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International audience; Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjögren's syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient's management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs.

Background Numerous inclusion and exclusion criteria are involved in phase III moderate to severe psoriasis trials investigating the safety and efficacy of biologics. This questions the generalization of results. Methods In this cohort study, we applied inclusion/exclusion criteria for phase III trials from original protocols (adalimumab - REVEAL, ustekinumab - PHOENIX, brodalumab - AMAGINE, secukinumab FIXTURE) to all patients enrolled in the PsoBioTeq prospective registry who received a biological agent for the first time between July 2012 and November 2017. We then compared the efficacy, drug survival and occurrence of adverse events between patients who satisfied/did not satisfy the eligibility criteria for these phase III trials. Results A total of 1267 patients were enrolled, of whom 993 (78.4%) were not eligible for at least one RCT (randomized controlled trial) and 251 (19.1%) did not meet the PASI/PGA severity requirements. Apart from disease severity, the most frequent criteria resulting in exclusion were as follows: non-plaque psoriasis (12.6%), significant cardiac disease (8.4%), significant liver disease (7.3%), elevated liver enzymes (4.9-9.6%) and personal history of diabetes (9.2%). There was no difference in drug survival between the two groups. The incidence ratio of adverse events was significantly lower in eligible versus non-eligible patients [0.78 (95% CI 0.62-0.97) (P = 0.03)]. Conclusion The majority of patients treated with biologics in the PsoBioTeq real-life registry would not have been eligible for phase III moderate to severe psoriasis trials. Patients not eligible for psoriasis phase III clinical trials have a higher incidence of adverse events.

IF 6.448 (2017); International audience; The Pemphigus Disease Area Index (PDAI) and Autoimmune Bullous Skin Disorder Intensity-Score (ABSIS) scores have been proposed to provide an objective measure of pemphigus activity. These scores have been evaluated only on already treated patients mainly with mild to moderate activity. The objective was to assess the interrater reliability of ABSIS and PDAI scores and their correlation with other severity markers in a large international study. Consecutive patients with newly diagnosed pemphigus were enrolled in 31 centers. Severity scores were recorded during a 24-month period by the same two blinded investigators. Serum was collected at each visit for ELISA measurement of anti-desmoglein antibodies. The intraclass correlation coefficient (ICC) and Spearman rank correlation coefficient were calculated. A total of 116 patients with pemphigus vulgaris (n = 84) or pemphigus foliaceus (n = 32) were included. At baseline, the ABSIS and PDAI ICCs were 0.90 (95% confidence interval [CI] = 0.85-0.93), and 0.91(95% CI = 0.87-0.94), respectively. The ICCs for PDAI were higher in moderate and extensive pemphigus (ICC = 0.82, 95% CI = 0.63-0.92 and ICC = 0.80, 95% CI = 0.62-0.90, respectively) than in patients with intermediate (significant) extent (ICC = 0.50, 95% CI = 0.27-0.68). Conversely, the ICCs for ABSIS were lower in patients with moderate extent (ICC = 0.44, 95% CI = 0.004-0.74) than in those with intermediate or extensive forms, (ICC = 0.69, 95% CI = 0.51-0.81 and ICC = 0.75, 95% CI = 0.51-0.88, respectively). During patients' follow-up, the ICCs of both ABSIS and PDAI scores remained higher than 0.70. ABSIS and PDAI skin (r = 0.71 and r = 0.75) but not mucosal (r = 0.32 and r = 0.37) subscores were correlated with the evolution of anti-DSG1 and anti-DSG3 ELISA values, respectively. ABSIS and PDAI scores are robust tools to accurately assess pemphigus activity.

