturers, the sensitivity was 95%, 80.5% and 86% for NV, FEIA and CIA, respectively. The corresponding specificity was 61% (NV), 97.5% (FEIA) and 88% (CIA). The sensitivity associated with a specificity of ~95% was 79%, 82% and 78% for NV, FEIA, and CIA, respectively. Receiver operating characteristics (ROC) curve analysis revealed no differences in area under the curve (AUC) between the 3 assays when all diseases were grouped. For Sjögren's syndrome, the AUC was higher for SPAs than for NV, whereas for systemic sclerosis, the AUC was higher for NV than for CIA. For all assays, the likelihood ratio for AARD increased with increasing antibody levels and for double positivity of NV with SPA. In conclusion, the performance of automated SPA and IIF was assay- and disease-dependent. Taking into account antibody levels and combining IIF with SPA adds value. ispartof: Autoimmunity Reviews vol:17 issue:6 pages:533-540 ispartof: location:Netherlands status: published

Background: Aging induces cardiac structural and functional changes linked to the increased deposition of extracellular matrix proteins, including OPN (osteopontin), conducing to progressive interstitial fibrosis. Although OPN is involved in various pathological conditions, its role in myocardial aging remains unknown. Methods: OPN deficient mice (OPN-/-) with their wild-type (WT) littermates were evaluated at 2 and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. OPN expression was determined by reverse-transcription polymerase chain reaction, immunoblot and immunofluorescence. Luminex assays were performed to screen plasma samples for various cytokines/adipokines in addition to OPN. Similar explorations were conducted in aged WT mice after surgical removal of visceral adipose tissue (VAT) or treatment with a small-molecule OPN inhibitor agelastatin A. Primary WT fibroblasts were incubated with plasma from aged WT and OPN-/- mice, and evaluated for senescence (senescence-associated β-galactosidase and p16), as well as fibroblast activation markers (Acta2 and Fn1). Results: Plasma OPN levels increased in WT mice during aging, with VAT showing the strongest OPN induction contrasting with myocardium that did not express OPN. VAT removal in aged WT mice restored cardiac function and decreased myocardial fibrosis in addition to a substantial reduction of circulating OPN and transforming growth factor β levels. OPN deficiency provided a comparable protection against age-related cardiac fibrosis and dysfunction. Intriguingly, a strong induction of senescence in cardiac fibroblasts was observed in both VAT removal and OPN-/- mice. The addition of plasma from aged OPN-/- mice to cultures of primary cardiac fibroblasts induced senescence and reduced their activation (compared to aged WT plasma). Finally, Agelastatin A treatment of aged WT mice fully reversed age-related myocardial fibrosis and dysfunction. Conclusions: During aging, VAT represents the main source of OPN and alters heart structure and function via its profibrotic secretome. As a proof-of-concept, interventions targeting OPN, such as VAT removal and OPN deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. Our work uncovers OPN’s role in the context of myocardial aging and proposes OPN as a potential new therapeutic target for a healthy cardiac aging.

Background: ELISA-BP180 values and direct immunofluorescence (DIF) are prognostic factors for relapse after treatment cessation in bullous pemphigoid (BP). Objective: To determine the relevance of ELISA-BP230 antibodies for predicting relapse 6 months after treatment cessation. Methods: We retrospectively selected patients with BP and available data from ELISA-BP180 and -BP230 and DIF performed at treatment cessation. The rate of relapse was calculated at 6 months. We compared ELISA-BP180 and -BP230 values and DIF in patients with relapse and remission. Results: We included 97 patients. At 6 months, 25.6% of patients showed relapse. The proportion of patients with an ELISA-BP230 value ≥27 UA/ml was higher, but not significantly, for those with relapse than for those with remission (p = 0.11). The frequency of positive DIF findings was significantly higher for patients with relapse (p = 0.005). Conclusion: DIF is of better value than ELISA-BP180 and -230 tests to predict relapse after treatment cessation in BP.

