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It is important to assess the burden of chronic urticaria (CU) with real-life studies. The AWARE study was performed in 36 countries over two years in CU patients resistant to H1-antihistamines.To correlate patient-reported outcomes and available therapeutic options in CU patients.The AWARE study was a prospective, non-interventional, international study that included adult patients who have had H1-antihistamine-resistant CU for at least two months. The primary endpoints were the evolution of disease activity (UAS7), urticaria control (UCT), dermatological quality of life (DLQI) and treatment satisfaction (visual analogic scale) during a two-year follow-up. The data from French centres are reported.Ninety-two patients were included (mean age: 47.8 years; women: 70.7%; mean disease duration: 6.5 years; angioedema: 34.1%). The percentage of patients with CU treatment increased from 56.5% at inclusion to 86.0% after two years (for patients with non-sedative H1-antihistamines from 52.2% to 74.4%, and omalizumab from 2.2% to 25.6%). During the follow-up, the percentage of patients with UAS7 score6 increased from 12.5% to 60.9%, and patients with well-controlled CU (UCT score12) increased from 11.1% to 62.2%. The negative impact on quality of life (DLQI10) decreased from 34.1% to 10.5%. The mean score of patient satisfaction for treatment increased from 4.6 to 7.6.The management of CU patients resistant to H1-antihistamines was not optimal at inclusion with uncontrolled disease, impaired quality of life and insufficient treatment. After a two-year follow-up, disease symptoms and quality of life improved, but the therapeutic management could be further optimized.

Resume Contexte Le pemphigus paraneoplasique (PPN) est une maladie tres rare et de mauvais pronostic associant un pemphigus, particulier par certains criteres cliniques, immunologiques et histologiques, a une neoplasie. Methodes Nous avons retrospectivement analyse les dossiers de patients presentant un PPN dans la region Poitou-Charentes entre 2000 et 2015. Resultats Sept patients presentaient neuf neoplasies diagnostiquees de 4 mois avant a 25 mois apres l’apparition des lesions cutanees (6/7) ou muqueuses (6/7) de pemphigus. Les lesions etaient cliniquement polymorphes. L’examen histologique revelait une acantholyse epidermique (7/7), des necroses keratinocytaires (4/7) et une dermite lichenoide d’interface (5/7). On mettait en evidence des depots d’IgG et de C3 intercellulaires ou le long de la jonction dermo-epidermique en immunofluorescence directe (IFD) (7/7), des anticorps anti-substance intercellulaire en immunofluorescence indirecte (IFI) sur vessie de rat (4/6), un immunotransfert reconnaissant les cibles antigeniques du PPN (2/4). La duree du suivi allait de 1 a 132 mois, la survie a 1 an etait de 85,7 %. Discussion Les presentations cliniques et histopathologiques observees chez nos patients sont polymorphes, avec un chevauchement entre les manifestations cliniques et histologiques de PPN et de pemphigus classique. Le pronostic est meilleur dans notre serie que dans la litterature. Les neoplasies associees sont diverses. Il semble exister des associations fortuites de pemphigus a des neoplasies, de meilleur pronostic que les veritables PPN. Un nouveau consensus pour les criteres diagnostiques du PPN est necessaire, qui aiderait les praticiens a diagnostiquer le PPN de maniere plus homogene pour realiser des etudes pronostiques ou des essais therapeutiques.

Summary Background Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).

The AWARE study is an ongoing international study of patients with chronic urticaria refractory to H1-antihistamines. The aim of this study is to evaluate the burden of disease and the use of healthcare resources in real-life conditions.To analyse the baseline data of French patients included in the AWARE study.AWARE is a prospective, non-interventional, international study that includes adult patients who have had chronic urticaria, refractory to at least one H1-antihistamine, for at least two months.Ninety-four patients (mean age: 47.9 years; 71.3% women) with chronic urticaria (50.0% spontaneous only, 9.6% inducible only, and 40.4% both) were included in French centres. The median duration from diagnosis was three years and angioedema was present in 31.5% of patients for the past six months. In 63.8% of cases, the patients received at least one treatment for urticaria (H1-antihistamine for 66.0%). Chronic urticaria was poorly controlled (UCT score12) in 88.9% of patients and quality of life was severely impaired (mean DLQI score: 8.6). The use of healthcare resources was significant with frequent visits to general practitioners (80.8% of patients; mean: 8.1 visits). However, more than half of patients had not previously consulted a dermatologist.These baseline data of French patients in the AWARE study show that patients suffering from chronic urticaria, refractory to H1-antihistamines for a median of three years, are insufficiently treated and that their quality of life is impaired. Despite the significant use of healthcare resources, access to specialised consultations remains insufficient.

Resume Introduction Le naevus mucineux est une entite anatomoclinique rare puisque seulement 23 cas ont ete publies. Il appartient aux naevi conjonctifs et est caracterise par des depots de mucine dans le derme. On en distingue deux types histologiques : le naevus mucineux dermique pur et le naevus mucineux combine, associant un naevus epidermique aux depots de mucine dermiques. Les lesions surviennent en principe toujours chez l’enfant ou l’adulte jeune. Nous en rapportons un cas observe chez un homme de 59 ans. Observation Un homme de 59 ans consultait pour une lesion unilaterale blaschko-lineaire du membre inferieur droit, developpee a l’âge de 50 ans. Cette lesion etait constituee d’elements papulo-verruqueux bruns. Le patient se plaignait d’un prurit au frottement des vetements. L’examen histologique de la biopsie d’une papule mettait en evidence un epiderme acanthosique avec elongation des cretes epidermiques et des depots dermiques de mucine colores au bleu alcian. La confrontation anatomoclinique permettait de retenir le diagnostic de naevus mucineux combine. Une dermabrasion au scalpel etait realisee, avec une cicatrice de qualite modeste jugee acceptable par le patient. Discussion Nous n’avons pas trouve de publication medicale decrivant des naevi mucineux d’apparition aussi tardive, ou donnant lieu a des symptomes. Notre revue de la litterature souligne par ailleurs l’importance de l’examen histologique pour orienter le traitement, qui est essentiellement a but esthetique. Le laser CO2 et la dermabrasion chirurgicale seraient efficaces dans le naevus mucineux combine, en traitant essentiellement la composante epidermique inesthetique avec un risque faible de cicatrice. En revanche, ces techniques doivent etre evitees dans le type dermique pur, ou seule l’excision chirurgicale semble envisageable pour un meilleur resultat esthetique possible.