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International audience

IntroductionAnti-glomerular basement membrane (GBM) antibodies are pathogenic antibodies first detected in renal-limited anti-GBM disease and in Goodpasture disease, the latter characterized by rapidly progressive crescentic glomerulonephritis combined with intra-alveolar hemorrhage. Studies have suggested that anti-GBM antibody positivity may be of interest in lupus nephritis (LN). Moreover, severe anti-GBM vasculitis cases in patients with systemic lupus erythematosus (SLE) have been described in the literature, but few studies have assessed the incidence of anti-GBM antibodies in SLE patients.ObjectiveThe main study objective was to determine if positive anti-GBM antibodies were present in the serum of SLE patients with or withoutproliferativerenal damage and compared to a healthy control group.MethodologyThis retrospective study was performed on SLE patients’ sera from a Franco-German European biobank, developed between 2011 and 2014, from 17 hospital centers in the Haut-Rhin region. Patients were selected according to their renal involvement, and matched by age and gender. The serum from healthy voluntary blood donors was also tested. Anti-GBM were screened by fluorescence enzyme immunoassay (FEIA), and then by indirect immunofluorescence (IIF) in case of low reactivity detection (titer >6 U/ml).ResultsThe cohort was composed of 100 SLE patients withproliferativeLN (27% with class III, 67% with class IV, and 6% with class V), compared to 100 SLE patients without LN and 100 controls. Patients were mostly Caucasian and met the ACR 1997 criteria and/or the SLICC 2012 criteria. Among the 300 tested sera, no significant levels of anti-GBM antibodies were detected (>10 U/ml) by the automated technique, three sera were found “ambivalent” (>7 U/ml): one in the SLE with LN group and two in the SLE without LN group. Subsequent IIF assays did not detect anti-GBM antibodies.ConclusionAnti-GBM antibodies were not detected in the serum of Caucasian patients with SLE, even in case of renal involvement, a situation favoring the antigenic exposure of glomerular basement membranes. Our results reaffirm the central role of anti-GBM antibodies as a specific diagnostic biomarker for Goodpasture vasculitis and therefore confirm that anti-GBM antibody must not be carried out in patients with SLE (with or without LN) in the absence of disease-suggestive symptoms.

Background Palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are rare variants of psoriasis. Knowledge of the efficacy of biologics is scarce. Objectives To evaluate the real-life efficacy of tumour necrosis factor blockers and ustekinumab in PPP and in ACH. Methods A multicentre retrospective descriptive study was conducted in 19 dermatology departments, including all patients with PPP or ACH seen from 2014 to 2016 who received one of the studied biologics. The data were collected by a standardized document. Factors associated with complete clearance (CC) were analysed by multivariate analysis, estimating odds ratios (ORs) and 95% confidence intervals (CIs). Results Among 92 patients included, 50 received adalimumab, 44 ustekinumab, 36 etanercept and 31 infliximab. Improvement and CC were observed in 83.9% and 20.0% patients receiving infliximab, 75.0% and 38.6% ustekinumab, 57.1% and 20.0% etanercept and 60.4% and 29.2% adalimumab. We found no significant difference in CC rates or duration of treatment among the biological treatments (P = 0.18 and P = 0.10, respectively). On multivariate analysis, CC with etanercept was associated with the ACH form and not smoking [OR = 9.5 (95% CI 1.1-82.7), P = 0.04 and 0.1 (0.01-0.9), P = 0.04]; with ustekinumab, male sex and absence of obesity [6.0 (1.3-28.6), P = 0.02 and 4.7 (1.0-22.7), P = 0.05]; with adalimumab, the ACH form [11.9 (2.7-52.3), P = 0.001]; and with infliximab, obesity [5.6 (1.1-29.4), P = 0.04]. Conclusions We found no difference in efficacy between TNF blockers and ustekinumab and among the three different TNF blockers in real life for PPP or ACH, which reveals the heterogeneity of clinical response to biologics in pustular psoriasis as compared with plaque psoriasis.