To evaluate the predictive value of soluble suppression of tumorigenicity 2 (sST2), a decoy receptor of IL-33 involved in several inflammatory and immune diseases, for death in HIV infection.Patients enrolled in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients, who had a plasma sample available in the biobank were systematically eligible.sST2, soluble CD14 (sCD14) and IL-6 were measured using Luminex multiplex bead-based technology (RD Systems) and a Bio-Plex 200 instrument (BioRad). Predictive capacities of sST2, sCD14, IL-6 and of the Veterans Aging Cohort Study clinical score at baseline on overall mortality were compared using multivariable Cox proportional hazards models.During a median follow-up of 7.2 years [interquartile range (IQR): 6.0; 7.9], 93 deaths from all causes (incidence rate 9.9 per 1000 patient-years; 95% confidence interval 7.9-11.9) were reported in 1414 patients. The median sST2 baseline concentration was 22.9 ng/ml (IQR: 17.7; 30.3) and was higher (30.8 ng/ml, IQR: 21.5; 42.1) in patients who died as compared with those who stayed alive (22.6 ng/ml; IQR: 17.5; 29.6) (P 10). An increased risk of death of 21% for a concentration 10.0 ng/ml higher of sST2 remained after adjustment for sCD14, IL-6 and Veterans Aging Cohort Study score (adjusted hazard ratio: 1.21; P 10). The predictive capacity of sST2 was confirmed in a validation cohort (n = 386, 31 deaths) with an improved area c-index from 0.804 without sST2 to 0.811 with sST2.sST2 is a new valuable biomarker to evaluate the risk of all-cause mortality in HIV disease.

Background We hypothesized that low-grade inflammation was driven by microbial translocation and associated with an increased risk of health care-associated infections (HAIs). Methods We included 121 patients aged 75 years or over in this prospective cohort study. High-sensitivity C-reactive protein (hs-CRP), I-FABP, and sCD14-as markers for low-grade inflammation, intestinal epithelial barrier integrity, and monocyte activation, respectively-were measured at admission. Results HAIs occurred during hospitalization in 62 (51%) patients. Elevated hs-CRP (≥6.02 mg/L, ie, the median) was associated with a significantly higher HAI risk when I-FABP was in the highest quartile (odds ratio [OR], 4; 95% confidence interval [95% CI], 1.39-11.49; p = .010). In patients with hs-CRP elevation and highest-quartile I-FABP, sCD14 elevation (≥0.65 µg/mL, ie, the median) was associated with an 11-fold higher HAI risk (OR, 10.8; 95% CI, 2.28-51.1; p = .003). Multivariate analyses adjusted for invasive procedures and comorbidities did not change the associations linking the three markers to the HAI risk. Conclusion Increased levels of hs-CRP, I-FABP, and sCD14 may reflect loss of intestinal epithelial barrier integrity with microbial translocation leading to monocyte activation and low-grade inflammation. In our cohort, these markers identified patients at high risk for HAIs.

BACKGROUND Linear IgA bullous dermatosis (LABD) is a clinically and immunologically heterogeneous, subepidermal, autoimmune bullous disease (AIBD), for which the long-term evolution is poorly described. OBJECTIVES To investigate the clinical and immunological characteristics, follow-up and prognostic factors of adult idiopathic LABD. METHODS This retrospective study, conducted in our AIBD referral centre, included adults, diagnosed between 1995 and 2012, with idiopathic LABD, defined as pure or predominant IgA deposits by direct immunofluorescence. Clinical, histological and immunological findings were collected from charts. Standard histology was systematically reviewed, and indirect immunofluorescence (IIF) on salt-split skin (SSS) and immunoblots (IBs) on amniotic membrane extracts using anti-IgA secondary antibodies were performed, when biopsies and sera obtained at diagnosis were available. Prognostic factors for complete remission (CR) were identified using univariate and multivariate analyses. RESULTS Of the 72 patients included (median age 54 years), 60% had mucous membrane (MM) involvement. IgA IIF on SSS was positive for 21 of 35 patients tested; 15 had epidermal and dermal labellings. Immunoelectron microscopy performed on the biopsies of 31 patients labelled lamina lucida (LL) (26%), lamina densa (23%), anchoring-fibril zone (AFz) (19%) and LL+AFz (23%). Of the 34 IgA IBs, 22 were positive, mostly for LAD-1/LABD97 (44%) and full-length BP180 (33%). The median follow-up was 39 months. Overall, 24 patients (36%) achieved sustained CR, 19 (29%) relapsed and 35% had chronic disease. CR was significantly associated with age > 70 years or no MM involvement. No prognostic immunological factor was identified. CONCLUSIONS Patients with LABD who are < 70 years old and have MM involvement are at risk for chronic evolution.