Resume Introduction Les manifestations cutanees de la sarcoidose sont extremement polymorphes ; elles ont ete repertoriees a travers plusieurs classifications. Observation Nous rapportons le cas d’une patiente de 51 ans qui presentait un livedo bilateral des genoux accompagne de signes generaux avec polyarthralgies, alteration de l’etat general, perte de poids et sensation de dyspnee. La biopsie cutanee montrait des granulomes giganto-cellulaires disposes autour des vaisseaux du derme, sans necrose caseeuse. L’examen des vaisseaux sanguins ne montrait pas d’anomalies en histopathologie. Les examens complementaires mettaient en evidence un taux d’angiotensine convertase eleve (1,5 fois la normale), des adenomegalies mediastinales bilaterales ainsi qu’une fibrose pulmonaire debutante. Une sarcoidose systemique etait diagnostiquee sur l’ensemble du tableau clinico-biologique. La patiente presentait ulterieurement une atteinte hepatique de la sarcoidose ainsi qu’une hypercalcemie ; une corticotherapie generale (prednisone) etait alors debutee, avec une decroissance lente des doses. L’evolution etait favorable, avec correction des anomalies biologiques, regression des adenomegalies et disparition du livedo. Discussion Quelques cas de livedo revelant une sarcoidose ont deja ete rapportes dans la litterature. Ces patients etaient en majorite des femmes d’origine asiatique, jeunes ou d’âge moyen, qui presentaient une sarcoidose systemique avec une frequence elevee d’atteintes oculaires et nerveuses. Le livedo pourrait etre explique par la disposition particuliere des granulomes autour des arterioles, entrainant des perturbations de la circulation sanguine locale probablement liees a la compression mecanique des vaisseaux et aux microthrombus vus sur a l’examen histologique. Conclusion Le livedo pourrait etre considere comme une des manifestations cliniques de la sarcoidose cutanee. Des examens complementaires orientes vers la recherche d’une sarcoidose pourraient etre proposes dans le cadre de l’exploration d’un livedo atypique.

International audience; BACKGROUND: Methotrexate is currently used to treat atopic dermatitis but has never been assessed versus cyclosporine in adults. OBJECTIVE: This study evaluated the efficacy and safety of methotrexate versus cyclosporine in patients with moderate-to-severe atopic dermatitis. METHODS: Patients were randomized to receive either oral methotrexate (15 mg/wk) or cyclosporine (2.5 mg/kg/d) for 8~weeks. The primary end point was a patient achieving 50% improvement in the SCORing Atopic Dermatitis index (SCORAD 50) at week 8. When the primary end point was not achieved, methotrexate was increased to 25 mg and cyclosporine to 5 mg during the next 16 weeks. The secondary end points were a patient achieving a 50% reduction in the Eczema Area Severity Intensity index (EASI 50) and SCORAD 50 at each visit (ClinicalTrials.gov no. NCT00809172). RESULTS: A total of 97 patients received methotrexate 15 mg (n~= 50) or cyclosporine 2.5 mg (n~= 47). Regarding the primary end point at week 8, methotrexate was inferior to cyclosporine because the proportion of patients with SCORAD 50 was 8% (4 of 50) in the methotrexate arm versus 42% (18 of 43) in the cyclosporine arm. The difference in percentages for the 2 treatment groups (2-sided 90% CI) was~-34% (-48% to~-20%). At week 8, methotrexate and cyclosporine dosages were increased in 56% and 49% of the patients, respectively. Regarding EASI 50, the noninferiority end point was reached at week 20 in 92% (22 of 24) of patients in the methotrexate arm and 87% (26 of 30) of patients in the cyclosporine arm. The treatment-related adverse events were more frequent with cyclosporine (P \textless .0001). CONCLUSIONS: Methotrexate 15 mg/wk was inferior to cyclosporine 2.5 mg/kg/d at week 8. Increasing the doses of methotrexate to 25 mg/wk induced a significant improvement versus cyclosporine at week~20.

Resume Introduction Le kwashiorkor est une manifestation clinique de carence proteino-energique globale qui a ete principalement decrite chez l’enfant dans des pays en voie de developpement, avec au premier plan une atteinte cutanee eczematiforme associee a un tableau d’anasarque. Observation Nous rapportons le cas d’une femme d’ascendance africaine âgee de 44 ans, aux antecedents d’obesite severe traitee par chirurgie bariatrique sans surveillance ulterieure reguliere. Quatre ans plus tard, la patiente etait hospitalisee dans notre unite de dermatologie pour des œdemes diffus et des lesions cutanees a type d’eczema craquele evoluant depuis deux mois malgre des applications quotidiennes de dermocorticoides forts. L’ensemble des signes cliniques, l’effondrement de l’albuminemie et l’analyse histopathologique du tissu cutane evoquaient un kwashiorkor. La resolution des symptomes etait obtenue en quelques semaines apres renutrition. Discussion Le kwashiorkor est une entite clinique majoritairement decrite comme une maladie du nourrisson survenant dans des pays en voie de developpement. L’atteinte cutanee est au premier plan, avec un eczema craquele associe a des œdemes diffus. Le traitement par simple supplementation proteique est efficace et permet d’eviter de nombreuses complications (infections, troubles hemodynamiques). L’obesite est une maladie chronique frequente touchant pres du tiers de la population mondiale, pour laquelle un traitement par chirurgie bariatrique peut etre indique. Sans suivi regulier, cette chirurgie peut entrainer une carence proteique importante. Ainsi, il sera sans doute de moins en moins rare d’etre confronte a un kwashiorkor de l’adulte, complication iatrogene d’un traitement chirurgical de l’obesite. Aussi, la semiologie de cette complication est-elle importante a connaitre, d’autant que son traitement est simple et efficace.

In psoriasis, a specific cytokine network has been described to play a central role in the pathophysiology of the disease. Anti-cytokine therapeutic approaches have been largely developed and TNFα constitutes the main target. Adalimumab is a human anti-TNFα monoclonal antibody that has been reported to demonstrate clinical efficacy and safety, resulting in reversal of epidermal hyperplasia and cutaneous inflammation. We aimed to analyse changes in the skin inflammatory transcriptomic profile in psoriatic patients during adalimumab therapy. In addition, the circulating cytokine profile was analysed to define systemic inflammation. Eighteen patients with chronic plaque psoriasis were treated with adalimumab. After four and 16 weeks, clinical efficacy was assessed using PASI and DLQI, and skin mRNA profiles were determined and circulating cytokines quantified. We identified a rapid effect of adalimumab therapy on a large array of Th17 cytokines of the skin, which may account for the modification of keratinocyte expression profile and clinical response. In contrast, analysis of serum cytokine concentrations was uninformative, confirming the need for characterization of local cytokines in skin lesions. Finally, in non-responders, local cytokine expression was shown to be unchanged. We show that TNFα inhibition in psoriasis patients treated with adalimumab has a broad effect on the expression profile of cytokines and keratinocyte markers of skin inflammation, which may account for its clinical efficacy.

Background Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPβ, STAT3 activated by proinflammatory cytokines. Objectives We investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients. Methods NHEK were stimulated by A-SAA or the cytokines IL-1α, IL-17A, IL-22, OSM, TNF-α alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay. Results IL-1α, TNF-α and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed. Conclusion Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.