Highlights • Severe COVID-19 patients present overwhelming inflammatory reactions leading to lung injury. • Corticosteroids may beneficially modulate the host immune response to COVID-19 pneumonia. • Before–after study evaluating the effect of corticosteroid addition to COVID-19 pneumonia treatment on hospital mortality. • In multivariate analysis, the ‘after’ period was associated with an adjusted lower risk of death (aHR = 0.47; P = 0.04). • ‘After’ period was also associated with lower risk of ICU admission or death before ICU admission (aHR = 0.37; P < 0.001)., Anti-inflammatory drugs such as corticosteroids may beneficially modulate the host inflammatory response to coronavirus disease 2019 (COVID-19) pneumonia. The aim of this study was to evaluate the impact of addition of corticosteroids to the hospital protocol for treatment of suspected or confirmed COVID-19 pneumonia on rates of death or intensive care unit (ICU) admission. A before–after study was performed to evaluate the effect of addition of corticosteroids to our institution's COVID-19 treatment protocol on hospital mortality. A total of 257 patients with a COVID-19 diagnosis were included in this study between 3 March 2020 and 14 April 2020. As corticosteroids were widely used after 27 March 2020, two periods were considered for the purposes of this study: the ‘before’ period from 3–20 March 2020 (n = 85); and the ‘after’ period from 26 March–14 April 2020 (n = 172). The ‘after’ period was associated with a lower risk of death [adjusted hazard ratio (aHR) = 0.47, 95% confidence interval (CI) 0.23–0.97; P = 0.04] and a lower risk of ICU admission or of death before ICU admission (aHR = 0.37, 95% CI 0.21–0.64; P = 0.0005) by multivariate analysis adjusted for age, National Early Warning score and institutionalisation status. In conclusion, addition of corticosteroids to our institution's COVID-19 treatment protocol was associated with a significant reduction in hospital mortality in the ‘after’ period.

International audience; Rationale: Lymphoid interstitial pneumonia is a rare benign pulmonary lymphoproliferative disorder usually presenting with a subacute or chronic condition and frequently associated with autoimmune disorders, dysgammaglobulinemia, or infections. Patient concerns: A 74-year-old woman with no past medical history presented with acute dyspnea, nonproductive cough, hypoxemia (room air PaO 2 : 48 mmHg) and bilateral alveolar infiltrates with pleural effusion. Antibiotics and diuretics treatments did not induce any improvement. No underlying condition including cardiac insufficiency, autoimmune diseases, immunodeficiency, or infections was found after an extensive evaluation. Bronchoalveolar lavage revealed a lymphocytosis (60%) with negative microbiological findings. High-dose intravenous corticosteroids induced a mild clinical improvement only, which led to perform a surgical lung biopsy revealing a lymphoid interstitial pneumonia with no sign of lymphoma or malignancies. Diagnoses: Acute severe idiopathic lymphoid interstitial pneumonia. Interventions: Ten days after the surgical lung biopsy, the patient experienced a dramatic worsening leading to invasive mechanical ventilation. Antibiotics and a new course of high-dose intravenous corticosteroids did not induce any improvement, leading to the use of rituximab which was associated with a dramatic clinical and radiological improvement allowing weaning from mechanical ventilation after 10 days. Outcomes: Despite the initial response to rituximab, the patient exhibited poor general state and subsequent progressive worsening of respiratory symptoms leading to consider symptomatic palliative treatments. The patient died 4 months after the diagnosis of lymphoid interstitial pneumonia. Lessons: Idiopathic lymphoid interstitial pneumonia may present as an acute severe respiratory insufficiency with a potential transient response to rituximab. Abbreviations: EBV = Epstein-Barr virus, HIV = human immunodeficiency virus, HTLV-1 = human T-cell lymphotropic virus-1, LIP = lymphoid interstitial pneumonia.

IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2–41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.

International audience

International audience; Background-Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. Objective-We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. Methods-A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. Results-The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. Limitations-Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. Conclusions-We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus. Keywords CD20 inhibitor; consensus; guidelines; pemphigus foliaceus; pemphigus vulgaris; treatment Pemphigus encompasses a spectrum of rare mucocutaneous bullous diseases that are autoimmune in origin. Because of the rarity of these diseases, it can take patients months before their pemphigus is diagnosed, during which time many are treated for other blistering diseases. 1,2 Even once the diagnosis has been made, treatment regimens can vary greatly, as