The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-alpha and interferon-gamma as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD.

International audience; Anti-signal recognition particle (SRP) antibodies are important serological markers for the diagnosis and the prognosis of idiopathic inflammatory myopathy (IIM), especially to distinguish immune-mediated necrotizing myopathy (IMNM). This study was set up to investigate the phenotype associated with anti-SRP antibodies and to evaluate the methods for detecting these antibodies. Clinical and biological data were retrospectively obtained from 60 adult patients with anti-SRP antibodies detected by a dot immunoassay from 12 centers. Thirty-six (60 %) out of these 60 patients suffered from an IIM, and among them, 21 patients were diagnosed as IMNM. Among patients with a definite IIM, proximal weakness and myalgia were prominent symptoms at the time of diagnosis. Only few patients displayed severe extra-muscular symptoms such as cardiac involvement or severe myositis. Mean creatine kinase levels were high for all patients except for two of them. When testing by indirect immunofluorescence (IIF) on HEp2 cells, the fraction of patients displaying the typical anti-SRP fine speckled staining of the cytoplasm was higher in patients with IIM (30/36) (83 %) than in patients with non-IIM (3/24) (12.5 %) (p

Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells. Pre-exposure of CD4(+) CD25(-) effector T cells to the Notch ligands Delta-4 and Jagged-1, but not Delta-1, increases significantly effector T-cell sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-β Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-sRII by binding the TGF-βRII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-β pathway leads to potentiation of the suppressive effect of Treg cells.

Background: The value of 230-kDa bullous pemphigoid antibody (BP230) enzyme-linked immunosorbent assay (ELISA) for the diagnosis of bullous pemphigoid (BP) was investigated, but in the immunological follow-up of the disease remains unknown. Objective: Evaluation of BP230 ELISA for diagnosis, follow-up and prediction of relapse in BP. Methods: Monocenter retrospective and prospective study. Patients with typical BP. Detection of autoantibodies by indirect immunofluorescence (IIF), BP180 and BP230 ELISA tests at diagnosis, during the treatment (disease control or failure) and at treatment stop (relapse or not 3 months after). Results: 74 patients were included. At diagnosis, BP230 ELISA sensitivity was lower than IIF and BP180 ELISA. Combining both ELISA added a weak gain of sensitivity. Both tests paralleled the clinical evolution, especially in case of disease control. At the end of the treatment, BP230 ELISA was not different in patients with or without relapse. Conclusion: In routine practice, BP230 ELISA does not seem to be a useful additional test in typical BP.

TPS334Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and ar...

Rationale Chronic obstructive pulmonary disease (COPD) is often associated with age-related systemic abnormalities that adversely affect the prognosis. Whether these manifestations are linked to the lung alterations or are independent complications of smoking remains unclear. Objectives To look for aging-related systemic manifestations and telomere shortening in COPD patients and smokers with minor lung destruction responsible for a decline in the diffusing capacity for carbon monoxide (DLCO) corrected for alveolar volume (KCO). Methods Cross-sectional study in 301 individuals (100 with COPD, 100 smokers without COPD, and 101 nonsmokers without COPD). Measurements and Main Results Compared to control smokers, patients with COPD had higher aortic pulse-wave velocity (PWV), lower bone mineral density (BMD) and appendicular skeletal muscle mass index (ASMMI), and shorter telomere length (TL). Insulin resistance (HOMA-IR) and glomerular filtration rate (GFR) were similar between control smokers and COPD patients. Smokers did not differ from nonsmokers for any of these parameters. However, smokers with normal spirometry but low KCO had lower ASMMI values compared to those with normal KCO. Moreover, female smokers with low KCO, had lower BMD and shorter TL compared to those with normal KCO. Conclusions Aging-related abnormalities in patients with COPD are also found in smokers with minor lung dysfunction manifesting as a KCO decrease. Decreased KCO might be useful, particularly among women, for identifying smokers at high risk for aging-related systemic manifestations and telomere shortening.