Background Previous clinical trials have not evaluated improvement in nail psoriasis as a primary end point. Objective This phase 3 trial evaluated the safety and efficacy of adalimumab in patients with moderate-to-severe fingernail psoriasis and moderate-to-severe plaque psoriasis. Methods Patients were randomized 1:1 to 40 mg adalimumab every other week or placebo. The primary efficacy end point was at least 75% improvement in total-fingernail modified Nail Psoriasis Severity Index (NAPSI75) response rate at week 26. Ranked secondary end point scores evaluated at week 26 were total-fingernail NAPSI and modified NAPSI, nail pain, Nail Psoriasis Physical Functioning Severity, Brigham Scalp Nail Inverse Palmo-Plantar Psoriasis Index, and Physician's Global Assessment (fingernail psoriasis). Results Of the 217 randomized patients (108 received placebo and 109 received adalimumab), 188 (86.6%) completed 26 weeks of treatment (period A) or escaped early to the open-label period. The study met the primary end point (response rate of 3.4% with placebo vs 46.6% with adalimumab [ P .001]) and all ranked secondary end points. The serious adverse event rates (placebo vs adalimumab) in period A were 4.6% versus 7.3%; the serious infections rates were 1.9% versus 3.7%. Limitations Patients with less than 5% BSA involvement were not eligible for enrollment. Conclusions After 26 weeks of adalimumab treatment, significant improvements were seen in the primary and all ranked secondary end points and in signs and symptoms of moderate-to-severe nail psoriasis versus with placebo and no new safety risks were identified.

Background Environmental factors play a major role on atopic dermatitis (AD) which shows a constant rise in prevalence in western countries over the last decades. The Hygiene Hypothesis suggesting an inverse relationship between incidence of infections and the increase in atopic diseases in these countries, is one of the working hypothesis proposed to explain this trend. Objective This study tested the efficacy and safety of oral administration of the bacterial lysate OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), in the treatment of established AD in children. Methods Children aged 6 months to 7 years, with confirmed AD diagnosis, were randomized in a double-blind, placebo-controlled trial to receive, in addition to conventional treatment with emollients and topical corticosteroids, 3.5mg of the bacterial extract OM-85 or placebo daily for 9 months. The primary end-point was the difference between groups in the occurrence of new flares (NF) during the study period, evaluated by Hazard Ratio (HR) derived from conditional Cox proportional hazard regression models accounting for repeated events. Results Among the 179 randomized children, 170 were analysed, 88 in the OM-85 and 82 in the placebo group. As expected most children in both treatment groups experienced at least 1 NF during the study period (75 (85%) patients in the OM-85 group and 72 (88%) in the placebo group). Patients treated with OM-85 as adjuvant therapy had significantly fewer and delayed NFs (HR of repeated flares = 0.80; 95% confidence interval (CI): 0.67-0.96), also when potential confounding factors, as family history of atopy and corticosteroids use, were taken into account (HR = 0.82; 95% CI: 0.69-0.98). No major side effect was reported, with comparable and good tolerability for OM-85 and placebo. Conclusions Results show an adjuvant therapeutic effect of a well standardized bacterial lysate OM-85 on established AD.

Introduction Le dermatoneuro syndrome est une complication neurologique particuliere du scleromyx�deme, rapportee une vingtaine de fois dans la litterature medicale. Il associe fievre, coma, convulsions et syndrome pseudo-grippal. Le devenir des patients atteints est mal connu. Nous decrivons l�observation d�une patiente ayant repondu favorablement a l�association de plasmaphereses et d�immunoglobulines intraveineuses (IgIV). Observation Une femme de 57 ans etait atteinte de scleromyx�deme evoluant depuis 14 ans, resistant a de multiples therapeutiques. En novembre 2011, elle presentait un premier episode de crises convulsives suivi d�un coma post-critique, puis d�un syndrome confusionnel associe a des hallucinations visuelles, spontanement resolutif en quelques jours. La recherche d�une infection etait negative et l�imagerie cerebrale (tomodensitometrie et IRM) ainsi que l�electroencephalogramme etaient parfaitement normaux, soulevant l�hypothese d�une atteinte neurologique de son scleromyx�deme. En decembre 2012 et aout 2013, elle presentait deux nouveaux episodes d�etat de mal epileptique, suivis a nouveau d�un etat confusionnel, pour lequel la recherche etiologique etait encore negative. Cette fois, l�etat confusionnel se perennisait pendant deux mois, jusqu�a la mise en place des echanges plasmatiques, suivie d�une cure d�IgIV. Cette association therapeutique permettait d�obtenir une regression rapide de l�ensemble des symptomes neurologiques et une amelioration de l�etat general. Discussion Le dermatoneuro syndrome est une complication neurologique centrale rare du scleromyx�deme. Sa physiopathologie est inconnue. La gammapathie monoclonale associee au scleromyx�deme pourrait expliquer un etat d�hypercoagulabilite ou la formation d�agregats neutrophiliques aboutissant a une alteration de la microcirculation. Le traitement est empirique et mal codifie. L�evolution est imprevisible et potentiellement letale. Summary Background Dermato-neuro syndrome is a specific neurological complication of scleromyxedema presenting with fever, coma, seizures and flu-like syndrome. To our knowledge, it has only been reported about twenty times in the literature. Its outcome is uncertain. We describe the case of a patient in whom a favorable outcome was achieved using a combination of plasmapheresis and intravenous immunoglobulin (IVIG). Patients and methods A 57-year-old woman was diagnosed 14 years ago with scleromyxedema resistant to multiple lines of treatment. In November 2011, she presented an initial episode of epileptic seizure followed by post-seizure coma, and later, confusional state with visual hallucinations. She recovered spontaneously within a few days. CT scan, MRI, EEG and screening for infection were perfectly normal, resulting in suspicion of neurological involvement associated with her scleromyxedema. In December 2012 and August 2013, she presented two further episodes of status epilepticus, followed once more by a confusional state, with etiological explorations again proving unfruitful. On this occasion, her confusional state persisted for two months until the initiation of plasmapheresis and IVIG. This combination therapy led to rapid regression of all neurological symptoms and an improvement in her general condition. Discussion The dermato-neuro syndrome is a rare neurological complication of scleromyxedema. Its pathophysiology is unknown. The monoclonal gammopathy induced by the scleromyxedema could account for the patient's hypercoagulable state and for the formation of neutrophilic aggregates leading to impaired microcirculation. Treatment is empirical and poorly codified. The course of the disease is unpredictable and may be lethal.