Bullous Pemphigoid is the most common auto-immune bullous skin disease. It is characterized by the production of auto-antibodies directed against 2 proteins of the hemi-desmosome (BP180 and BP230). We assessed the efficacy and mechanisms of action of rituximab, an anti-CD20 monoclonal antibody, in 17 patients with severe and relapsing type of bullous pemphigoid. The phenotype, cytokine gene expression, and rearrangement of BP180-specific B-cell receptor genes were performed over 2 years following treatment. At the end of the study, 5 patients had died, 3 had withdrawn from the study, and 9 patients were in complete remission. The one- and two-year relapse rates were 44.1% (95% Confidence Interval (CI): 21.0–76.0%) and 66.5%, (95% CI: 38.4–91.4%), respectively. Phenotypic analyses confirmed dramatic B-cell depletion, which lasted for 9 to 12 months. The ELISA values of serum anti-BP180 antibodies and the frequency of BP180-specific circulating B cells decreased dramatically following treatment, which paralleled the improvement of skin lesions. During B-cell reconstitution, a polyclonal IgM repertoire appeared and a shift in the rearrangement of the B-cell receptor genes of BP180-specific circulating B cells was observed. Concurrently, we observed a decrease of IL-15, IL-6 and TNFα expressing BP180-specific B cells, and the emergence of IL-10 and IL-1RA-expressing BP180-specific IgM+ B cells in patients in complete remission off therapy, suggesting the functional plasticity of BP180-specific auto-immune B cells after rituximab treatment.

Summary Background Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid‐related adverse events (AEs) is unproven. Objectives To utilize data collected in a French investigator‐initiated, phase III, open‐label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. Methods This was an independently conducted post hoc analysis of the moderate‐to‐severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg−1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg−1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24‐month efficacy and safety results were also reported. Results At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab‐plus‐prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS‐related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. Conclusions In patients with moderate‐to‐severe PV, rituximab plus short‐term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life‐threatening CS‐related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus.Corticosteroids, a standard first‐line treatment for PV, have significant side‐effects.Although their effects are unproven, adjuvant corticosteroid‐sparing agents are routinely used to minimize steroid exposure and corticosteroid‐related side‐effects.There is evidence that the anti‐CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator‐initiated trial.Rituximab plus prednisone had a steroid‐sparing effect and more patients achieved complete remission off prednisone.Fewer patients experienced grade 3 or grade 4 steroid‐related adverse events than those on prednisone alone.This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate‐to‐severe PV., Linked Comment: Scorer et al. Br J Dermatol 2020; 182:1078–1079.

Resume La sclerodermie systemique est une connectivite rare, caracterisee par une fibrose de la peau et de differents organes internes, une vasculopathie systemique et des anomalies de l’immunite innee et adaptative. Des dysfonctions des fibroblastes, des cellules endotheliales et des lymphocytes, mais egalement d’autres cellules de l’immunite sont de mieux en mieux decrites, meme si l’origine exacte et la chronologie de ces anomalies restent inconnues. Le stress oxydatif semble jouer un role cle dans la maladie. Il semble en effet implique tres precocement dans le developpement de la fibrose, de la vasculopathie et dans les anomalies de la tolerance immunitaire observees chez tous les patients, bien que l’expression de la maladie soit tres heterogene. Ce stress semble influence par des facteurs genetiques et environnementaux. Sur le plan therapeutique, il n’existe actuellement aucun traitement curatif. Des immunosuppresseurs et des molecules actives sur l’atteinte vasculaire sont proposes dans certains cas avec une efficacite variable d’un patient a l’autre et globalement moderee. Seule l’autogreffe de cellules souches hematopoietiques, reservee aux formes severes ou rapidement progressives, a montre une regression de la fibrose prolongee ainsi qu’une reduction de la morbi-mortalite, mais expose a une potentielle toxicite. Au cours de la derniere decennie, de nouveaux mecanismes impliques dans la physiopathologie de la sclerodermie systemique ont ete decouverts, offrant de nouvelles perspectives therapeutiques. Dans cette revue, nous nous proposons de faire le point sur les recentes avancees dans la connaissance de la physiopathologie de la sclerodermie systemique et leurs implications dans la prise en charge therapeutique, actuelle et future.