Objective Behcet's disease is a chronic, relapsing, multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers and by ocular, articular, vascular, and central nervous system involvement. The tumor necrosis factor α (TNFα) pathway is likely involved in the pathophysiology of Behcet's disease. One of the 2 TNFα receptors is TNF receptor superfamily 1A (TNFRSF1A). We searched for R92Q TNFRSF1A mutations in patients with Behcet's disease. Methods A search for TNFRSF1A mutations was performed by polymerase chain reaction amplification of the TNFRSF1A gene, followed by denaturing high-performance liquid chromatography scanning. Results Among the 74 unrelated European patients with Behcet's disease, 5 (6.8%) carried the R92Q TNFRSF1A mutation. The frequency of the R92Q mutation in patients with Behcet's disease was significantly higher than that in controls (P = 0.006 by Fisher's exact test). Deep vein thrombosis was significantly associated with the R92Q mutation (P = 0.001 [with Bonferroni adjustment for multiple comparisons]). Among the 30 patients with thrombosis, 10 had cerebral thrombophlebitis. None of these patients had the R92Q mutation. Among the 20 patients with Behcet's disease who had extracranial deep vein thrombosis, 6 had the R92Q mutation, whereas 14 did not (P < 0.0001) Conclusion The R92Q mutation in patients with Behcet's disease is associated with an increased risk of extracranial venous thrombosis. This new finding may help in understanding the complex prothrombotic state in patients with Behcet's disease.

Importance The main component of the first-line treatment of pemphigus vulgaris is high doses of systemic corticosteroids, but adverse effects of these drugs are frequent and sometimes severe. Rituximab has shown effectiveness as a corticosteroid-sparing agent or in case of relapse. To our knowledge, the effectiveness of rituximab as a first-line treatment without systemic corticosteroids has not been evaluated. Observations Five women in their 50s, 60s, or 70s with pemphigus vulgaris (Pemphigus Disease Area Index score, 15-84 at diagnosis) and contraindications to systemic corticosteroid treatment received rituximab with high-potency topical corticosteroids as first-line treatment. All patients experienced a favorable response, with a mean time to healing of skin and mucosal lesions of 15 weeks. Two patients, with 42- and 48-month follow-up evaluations, did not experience relapse. Three patients developed 2 to 4 relapses, with effective retreatment achieved using rituximab and topical corticosteroids. No severe adverse effects were observed. Conclusions and Relevance Considering the high rate of severe adverse effects induced by prolonged administration of high doses of systemic corticosteroids, new therapeutic options are warranted in the treatment of pemphigus vulgaris. The combination of rituximab and topical corticosteroids could be considered in mild to severe cutaneous disease. Larger long-term studies are needed to evaluate the optimal treatment strategies according to the severity of the disease and the benefit-risk ratio of rituximab.

HLA class I polymorphism in Moroccan patients with Behcet’s disease has not been investigated so far. In this study, HLA-B∗ phenotype frequencies were analyzed in 86 unrelated Moroccan patients (45 males, 41 females) and 111 ethnically matched healthy controls. The predisposing effect of the B∗51 was confirmed (30.2% in patients and 15.3% in controls, OR = 2.39, 95% CI [1.2–4.8], p = 0.015). It was mostly observed in males with young age at disease onset (OR= 5.5 [1.9–15.9], p = 0.002 compared to controls). The Moroccan BD group also presented a previously unknown association with HLA-B∗15 (25.6% of patients versus 11.7% of controls, OR = 2.59 [1.2–5.5], p = 0.014), both in females and in males with late-onset of the disease. Altogether, the B∗15 and/or B∗51 alleles were expressed in 55.8% of patients compared to 27% of controls (OR = 3.4 [1.9–6.2], p P c = 0.003). Our data indicate HLA-B effects on BD pathogenesis should be considered separately for men and women.