Resume Introduction L’epidermolyse bulleuse acquise (EBA) est une dermatose bulleuse auto-immune sous-epidermique rare, secondaire a la production d’anticorps anti-collagene VII. La reaction du greffon contre l’hote (GVH) survenant apres transplantation allogenique de moelle osseuse peut, dans sa forme chronique, etre associee a diverses maladies auto-immunes. Dix observations de dermatoses bulleuses auto-immunes survenues apres greffe de moelle allogenique sont rapportees dans la litterature. Nous en decrivons un nouveau cas, a type d’EBA. Observation Une femme de 46 ans developpait une maladie bulleuse quatre ans apres le traitement d’un lymphome non hodgkinien de type T par une allogreffe de sang de cordon compliquee d’une GVH cutanee et digestive aigue, puis d’une GVH chronique pulmonaire. Elle presentait quelques lesions bulleuses cutanees des membres superieurs, de l’abdomen et du visage, et de nombreuses erosions de la cavite buccale. L’etude en immunofluorescence directe d’une biopsie cutanee mettait en evidence des depots d’IgG et de C3 le long de la membrane basale epidermique. La recherche d’anticorps anti-membrane basale sur peau clivee par le NaCl molaire etait positive en IgG4 sur le versant dermique et la recherche d’auto-anticorps anti-collagene VII par immunofluorescence indirecte sur cellules transfectees etait positive. Un diagnostic d’EBA etait pose. Apres echec de la dapsone et de l’association mycophenolate–prednisone, un traitement par rituximab se montrait efficace. Discussion L’EBA peut s’integrer dans les manifestations auto-immunes associees a la GVH chronique. La destruction de la membrane basale et des cellules basales epidermiques dans la GVH pourrait induire l’apparition de pathologie bulleuse auto-immune. Mais chez notre patiente dont la GVH chronique s’exprimait seulement aux poumons, il est difficile d’eliminer la survenue fortuite d’EBA a distance de la GVH aigue.

Resume Introduction La douleur est le principal effet indesirable de la phototherapie dynamique (PTD) et peu de moyens analgesiques efficaces sont actuellement disponibles. Notre objectif etait d’evaluer l’efficacite de l’hypno-analgesie dans la PTD. Patients et methodes D’aout 2011 a fevrier 2013, une seance d’hypno-analgesie etait proposee a des patients necessitant une seance de PTD pour le traitement de lesions cancereuses ou precancereuses. A la fin de la seance, la douleur etait evaluee a l’aide d’une echelle numerique (EN) cotee de 0 a 10. Resultats Douze patients, d’un âge moyen de 74,6 ans, ont ete inclus. L’indication de la PTD etait des keratoses actiniques chez 9 patients, 1 maladie de Bowen du gland, 1 maladie de Paget mammaire et 1 papulose bowenoide du gland. L’hypno-analgesie etait efficace chez 8 patients, avec une EN moyenne de 2,9/10. Six de ces 8 patients avaient eu une seance anterieure sans hypnose avec une EN moyenne de 8,3/10. Discussion L’hypnose semble etre interessante dans le controle de la douleur induite par la PTD. C’est un moyen simple, peu couteux, denue d’effets secondaires, qui agit a la fois sur la douleur et sur l’anxiete du patient. Pour ameliorer l’utilisation de l’hypno-analgesie en PTD, il faudrait mieux connaitre les facteurs predictifs de douleur, savoir comment selectionner au mieux les patients « sensibles » a l’hypnose et encourager la formation des infirmieres et des medecins a cette methode.

Differentiation marker, multifunctionality and magnitude analyses of specific-CD8(+) memory T cells are crucial to improve development of HIV vaccines designed to generate cell-mediated immunity. Therefore, we fully characterized the HIV-specific CD8(+) T cell responses induced in volunteers vaccinated with HIV lipopeptide vaccines for phenotypic markers, tetramer staining, cytokine secretion, and cytotoxic activities. The frequency of ex vivo CD8(+) T cells elicited by lipopeptide vaccines is very rare and central-memory phenotype and functions of these cells were been shown to be important in AIDS immunity. So, we expanded them using specific peptides to compare the memory T cell responses induced in volunteers by HIV vaccines with responses to influenza (FLU) or Epstein Barr virus (EBV). By analyzing the differentiation state of IFN-γ-secreting CD8(+) T cells, we found a CCR7(-)CD45RA(-)CD28(+int)/CD28(-) profile (>85%) belonging to a subset of intermediate-differentiated effector T cells for HIV, FLU, and EBV. We then assessed the quality of the response by measuring various T cell functions. The percentage of single IFN-γ T cell producers in response to HIV was 62% of the total of secreting T cells compared with 35% for FLU and EBV, dual and triple (IFN-γ/IL-2/CD107a) T cell producers could also be detected but at lower levels (8% compared with 37%). Finally, HIV-specific T cells secreted IFN-γ and TNF-α, but not the dual combination like FLU- and EBV-specific T cells. Thus, we found that the functional profile and magnitude of expanded HIV-specific CD8(+) T precursors were more limited than those of to FLU- and EBV-specific CD8(+) T cells. These data show that CD8(+) T cells induced by these HIV vaccines have a similar differentiation profile to FLU and EBV CD8(+) T cells, but that the vaccine potency to induce multifunctional T cells needs to be increased in order to improve vaccination strategies.

Resume Introduction L'endophtalmie endogene est une infection redoutable de l'�il, aboutissant a une cecite chez environ deux-tiers des patients. Elle resulte de la dissemination hematogene d'un micro-organisme a partir d'un foyer septique, principalement gastro-intestinal, genito-urinaire ou cardiaque. Observation Nous decrivons le cas d'un patient diabetique ayant developpe une endophtalmie endogene a la suite d'un erysipele de jambe a Streptococcus agalactiae. L'evolution a ete favorable grâce a la mise en route precoce d'une antiobiotherapie adaptee. Discussion L'endophtalmie endogene compliquant une infection cutanee est une entite rare, avec une trentaine de cas decrits dans la litterature. La connaissance de cette affection par les dermatologues permettrait une intervention rapide, indispensable a la preservation du pronostic visuel. ________________________________________ Summary Background Endogenous endophthalmitis is a devastating infection of the eye that leads to blindness in about two-thirds of patients. It results from the haematogenous spread of a microorganism from a focus of sepsis, mainly gastro-intestinal, genitourinary or cardiac. Patients and methods We describe the case of a diabetic subject presenting endogenous endophthalmitis following erysipelas of the leg due to Streptococcus agalactiae. The outcome was favourable thanks to prompt initiation of appropriate antibiotic treatment. Discussion Endogenous endophthalmitis as a complication of a skin infection is a rare entity, with only about 30 reported cases in the literature. Awareness of this condition among dermatologists would allow prompt intervention, which is essential for sparing of the patient's eyesight. Mots cles " Erysipele; " Endophtalmie endogene; " Streptococcus agalactiae; " Diabete de type 2 Keywords " Erysipelas; " Endogenous endophthalmitis; " Streptococcus agalactiae; " Diabetes mellitus ________________________________________ Figures and tables from this article: Figure 1. Symptomatologie oculaire discrete avec un simple erytheme de la conjonctive, contrastant avec la severite du pronostic.