Tumour necrosis factor-α [TNF-α] inhibitors have revolutionised the management of chronic inflammatory conditions. A number of cutaneous adverse events have been reported with TNF inhibition, including vasculitis. Most reactions are mild and rarely warrant treatment withdrawal. Here we describe a patient with Crohn’s disease treated with adalimumab in whom severe multivisceral Henoch-Schönlein purpura developed, including neurological involvement, requiring definitive TNF blocker withdrawal.

International audience

International audience; Anti-SS-A antibodies are often sought for in autoimmune diseases diagnosis. Two different target proteins have actually been identified: Ro52 and Ro60. Clinical and immunological associations seem different depending on anti-Ro52 or anti-Ro60 antibodies presence. However, due to a heterogeneous presentation in the literature, some immunology laboratories in France have stopped providing anti-Ro52 antibody findings. We report here a new hospital study designed to determine the diagnostic utility of the separate detection of anti-Ro52 and anti-Ro60 antibodies. We conducted a retrospective, observational study, including every adult patient with positive antinuclear antibodies (ANA) tested in our immunology laboratory, and associated with anti-Ro52 and/or anti-Ro60 antibodies, between 2011 and 2014. Out of 13032 sera tested for ANA, 399 adults had antibodies to Ro52 and/or Ro60; 81.7% were female, with a mean age of 54.5 ± 17.0 years. Anti-Ro52 antibodies were found in 75.7% of the patients and anti-Ro60 antibodies in 56.9%. Among them, 43.1% were classified in the Ro52 + Ro60- group, 32.6% in the Ro52 + Ro60 + group and 24.3% in the Ro52-Ro60+ group. In the Ro52-Ro60+ group, systemic lupus was the most frequent diagnosis (48.5%), with a possible association with antiphospholipid antibodies (anti-cardiolipin antibodies: OR 2.5 (CI95 [1.0–5.0], p = 0.05) and lupus anticoagulant {OR 3.6 (CI95 [1.10–10.0] p = 0.02)}. In the Ro52+Ro60+, primary Sjögren Syndrome was the most likely (OR 4.2 95% CI [2.1–8.3] p < 10−4), especially in patients Ro52+Ro60+La+. Patients with isolated anti-Ro52 had a wider variety of diseases associated, but among auto-immune diseases they were more prone to inflammatory myositis (OR 10.5 [1.4–81.7], p = 0.02) and inflammatory rheumatism (OR 4.6 [1.6–13.8], p = 0.006) in contrast to systemic lupus (OR 0.2 [0.1–0.3], p < 10−4) or primary Sjögren's syndrome (OR 0.1 [0.06–0.2], p < 10−4). We therefore suggest that, when anti-ENA antibodies are prescribed, it should include separate anti-Ro52 and anti-Ro60 antibodies determination. To go even further, we would like to suggest a change in ENA nomenclature to avoid confusion, abandoning the anti-SS-A label in favor of the anti-Ro52/TRIM21 or anti-Ro60 antibody for a clearer designation.

International audience; These guidelines were developed by the psoriasis research group of the French Society of Dermatology with the aim of providing updated decision-making algorithms for the systemic treatment of adult patients with moderate-to-severe psoriasis. Our algorithms were generated after rigorous evaluation of existing guidelines on the treatment of psoriasis and of publications concerning new systemic treatments, not yet incorporated into existing guidelines. A total of nine existing guidelines and 53 publications related to new systemic treatments were found to meet our criteria for use in the generation of the algorithms. We have proposed two new algorithms to assess therapeutic responses, both of which incorporate emerging criteria for evaluating treatment goals. Updated therapeutic strategy algorithms, incorporating both established and new systemic therapies, were also generated for the treatment of plaque psoriasis and psoriatic arthritis, together with recommendations for the treatment of particular forms of psoriasis and treatment of patients with comorbidities.

International audience; Bullous Pemphigoid (BP) is a skin autoimmune blistering disease characterized by immune-mediated degradation of the dermo-epidermal junction and release of a large number of inflammatory cytokines. Interleukin-1β (IL-1β) is a pleiotropic pro-inflammatory cytokine associated with inflammasome activation and known to be pivotal in several auto-immune and auto-inflammatory diseases. We sought to clarify the presence of inflammasome-dependent IL-1β and to investigate its role in BP. Skin biopsy specimens (n = 13), serum (n = 60), blister fluid (n = 26), and primary inflammatory cells from patients with BP were used to investigate inflammasome activation and function. We here highlighted a differential occurrence of a functional in situ inflammasome in patients with BP, biologically distinguished by IL-1β and NLRP3 expression. Clinically, elevated IL-1β levels were associated with the presence of erythema and urticarial plaques reflecting the inflammatory phase preceding blister formation. We further identified IL-17 and IL-23 as important molecules favoring IL-1β expression in monocyte-derived macrophages from BP patients. Finally, we demonstrated the ability of IL-1β to stimulate the release of the matrix metalloproteinase-9 in those macrophages, reinforcing the role of IL-1β in the auto-amplification loop of the inflammatory response associated to BP. However, whether this inflammasome is an epiphenomenon associated with BP disease or constitutes an amplification inflammatory step in certain patients still need to be determined. In the context of a precision medicine approach, our findings allowed us to delineate a subgroup of patients with BP that showed similarities with auto-inflammatory diseases. Subsequently, this opens up alternative therapeutic strategies targeting IL-1β pathway in the aim to control the early, pre-blistering inflammatory phase. Ultimately, this could also help in reducing the detrimental effects associated with high doses of corticosteroids treatment.

International audience; Inflammation is largely implicated in bullous pemphigoid (BP), the most frequent skin auto-immune blistering disease. IL-17, essentially IL-17A/F, has been involved in blister formation through regulation of protease production, and its specific serum profile within BP was related to disease outcome. However, relationships between IL-17 family ligands and receptors are quite complex with six different IL-17 isoforms, and five different receptors. We here aimed at clarifying the contribution of the IL-17 axis in BP by characterizing not only the expression of IL-17 receptor (IL-17R) members within immune cells isolated from BP patients (PMNs, n = 9; T-lymphocytes, n = 10; and monocytes, n = 10) but also the expression of IL-17 isoforms in sera (n = 83), and blister fluid (n = 31) of BP patients. We showed that at diagnosis, IL-17RA and IL-17RC expression were significantly increased in monocytes isolated from BP patients as compared to those from control subjects (p = 0.006 and p = 0.016, respectively). Notably, both IL-17RA and IL-17RC mRNA expression remained elevated in BP monocytes at time of relapse. We further demonstrated a significant increase of all IL-17 isoforms tested in BP blister fluid compared with BP serum (IL-17A, p < 0.0001; IL-17A/F, p < 0.0001; IL-17B, p = 0.0023; IL-17C, p = 0.0022; IL-17E, p < 0.0001). Among all, IL-17B was the only cytokine for which a significant decreased concentration within blister fluid was observed in BP patients with severe disease compared to patients with moderate disease (p = 0.012). We further evidenced a significant negative correlation between IL-17B levels and blister/erosion BPDAI subscore (r = −0.52, p = 0.003). We finally identified mast cells as a potential target of IL-17B in lesional skin of BP patients. In conclusion, we showed here that IL-17RA and IL-17RC expression in monocyte was associated with disease activity and evidenced in situ a negative correlation between BP disease activity and IL-17B, whose effects could be mediated by IL-17RB expressed by mast cell in BP lesional skin

International audience; Breast cancer (BC) is the most common cancer in women worldwide and remains a major cause of mortality with an expected 137,000 death this year in Europe. Standard management of metastatic BC comprises hormonotherapy, chemotherapy, and targeted therapies. Cyclin dependent kinase (CDK) and mammalian target of rapamycin (mTOR) inhibitors have recently proved their efficiency in hormonal receptor expressing BC. Checkpoint proteins inhibition is being evaluated in phase 3 studies. Since inflammation is constantly present in cancers, research teams have focused their attention on the interleukin-17 (IL-17) family of proinflammatory cytokines. Preclinical experiments have reported both pro and antitumor effects depending on the conditions. In the present article, we review the accumulating evidences about the roles of IL-17 in BC and discuss whether this family of cytokines could be a new target in anticancer treatments.