Resume Introduction Nous rapportons une observation de maladie des griffes du chat (MGC) en raison de sa presentation atypique. Observation Une femme de 21 ans presentait un erytheme noueux associe a des adenopathies inguinales bilaterales douloureuses, une odynophagie, des arthralgies et une urticaire vesperale, dans un contexte d'alteration de l'etat general. La serologie initiale de Bartonella henselae etait negative. La PCR de Bartonella henselae, realisee sur un fragment d'adenectomie, etait positive. L'evolution etait favorable sous azithromycine. Commentaire Cette observation illustre une presentation atypique et severe d'une MGC, et souleve le probleme de la sensibilite de la serologie. ________________________________________ Summary Background Herein we report a case of cat scratch disease on account of its atypical presentation. Patients and methods A 21-year-old woman presented erythema nodosum associated with painful bilateral inguinal adenopathy, odynophagia, joint pain and evening urticaria in a setting of impaired general condition. Initial serological testing for Bartonella henselae was negative. PCR for Bartonella henselae performed on an adenectomy fragment was positive. A favourable outcome was achieved with azithromycin. Comments This case shows an atypical and severe presentation of cat scratch disease and raises the problem of sensitivity of serotyping. Mots cles " Maladie des griffes du chat; " Erytheme noueux; " Adenopathies bilaterales; " Urticaire vesperale Keywords " Cat scratch disease; " Erythema nodosum; " Bilateral adenopathy; " Evening urticaria ________________________________________ Figures and tables from this article: Figure 1. Urticaire vesperale et erytheme noueux des membres inferieurs. Figure options Figure 2. Urticaire vesperale. Figure options Figure 3. Biopsie cutanee : Dermohypodermite septale avec atteinte vasculaire en faveur d'un erytheme noueux (coloration par le PAS). Figure options Figure 4. Biopsie ganglionnaire inguinale : lymphadenite granulomateuse necrosante (HES).

Resume Introduction Le myxœdeme localise est une manifestation rare de la maladie de Basedow. Sa topographie est classiquement pretibiale mais nous presentons le cas d’un myxœdeme localise aux hallux. Observation Un patient de 44 ans, atteint d’une maladie de Basedow depuis sept ans, presentait une ophtalmopathie bilaterale et un myxœdeme des deux hallux. Le myxœdeme etait efficacement traite par injections intralesionnelles de corticoides. Discussion La physiopathologie du myxœdeme implique l’activation des fibroblastes produisant des glycosaminoglycanes. Cette activation pourrait etre liee a la stimulation du recepteur de la TSH present a leur surface par les anticorps anti-recepteurs de la TSH (TRAK), ainsi qu’a un processus inflammatoire. La localisation preferentielle pretibiale pourrait etre expliquee par la frequence des microtraumatismes a cet endroit, modulant l’environnement cytokinique. Conclusion La localisation atypique semble en rapport avec un phenomene de Koebner. Le traitement de la maladie de Basedow est souvent insuffisant pour ameliorer l’atteinte cutanee. Une corticotherapie locale permet en general une amelioration rapide des lesions recentes.

Although it is a frequent disease, atopic dermatitis is poorly recognised and therefore under-diagnosed. The aim of this study was to define and validate a convenient tool allowing presumption of atopic dermatitis for non-dermatologists. A 20-item questionnaire (PPAD) and an 8-item short version (PPAD-S) were developed in French by a board of experts, then tested on outpatients presenting with atopic dermatitis or not. Diagnosis was confirmed by a dermatologist, who measured the severity of the disease by using SCORAD. PPAD and PPAD-S proved to be efficient tools for presumption of atopic dermatitis, but not tools for diagnosis. Scores were correlated to the severity of the disease. PPAD and PPAD-S can be considered useful tools for orientating patients with undiagnosed atopic dermatitis to a specialised consultation, all the more quickly since atopic dermatitis is severe.

Resume Introduction L’erlotinib (Tarceva ® ), membre de la famille des inhibiteurs de l’ epidermal growth factor receptor (EGFR), est utilise dans les neoplasies pancreatiques et pulmonaires non a petites cellules, en situation d’echec des premieres lignes de traitement. Cette molecule est responsable de nombreux effets secondaires cutanes. Nous rapportons un cas de fasciite aigue symptomatique et radiologiquement documentee survenue sous erlotinib. Nous n’avons pas eu connaissance d’autre observation similaire dans la litterature. Observation Un homme de 56 ans etait traite par erlotinib pour un adenocarcinome bronchique non a petites cellules, au stade metastatique. Un mois apres l’introduction du traitement apparaissait une eruption cutanee acneiforme, qui persistait malgre un traitement par doxycycline. Apres un an de traitement apparaissait une douleur aigue des deux jambes avec impotence fonctionnelle, revelant une fasciite confirmee par l’imagerie. La fasciite regressait parallelement a l’eruption cutanee en une dizaine de jours, sous traitement par dermocorticoides forts. Discussion A cote des fasciites bacteriennes, les fasciites inflammatoires œdemateuses ont des causes variees. La survenue d’une fasciite radiologiquement documentee au cours d’un traitement par inhibiteur de l’EGFR est originale et pose la question du mecanisme physiopathologique implique. Nous proposons trois hypotheses : une atteinte par contiguite, une fasciite paraneoplasique ou encore une atteinte propre du fascia liee aux anti-EGFR.

Resume Introduction La chimiotherapie de type mitoguazone, ifosfamide, navelbine, etoposide (MINE) est employee dans la maladie de Hodgkin en rechute ou refractaire aux traitements usuels. Les effets indesirables cutanes de cette chimiotherapie sont rares, comprenant principalement des erythemes et des œdemes des extremites. Plus recemment, quelques cas de panniculite et d’œdemes hyperalgiques ont ete decrits. Observation Nous rapportons le cas d’une jeune fille de 17 ans qui a developpe un œdeme aigu hyperalgique des membres associe a une panniculite du tronc. Ce tableau s’est complete ensuite par l’apparition de bulles et de manifestations inflammatoires des muqueuses, a type de vulvite et de glossite. Les premiers symptomes etaient survenus sept jours apres le debut d’une chimiotherapie de type MINE, sans qu’aucun autre nouveau medicament n’ait ete introduit. L’evolution a ete lentement favorable sous traitement symptomatique a visee antalgique. La chimiotherapie a par la suite ete modifiee. Discussion L’argument d’imputabilite chronologique, l’amelioration spontanee a l’arret du traitement et l’absence d’autre etiologie ont fait evoquer le diagnostic de reaction cutanee secondaire au protocole MINE. La symptomatologie pourrait reposer sur un syndrome de fuite capillaire du a la toxicite de la vinorelbine sur les cellules endotheliales. Ces manifestations secondaires sont a connaitre des dermatologues, notamment l’atteinte inflammatoire des muqueuses, nouvellement decrite.

Introduction En l’absence d’etudes en vie reelle, le fardeau de l’urticaire chronique (UC) reste meconnu. L’etude AWARE conduite dans 36 pays a recueilli pendant 2 ans des donnees cliniques de « vraie vie » chez des patients souffrant d’UC. Son objectif principal etait de correler les resultats rapportes par le patient « patient reported outcomes » avec les options therapeutiques proposees. Les donnees des centres francais sont presentees dans cette analyse. Materiel et methodes L’etude AWARE est une etude prospective, non interventionnelle, internationale qui a inclus des patients adultes atteints d’UC depuis au moins 2 mois et resistante aux antihistaminiques anti-H1. Les principaux parametres evalues etaient l’evolution des scores moyens d’activite de la maladie (UAS7), de controle de l’urticaire (UCT), de qualite de vie (DLQI) et de satisfaction au traitement (EVA) au cours du suivi. Resultats Quatre-vingt-douze patients ont ete inclus (âge moyen, 47,8 ans ; femmes, 70,7 %), seuls 43 patients (46,7 %) etaient presents a la derniere visite, en raison de la nature observationnelle de l’etude ; 7 patients ont eu une remission spontanee de la maladie avant la fin de l’etude (selon le jugement de l’investigateur). L’anciennete moyenne de la maladie etait de 6,5 ans. Le pourcentage de patients qui ne recevaient aucun traitement etait de 43,5 % avant l’inclusion et diminuait a 14 % a la fin des 2 ans de suivi. L’utilisation des antihistaminiques de seconde generation augmentait de 52,2 % a 74,4 % a la fin de l’etude (dont respectivement 10,9 % et 20,9 % a dose optimisee). L’omalizumab etait prescrit chez 2,2 % des patients en debut d’etude contre 25,6 % a la fin du suivi. Le pourcentage de patients avec un score UAS7 12) augmentait de 11,1 % a 62,2 %. Un angiœdeme au cours des 6 derniers mois etait present chez 34,1 % des patients, ce chiffre diminuait a 7 % au bout des 2 ans de suivi. L’impact sur la qualite de vie (QdV) etait important a extremement important pour 34,1 % des patients a l’inclusion, et 10,5 % des patients a 2 ans (score DLQI > 10). Le score moyen de satisfaction du patient (EVA) vis-a-vis de son traitement augmentait en moyenne de 4,6 ± 3,0 a 7,6 ± 3,0. Discussion Cette etude observationnelle confirme le retentissement de l’UC resistante aux antihistaminiques anti-H1 sur la QdV des patients. La prise en charge des patients a l’inclusion n’etait pas optimale avec une maladie non controlee, une QdV alteree et un nombre important de patients (43,5 %) ne recevant aucun traitement. Au cours du suivi de 2 ans, les resultats rapportes par le patient se sont ameliores notamment la satisfaction vis-a-vis de son traitement. Conclusion La prise en charge therapeutique des patients souffrant d’UC resistante aux antihistaminiques peut etre optimisee dans le but d’attenuer les symptomes de la maladie et d’ameliorer la QdV des patients.

Stewart-Treves syndrome (SST) or former lymphangiosarcoma is a rare complication of chronic lymphoedema mainly related to the breast cancer (90% of cases). It occurs in 0.03% of patients surviving 10 or more years after radical mastectomy. The prognosis is very poor with a five-year survival close to 10% despite the various treatment modalities. The treatment of choice is a large resection, but some authors recommend radical resection in the form of shoulder disarticulation or forequarter amputation. Surgical treatment can be preceded or followed by radiation therapy. Locally advanced tumors or metastatic forms can be treated with mono or polychemotherapy, systemic or local.

Resume Introduction La symptomatologie dermatologique de la primo-infection par le parvovirus B19 est variable. Nous rapportons deux cas ou elle a ete revelee par un erytheme des grands plis similaire au « syndrome babouin » induit par divers medicaments, mais avec une inflexion purpurique ou œdemato-bulleuse. Observations Une femme de 23 ans, enceinte a 39 semaines d’amenorrhee, et une femme de 49 ans ont consulte pour une eruption des plis evoluant dans un contexte febrile. L’examen clinique montrait dans les deux cas une eruption erythemateuse des grands plis, particuliere chez la premiere par la presence de vesicules et d’elements purpuriques, et chez la seconde par une composante œdemato-bulleuse. Dans les deux cas, le diagnostic de primo-infection a parvovirus B19 etait affirme par la positivite de la recherche du genome viral en PCR et par une seroconversion apres 15 jours. Les lesions cutanees regressaient spontanement en quelques jours. Discussion Initialement rattache exclusivement a une cause toximedicamenteuse, le « syndrome babouin » est aujourd’hui rapporte a plusieurs etiologies (toxidermie, dermite de contact et causes infectieuses virales et streptococciques). Parmi ces dernieres, la primo-infection a parvovirus B19 merite d’etre consideree.

Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screening of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-α, and IL-1α as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and β-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin. Our results demonstrate the important potentiating activities of IL-17A, IL-22, oncostatin M, TNF-α, and IL-1α on keratinocytes. This is particularly interesting in the context of psoriasis where these cytokines are overexpressed and could synergize to play an important role in upregulation of chemokines and antimicrobial peptides production.

Resume Introduction L’aspergillose est une mycose rare dont les localisations cutanees primitives sont exceptionnelles. La majorite des cas decrits correspond a des patients immunodeprimes presentant une dissemination hematogene. Nous rapportons une observation rare d’aspergillose cutanee primitive mimant un kerion chez un patient immunocompetent. Observation Un agriculteur de 37 ans consultait pour des lesions nodulaires erythemateuses du visage. Ces lesions n’etaient associees a aucune symptomatologie generale ; elles n’avaient pas repondu a des traitements antibiotiques. L’examen histologique d’une biopsie cutanee montrait une reaction inflammatoire dermique granulomateuse avec un dense infiltrat neutrophilique. La coloration par le PAS mettait en evidence des filaments myceliens ramifies a angles droits associes a des spores. Aspergillus fumigatus etait isole et identifie a la culture. L’examen clinique et les explorations paracliniques ne trouvaient aucun autre foyer d’aspergillose, ce qui ecartait l’hypothese d’une dissemination hematogene. Cette atteinte cutanee primitive survenait chez un patient immunocompetent, des examens complementaires ayant ecarte l’eventualite d’une immunosuppression sous-jacente. Un traitement systemique par voriconazole permettait une remission complete. Discussion Des observations d’aspergillose cutanee primitive d’inoculation survenant chez le sujet immunocompetent sont exceptionnellement decrites dans la litterature medicale. Les lesions cliniques peuvent etre des maculopapules a tendance suppurative ou necrotique, souvent douloureuses, ou des nodules dermohypodermiques pouvant evoluer vers la necrose et l’abcedation. La ressemblance semiologique de ces lesions avec celles du kerion pourrait mener a une errance diagnostique et a un retard dans la prise en charge therapeutique.

Resume Introduction Nous rapportons l’observation d’une patiente qui a developpe un pyoderma gangrenosum (PG) au troisieme trimestre de deux grossesses consecutives. Observation Une femme de 25 ans developpait un PG de la jambe gauche a 32 semaines d’amenorrhee (SA) d’une deuxieme grossesse. L’anamnese retrouvait la notion de syndrome douloureux abdominal associe a un syndrome inflammatoire a 36 SA de sa premiere grossesse ; la cesarienne pratiquee alors s’etait compliquee d’abces aseptiques profonds et parietaux, ainsi que d’une endometrite aseptique a polynucleaires neutrophiles ; des signes cutanes retrospectivement evocateurs de PG etaient ensuite apparus sur la paroi abdominale. Les nouveau-nes issus des deux grossesses etaient eutrophiques. Aucune pathologie classiquement associee aux dermatoses neutrophiliques n’est apparue apres cinq ans de recul. Discussion Cette observation souleve la question de la relation entre grossesse et dermatoses neutrophiliques. La survenue du PG lors de la grossesse est rare : 16 cas dans la litterature, dont sept en post-partum. Cette association pourrait etre liee a un phenomene de pathergie ou bien etre induite par l’elevation des taux de G-CSF constatee chez les femmes enceintes.