Anti-tumor necrosis factor (TNF)-α agents may induce skin reactions, in particular in patients with inflammatory bowel diseases (IBD). The objective of this study was to determine the efficacy of ustekinumab in these patients. IBD patients facing therapeutic issues because of cutaneous reactions or tolerance issues, consequently treated with ustekinumab in our department, were included. Retrospective review of case records and clinical photographs was carried out. Twenty-six patients were included. Twenty-three patients were treated for Crohn's disease and three for ulcerative colitis. Fourteen patients presented psoriasiform lesions, nine eczematiform lesions, four anaphylactoid reactions, two alopecia areata-like lesions, one injection-site reaction, one cutaneous polyarteritis nodosa and five other skin reactions. Most of them resolved under ustekinumab. In detail, eczematiform lesions completely resolved in all cases, psoriasiform lesions completely resolved in 12 cases (85.7%) and had partial response in two cases (14.3%). Two cases of alopecia areata showed complete response (complete hair regrowth). Fourteen patients showed complete digestive response, 10 patients partial digestive response (seven of which needed IBD treatment optimization) and only two failure. In conclusion, ustekinumab is a drug of choice in patients with IBD who cannot tolerate TNF blockers.

International audience; Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle, associated with considerable tissue remodelling. Although abnormal cytokine expression was detected both in perilesional and in uninvolved skin, up to now there is no model allowing a better understanding of the implicit inflammatory mechanisms in HS. The aim of this study was to investigate the inflammatory response in HS skin by mean of an ex vivo model culture. To that purpose, nine skin biopsy specimens from patients suffering from HS and controls were cultured up to 4 days. Microscopy imaging investigations showed variations of collagen I and III organization, and an increase in elastin fibres fragmentation in HS skin after 4 days of culture. The HS matrix structure remodelling was associated with high level of MMP-2 and MMP-9 in HS lesional skin. After 4 days of culture, the MMP expression in HS perilesional skin reached the level observed in HS lesional skin. Concomitantly, an increase in IL-1β concentration was observed in all skin samples after 4 days of culture, although IL-1β concentrations remained significantly higher in HS lesional skin as compared with control skin. Meanwhile, neither IL-17 concentrations nor the inflammasome components NLRP3 and caspase-1 varied. Thus, our HS skin model culture showed that MMP-induced matrix alteration could participate in HS inflammation by releasing biological active peptides and inflammatory factors from the extracellular matrix (ECM), and open new opportunities to investigate the regulation of the inflammatory mechanism associated with HS.