Resume Introduction Le carcinome basocellulaire (CBC) est le cancer cutane le plus frequent, survenant principalement sur la tete et le cou. Nous en rapportons une forme inhabituelle, se presentant comme un ulcere chronique de jambe et envahissant le plan osseux sous-jacent. Observation Une femme de 70 ans consultait pour un ulcere de jambe evoluant depuis 15 ans, qui ne s’ameliorait pas sous differents traitements locaux et contention veineuse. Devant le caractere hyperbourgeonnant du fond et indure des bords de cet ulcere circonferentiel, plusieurs biopsies etaient effectuees sur les berges et le fond de l’ulcere. L’analyse histologique revelait un CBC infiltrant. Le traitement consistait en l’excision de 80 % de la lesion initiale, suivie d’une greffe de peau mince. L’analyse de la piece operatoire retrouvait un envahissement de l’os par les structures carcinomateuses. Une radiotherapie etait effectuee sur la lesion restante, non accessible a la chirurgie. Discussion Le cas presente correspond a un CBC de jambe, dans une variete infiltrante et ulceree. La presence d’un hypothetique ulcere veineux preexistant au carcinome ne peut etre formellement ecartee en l’absence de biopsie anterieure. Les cancers cutanes developpes sur des plaies chroniques sont classiquement des carcinomes epidermoides (spinocellulaires) et non des CBC, mais des observations de CBC developpes sur des ulceres veineux ont ete deja decrites dans la litterature et posent la question d’une possible association entre les deux pathologies. Quoi qu’il en soit, les signes cliniques qui font suspecter un carcinome devant une ulceration chronique de jambe devraient etre connus de tout medecin, afin de prelever une biopsie sur tout ulcere cliniquement suspect. Le cas de CBC que nous rapportons est exceptionnel de par l’envahissement osseux sous-jacent, documente par l’imagerie et l’histologie.

Resume Propos L’infection par le VIH/sida est responsable de plus de 40 millions de deces dans le monde au cours des 20 dernieres annees. Les traitements actuellement disponibles ne permettant pas d’eradiquer le virus, la vaccination est un enjeu majeur dans la lutte contre cette maladie. Cet article fait le point sur les difficultes rencontrees dans la recherche d’un vaccin et les differents candidats vaccins en developpement clinique. Actualites et points forts En 2008, en depit de progres considerables realises dans la connaissance du VIH, les principaux obstacles a la mise au point d’un vaccin restent d’ordre scientifique lies aux specificites du virus lui-meme, a l’absence d’identification de correlat de protection et aux limites des modeles animaux. Differentes approches vaccinales ont ete envisagees avec plus de 30 candidats vaccins testes chez l’homme : proteines recombinantes, vecteurs recombinants ou vaccins sous-unitaires, et plus recemment des combinaisons de differents candidats vaccins dans des strategies de « prime-boos t». Bien que l’efficacite protectrice de ces vaccins n’ait pu etre demontree, certaines combinaisons testees en preclinique ont montre une diminution de la charge virale apres infection et une prolongation de la survie des animaux vaccines. Perspectives et projets Pour relever le defi de la mise au point d’un vaccin prophylactique de l’infection VIH, un consortium international s’est cree qui propose de nouvelles methodologies permettant d’accelerer le screening et le developpement de candidats vaccins. Toutefois, en l’absence d’un vaccin prophylactique, reste a preciser l’impact sur l’evolution de la maladie VIH/sida d’un vaccin conferant une immunite partielle.

The growth of immunogenic tumors in immunocompetent individuals is one of the oldest conundrums in tumor immunology. Although the ability of mouse CD8+ T cells to control transplanted tumors is well documented, little is known about their impact on autochthonous tumors. To gain insight into the role of CD8+ T cells during the course of cancer development, we produced a novel model of spontaneous melanoma. The metallothionein (MT)-ret/AAD mouse is transgenic for the RET oncogene and the chimeric MHC molecule AAD (α1-α2 domains of HLA-A2 linked to α3 domain of H2-Dd). This model recapitulates the natural history of human melanoma, and expression of the AAD molecule makes it suitable for analyzing CD8+ T cell responses directed against peptide Ags that have been previously identified in HLA-A2+ melanoma patients. We found that, as tumors grow, mice develop a broad melanoma-specific CD8+ T cell response. Occurrence of cutaneous nodules is not affected by CD8+ T cell depletion, showing that although CD8+ T cells are functional, they have no effect on established cutaneous tumors. However, depleted mice die from visceral disease much earlier than controls, showing that CD8+ T cells control metastasis spreading and disease progression. Antigenic modulation is observed in visceral metastases, suggesting that visceral nodules may be subject to immunoediting. Our data demonstrate that growth of melanoma in the MT-ret/AAD model involves several tolerance mechanisms sequentially. They also reveal a different role for CD8+ T cells toward early stage of cutaneous tumors and late visceral metastatic stage of the disease.

International audience; We screened the Neflaiprotein to identify new HLA-DR-restricted epitopes, because this small protein is expressed early during infection, and specific CD4(+) T cells are critical for effective immunity in HIV-1 infection. We synthesized a set of peptides that covers the sequence of the Nef protein, and performed binding assays using 10 common HLA-DR molecules. We defined four large regions in this protein able to bind very efficiently to eight HLADR molecules. We took advantage of healthy volunteers immunized with an HIV-1 lipopeptide vaccine that contains three of the four HLA DR-restricted regions to investigate their capacities to stimulate T cells. In 11 vaccinated volunteers, typed for their class II molecules, we were able to correlate sequences of the vaccine displaying binding activities to specific HLA-DR molecules and the induction of CD4(+) T cell proliferation. To identify potential HLA-DR epitopes, we synthesized 31 15-mer peptides and showed that 26 bound to one or more HLA-DR molecules. Interestingly, 12 of the 26 15-mer peptides identified are included in the sequence of lipopeptides. We used IFN-gamma ELISPOT and flow cytometer assays to investigate the capacity of these potential CD4(+) T cell epitopes to induce specific T cell responses. We showed that seven of these peptides were able to stimulate HIV-specific T cell responses in five of six tested volunteers. These cells are Nef-specific CD4(+) and CD4(+) CD8(+) T cells secreting IL-2/INF-gamma or IL-2 alone. To conclude, these 26 Nef HLA-DR-restricted peptides could be helpful to better evaluate CD4(+) deficiencies in HIV infection and, for new vaccine designs.

We showed that an anti-HIV lipopeptide vaccine injected to HIV-uninfected volunteers was well tolerated and able to induce a specific CD4(+) and CD8(+) T cell responses. The same vaccine was injected in HIV-1 chronically infected patients controlled by HAART to evaluate its immunogenicity. In this trial, 24 patients were immunized three times with a mixture of six lipopeptides (Nef 66-97, Nef 117-147, Nef 182-205, Gag 183-214, Gag 253-284, and Env 303-335) at 0, 3, and 6 weeks. We studied the HIV-1-specific CD4(+) T cell proliferative responses. The IFN-gamma secretion by activated CD8(+) T cells was evaluated, using an ex vivo ELISpot assay and 60 CD8(+) T cell epitopes derived from the vaccine. Before immunization (W0), anti-HIV CD4(+) T cell responses to Gag, Nef, and Env large peptides were detected in 7/23 (30%) analyzable patients. After three injections, 17/23 (74%) patients had a proliferative response and 16 of them induced new specific CD4(+) T cell responses. At W0, CD8(+) T cell responses to HIV-1 epitopes were detected in 6/23 (26%) patients. After vaccination, 16/23 (70%) patients showed CD8(+) T cell responses and 13 of these patients induced new T cell responses to 25 different HIV-1 epitopes. These HIV-1 epitopes were detected in patients with various HLA class I molecules (HLA-A2, -A3/A11, -A24, -B7 superfamily, -B8), as found in the majority of the white population. Lipopeptides induce new anti-HIV T cell responses in vaccinated infected patients and could be used as a new immunotherapy strategy. The majority of these responders induced specific new CD4(+) and CD8(+) T cell responses.

Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis (P = 0.02) and a lower progression rate of fibrosis (P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage.

Background: HIV-1 lipopeptides have been developed by the French National Agency for AIDS Research (ANRS) for use as candidate vaccine against HIV since 1994. Between 1996 and 2005, four different lipopeptide constructs were tested alone or in combination with recombinant canarypox HIV vaccines in 10 trials conducted in France. The aim of this study was to review clinical safety of HIV lipopeptides. Methods: A meta-analysis based on individual subject data examined clinical safety data collected in eight preventive trials and two therapeutic trials enrolling 200 HIV-1-uninfected healthy volunteers and 48 HIV-1-infected patients. Results: Of 248 trial participants, eight (3.2%) did not complete follow-up: seven among the 200 healthy volunteers, and one among the 48 HIV-1 infected patients. During the 354 person-years of follow-up, 860 lipopeptides injections were administered. Local reactions were common. However, in trials where lipopeptides were tested without adjuvant and appropriate diluents, none of the vaccinees experienced severe local response. Systemic reactions were generally mild and transient. No grade 4 reaction was reported; 18 subjects experienced grade 3 systemic events related to the vaccination, mainly asthenia, fever, headache and arthralgia. Multivariate analysis showed that female sex, number of injections and diluent (more reactions in 5% glucose alone than in combination with Tris-HCl buffer) significantly increased systemic reactions related to the vaccination. Conclusion: These data demonstrate that reactogenicity and systemic safety of HIV lipopeptides vaccine are acceptable both in healthy volunteers and HIV-infected adults.

Objective: Viral rebounds inevitably follow interruption of antiretroviral treatment in HIV-1-infected individuals. The randomized ANRS 093 aimed at investigating whether a therapeutic immunization was effective in containing the long-term viral replication following discontinuation of antiretroviral drugs in patients. Methods: Seventy HIV-1-infected patients effectively treated with antiretroviral drugs were randomized to continue treatment alone or in combination with four boosts of ALVAC 1433 and HIV-LIPO-6T vaccines followed by three cycles of subcutaneous interleukin-2. The impact of vaccination on viral replication was assessed by interrupting antiretroviral drugs first at week 40 and thereafter during follow-up until week 100. Antiretroviral drugs were re-initiated according to predefined criteria. Results: The median cumulative time (days) off treatment was greater in the vaccine group (177) than in the control group (89) (P = 0.01). The proportion of time (mean, SE) without antivirals per-patient was 42.8% (5.1) and 26.5% (4.2) in the vaccine and control groups, respectively (P = 0.005). Viremia (median log10 copies/ml), 4 weeks following the first, second and third treatment interruption was higher in control patients (4.81, 4.44, 4.53) in comparison with vaccinated patients (4.48, 4.00, 3.66) (P = 0.42, 0.015 and 0.024, respectively). HIV-specific CD4 and CD8 T-cell responses elicited by the therapeutic immunization strongly correlated with the reduction of the time of antiviral therapy (P = 0.0027 and 0.016, respectively). Conclusion: Our findings provide evidence that therapeutic immunization significantly impacts on HIV-1 replication. This translated into a decrease of up to 40% in the duration of exposure to antiretroviral drugs over 15 months of patients' follow-up.

Nine patients with Duchenne or Becker muscular dystrophy were injected via the radialis muscle with a full-length human dystrophin plasmid, either once with 200 or 600 microg of DNA or twice, 2 weeks apart, with 600 microg of DNA. In the biopsies taken 3 weeks after the initial injection, the vector was detected at the injection site in all patients. Immunohistochemistry and nested reverse transcription-polymerase chain reaction indicated dystrophin expression in six of nine patients. The level of expression was low (up to 6% weak, but complete sarcolemmal dystrophin staining, and up to 26% partial sarcolemmal labeling). No side effects were observed, nor any cellular or humoral anti-dystrophin responses. These results suggest that exogenous dystrophin expression can be obtained in Duchenne/Becker patients after intramuscular transfer of plasmid, without adverse effects, hence paving the way for future developments in gene therapy of hereditary muscular diseases.

We have treated extensive lentigo maligna in two elderly patients with Imiquimod 5% (Aldara). It was applied 3 times weekly, for 3 to 5 months. Clinical and histological remission was observed over 13 months of follow-up care. Tolerance was good. We suggest that topical imiquimod could be an interesting therapeutic alternative.

Tumor antigen-reactive T cells can be detected in a large proportion of melanoma patients, but their efficacy on tumor control in vivo remains unclear. On the other hand, vitiligo, a skin disorder characterized by patchy depigmented macules, may occur spontaneously or after antitumor therapies. Moreover, vitiligo is significantly associated with positive clinical response, but the mechanism is not understood. Therefore, the establishment of a relevant animal model in which melanoma and vitiligo spontaneously develop stepwise may be useful for better understanding of the parameters involved in the destruction of both benign and malignant melanocytes. In a previous work, we established a mouse model for melanoma in which MT/ret transgenic mice express the ret oncogene fused to the metallothionein promoter. Here we report that melanoma leads to spontaneous vitiligo. We further investigate, for the first time in this model, the natural antitumor T-cell response and evaluate the role of cellular immunity in the development of the disease. Interestingly, the occurrence of spontaneous tumor nodules in MT/ret mice with melanoma-associated vitiligo is significantly delayed when compared in melanoma mice without vitiligo. Moreover, a significant proportion of mice with melanoma-associated vitiligo resisted a challenge with syngeneic melanoma cells in contrast to animals without vitiligo. Our results confirm that vitiligo is associated with clinical benefit and further demonstrate the crucial role of CD8+ T cells for tumor control in melanoma-associated vitiligo.