Importance Development of transient palmoplantar keratoderma (PPK) with bullous pemphigoid (BP) has only been described in 2 isolated case reports. The clinical significance and the pathophysiologic mechanisms of this association are unknown. Objective To examine the clinical characteristics and immunological profile of patients with BP who develop transient PPK and analyze therapeutic options and outcomes. Design, Setting, and Participants In this case series, patients with BP who developed acquired, transient PPK, and were treated at a single institution from January 1, 2015, through December 31, 2017, were studied. Main Outcomes and Measures Clinical and immunological activity of BP, treatment administrated before and after PPK appearance, and patient outcomes. Results Six patients with BP and transient PPK were identified and included in the study. There were 5 women and 1 man with a mean age of 72 years. At baseline, all patients had a generalized, multibullous BP and high serum anti-BP180 antibodies (mean, 130 U/mL; range, 73-150), whereas anti-BP230 antibodies were elevated in only 1 case. The PPK appeared a mean 6.2 (range, 2-12) months after BP diagnosis, following a prolonged period of disease activity with recurrent flares. When the PPK occurred, BP was uncontrolled on therapy (mean Bullous Pemphigoid Disease Activity Index [BPDAI] score, 57; range, 34-105; mean anti-BP180 antibodies titer, 122 U/mL; range, 81-150). On administration of additional systemic immunosuppressive therapies, the PPK healed progressively in a mean 4.3 months (range, 2-9), along with BP clinical remission in 4 of 6 patients. No relationship was found between PPK occurrence and anti-BP180/230 antibodies profiles. In contrast, blister fluids collected at the time of PPK displayed a much higher level of interleukin 1β (IL-1β) compared with those collected in the absence of PKK. Expression of IL-17A, IL-17F, and IL-22 was also enhanced in the blister fluid of patients with BP who had PPK Conclusions and Relevance To our knowledge, this is the first report of 6 cases of BP with transient PPK with extensive immunological investigation. The PPK appeared after a prolonged period of clinical BP activity punctuated with recurrent relapses, was transient, and healed after BP control with additional immunosuppressive therapy. Enhanced expression of a particular cytokine panel in the blister fluid at time of PPK could support keratinocyte proliferation as described in patients with psoriasis. Transient PPK could represent a clinical marker of severe, treatment-resistant BP.

International audience; Background: The outcome of bullous pemphigoid (BP), the most frequent autoimmune skin-blistering disease, involves matrix metalloproteinase 9 (MMP-9), IL-17, and IL-23 release from infiltrated inflammatory cells. The chemokine CXCL10 has been associated with several autoimmune diseases, but its participation in BP pathophysiology still needs to be clarified. Objective: We sought to assess whether BP outcome was associated with different CXCL10 levels and to evaluate the contribution of CXCL10 to the described cytokine/protease inflammatory loop associated with disease outcome. Methods: Skin biopsy specimens (n 5 16), serum (n 5 114), blister fluid (n 5 23), and primary inflammatory cells from patients with BP were used to investigate CXCL10 expression and function. Results: At baseline, both resident cells, such as keratinocytes and fibroblasts, and infiltrating immune cells expressed CXCL10 at lesional sites in skin of patients with BP. CXCL10 levels were higher in blister fluid (P < .0001) and serum (P < .005) from patients with BP than in serum from age-and sex-matched control subjects (n 5 34). Furthermore, CXCL10 serum levels increased at day 60 only in patients who relapsed within the first year of treatment (n 5 33, P < .005). Interestingly, CXCL10 expression could be upregulated by itself and IL-17 in inflammatory cells. Notably, neutrophils and monocytes from patients with BP, but not lymphocytes, responded to CXCL10 by increasing MMP-9 secretion through the activation of extracellular signal-regulated kinase 1/2, p38, phosphoinositide-3 kinase signaling pathways. Finally, CXCL10-increased MMP-9 secretion was inhibited by methylprednisolone and also by compound A, a novel nonsteroidal glucocorticoid receptor ligand. Conclusion: We showed that increased levels of inflammatory biomarkers in patients with BP, such as CXCL10, favor neutrophil-and monocyte-associated MMP-9 release and disease relapse and opened new therapeutic horizons in patients with this autoimmune disease.

International audience; Elastin peptides, such as kappa-elastin (kE), bind to the elastin receptor at the cell surface of human dermal fibroblasts and stimulate collagenase-1 expression at the gene and protein levels. Using specific inhibitors and phosphospecific antibodies, we show here that the binding of elastin peptides to their receptor activates the extracellular signal-regulated kinase (ERK) pathway; this activation is essential for the induction of pro-collagenase-1 production. Moreover, protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI(3)K) signaling were found to participate in ERK activation. Concomitantly, we demonstrate that stimulation by elastin peptides leads to enhanced DNA binding of activator protein-1 (AP-1). Our data indicate that the up-regulation of collagenase-1 following treatment of fibroblasts with elastin peptides results from a cross-talk between PKA, PI(3)K and the ERK signaling pathways and that this regulation is accompanied by activation of AP-1 transcription factors.