OBJECTIVE:To investigate whether oral ivermectin or topical 5% permethrin can clinically cure scabies in index cases and in members of their households. DESIGN:Multicentre, assessor blinded, cluster randomised clinical trial. SETTING:28 French hospitals, 19 January 2016 to 16 December 2021. PARTICIPANTS:Index cases; adults and children weighing >15 kg with scabies, confirmed by dermoscopy. INTERVENTIONS:Index cases were randomly assigned to the ivermectin group or permethrin group (1:1 ratio). Each member of the cluster, defined as the household of each index case, received the same treatment as the index case, except for children weighing <15 kg who were prescribed topical 5% permethrin. All participants received oral ivermectin 200 µg/kg or 5% permethrin cream on day 0 and day 10. Permethrin cream was applied to the whole body, from head to toe. MAIN OUTCOME MEASURES:The primary outcome was clinical cure of the cluster on day 28 (ie, disappearance of clinical signs and symptoms of scabies for all cluster members). Secondary outcomes were index case and individual level analyses and safety. Dermatologists were used as assessors and were masked to the treatment. RESULTS:507 participants in 142 households (clusters) were treated with ivermectin and 568 participants in 147 households received permethrin. Cluster level cure rates were 71.8% versus 88.5% (-16.7 percentage point difference, 95% confidence interval (CI) -26.3 to -7.1) for ivermectin versus permethrin. Secondary outcome percentage point differences also showed the inferiority of ivermectin compared with 5% permethrin for index cases (76.6% v 91.5%; percentage point difference -14.9, 95% CI -23.6 to -6.2) and participants (85.3% v 94.2%; -9.2 percentage point difference, -14.9 to -3.5). Intraclass correlation coefficients were higher for permethrin than ivermectin for all clusters (0.68, 95% CI 0.61 to 0.75 v 0.46, 0.37 to 0.56) and for cluster size >1 (0.67, 0.60 to 0.74 v 0.47, 0.37 to 0.56). Cutaneous adverse events were found in 11.9% and 15.6% of participants treated with ivermectin and permethrin, respectively. CONCLUSIONS:The results of this cluster randomised trial of classic scabies, confirmed by dermoscopy, did not show the non-inferiority of oral ivermectin compared with 5% permethrin cream, given on days 0 and 10, in achieving clinical cure of scabies on day 28 in index cases and their household members. Conversely, the trial showed the statistical superiority of 5% permethrin cream. TRIAL REGISTRATION:NCT02407782.

We report three patients with nonsyndromic epidermal differentiation disorders associated with the same recurrent pathogenic NIPAL4 variantt who subsequently developed cutaneous T-cell lymphoma (Sézary syndrome in all cases). These observations suggest a possible link between congenital epidermal barrier defects and lymphomagenesis, and highlight the importance of considering skin biopsy in nEDD patients with phenotypic change, pruritus, or treatment resistance.

In our cohort of 13 patients with autosomal recessive nonsyndromic epidermal differentiation disorders (AR nEDDs) who developed psoriasis flare-ups, either plaque-type or pustular, 11 required systemic therapy. Although T-helper (Th)17 pathway activation has previously been shown to be elevated in AR nEDD skin and correlated with erythema and disease severity, in our cohort therapies targeting the interleukin (IL)-17/IL-23 axis achieved complete control of AR psoriasis flare-ups, while demonstrating minimal efficacy on the underlying EDD.

Recent evidence implicates altered RNA editing and dysregulated type I IFN signaling in immune-mediated diseases, including psoriasis, although the underlying genetic mechanisms remain poorly defined. We investigated four unrelated multiplex families with early-onset plaque psoriasis, with or without psoriatic arthritis, segregating as a monogenic trait and characterized by a strong IFN signature in skin and blood. Whole-exome sequencing identified four rare heterozygous loss-of-function mutations in ADAR1 cosegregating with disease and elevated IFN-stimulated gene expression. Six additional rare variants were detected in an independent cohort of 125 psoriasis patients. Single-cell transcriptomics identified keratinocytes and melanocytes as major IFN sources. Functional studies showed that ADAR1 knockdown or expression of ADAR1G1119R and ADAR1P3A alleles pathogenic variants reduced adenosine-to-inosine RNA editing and increased IFN-stimulated genes and inflammatory cytokines, effects reversed by upadacitinib and deucravacitinib. These findings define a novel IFN-dependent psoriasis subtype caused by inborn defects of ADAR1-mediated RNA editing, with direct implications for precision medicine in psoriatic disease.

ABSTRACT Primary cutaneous gamma‐delta T‐cell lymphoma has been described as an aggressive entity with a poor prognosis. However, gamma‐delta T‐cell receptor expression has been described in various types of skin lymphoproliferations. Paediatric cases of LyP are increasingly recognized, but paediatric LyP with a gamma‐delta phenotype have been rarely described. We report three paediatric patients with indolent gamma‐delta lymphoproliferation, with a relapsing‐remitting course evoking LyP. These three cases emphasize that TCR gamma‐delta expression in a lymphoproliferation is not a synonym of gamma‐delta lymphoma. Indeed, these cases raise the question of a paediatric variant of CD30‐negative lymphomatoid papulosis with histological features of atypical gamma‐delta‐positive T‐cell lymphoproliferation and underline the necessity of cautious clinico‐histological correlation when facing a gamma‐delta lymphoproliferation to avoid overtreatment.

Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering condition caused by pathogenic variants in the COL7A1 gene and may present with different disease endotypes. In this study, the authors characterise a cohort of RDEB adults to highlight variations in immune cell phenotypes and metabolic profiles, particularly in T cells and NK cells.

Alginate hydrogels are biocompatible and present tunable properties making them ideal for biomedical applications. We designed a novel Ca2+-Alginate hydrogel and investigated its bioactivity on key component of the immune inflammatory process, the monocytes/macrophages. Our results demonstrate that the developed Ca2+-Alginate hydrogel downregulated the expression of inflammation-related markers CD36 and CD64, in both classical and intermediate monocyte subsets. Additionally, the hydrogel upregulated the expression of the anti-inflammatory marker CD206 in both subsets and reduced their capacity to produce TNF alpha. In macrophages, the hydrogel modulated the pro-inflammatory M1 towards an anti-inflammatory profile, as evidenced by an increased population of CD163(+)CD206(+) macrophages, typically associated with anti-inflammatory/immunoregulatory activity, and a decreased production of TNF alpha. The hydrogel also affected mitochondrial function in M1-macrophages, increasing mitochondrial mass and reducing reactive oxygen species production. The translational potential of the hydrogel was evaluated on circulating monocytes from patients suffering from the severe skin disease recessive dystrophic epidermolysis bullosa. The hydrogel increased the anti-inflammatory classical monocyte subset at the expense of the intermediate inflammatory subset. It also reduced CD36 and CD64, and downregulated TNF alpha production. Collectively, our findings provide evidence of the anti-inflammatory potential of a Ca2+-Alginate hydrogel, suggesting its promising therapeutic application to modulate inflammation.

Neutrophilic dermatoses are rare in children. Systemic corticosteroids are the first-line treatment, but guidelines for second-line therapies are lacking. We report five cases of children with systemic steroid-resistant/dependent neutrophilic dermatoses, successfully treated with tumor necrosis factor inhibitors.

BACKGROUND:Renal manifestations in patients with recessive dystrophic epidermolysis bullosa (RDEB) due to collagen VII deficiency have been described only in case series and could thus be underestimated. OBJECTIVES:To describe the prevalence and types of kidney disease in a large cohort of patients with RDEB. METHODS:We conducted a retrospective study in two Parisian reference centres for RDEB and included patients with at least two concurrent blood and urine analyses. Kidney disease was defined as either glomerular with elevated albumin or tubulointerstitial with elevated β2-microglobulin. RESULTS:We included 120 patients with a confirmed molecular diagnosis of RDEB characterized by collagen VII deficiency between 2005 and 2021, of whom 36 (30%) exhibited kidney disease. Of these, 15 (12.5%) displayed glomerular disease, most commonly due to IgA nephropathy, and 21 (17.5%) presented with a tubulointerstitial presentation, often associated with complex hydroelectrolytic disorders. The immunohistochemistry study with anticollagen VII antibody was positive on glomerular and tubular basement membranes in controls and negative in patients with complete collagen VII deficiency. In multivariate analysis, kidney disease was significantly associated with disease severity (P = 0.002). Overall survival was reduced in patients with RDEB with kidney complications. Based on these findings, we propose recommendations for the detection and monitoring of kidney disease in this patient population, with early referral to a nephrologist specifically on the identification of renal abnormalities. CONCLUSIONS:Kidney disease is common, correlates with disease severity, and impacts the prognosis of patients with RDEB. Systematic screening is recommended in this population.

BACKGROUND:Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients. METHODS:We investigated a large, well-phenotyped NF1 cohort. RESULTS:We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants. CONCLUSION:The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

Introduction Les dermatoses neutrophiliques (DN) sont rares chez l’enfant. La présentation dermatologique est généralement similaire à celle de l’adulte, mais avec une fréquence plus élevée de manifestations extra-cutanées. Le traitement est mal codifié, en particulier dans les cas de résistance ou de dépendance aux stéroïdes. Nous présentons 4 cas de DN pédiatrique sévère ayant nécessité un traitement anti-TNFα. Matériel et méthodes Étude descriptive, rétrospective, multicentrique, incluant les patients <18 ans avec un diagnostic de DN confirmé par l’histologie, et traité par anti TNFα. Résultats Quatre patients, 2 filles et 2 garçons, âgés de 3 à 14 ans, ont été admis pour fièvre, syndrome inflammatoire biologique, asthénie, et lésions cutanées nodulaires nécrotiques des membres (n=3), du visage (n=1), des fesses (n=1) associées chez 2 patients à une atteinte muqueuse comprenant une laryngite sévère avec dyspnée. Les biopsies cutanées étaient compatibles avec une DN (2 syndromes de Sweet et 2 pyoderma gangrenosum). Chez 2 patients les lésions étaient précédées d’un épisode infectieux ; un patient avait une maladie inflammatoire de l’intestin et un patient avait eu une vaccination BCG avant le début de la maladie. Tous les patients ont reçu initialement des corticoïdes oraux ou intraveineux à des doses allant de 1 à 2mg/kg/jour, sans efficacité ou avec cortico-dépendance. Dans les suites, une patiente avec atteinte muqueuse sévère a été traitée directement par infliximab (10mg/kg) tous les mois avec une réponse partielle, puis toutes les 3 semaines avec une réponse complète. Deux patients ont été traités par dapsone (2mg/kg/j) sans efficacité. Trois patients ont reçu de la ciclosporine jusqu’à 5mg/kg/j sans efficacité (n=2) ou avec toxicité rénale (n=1). Un patient a été guéri sous adalimumab (40mg/15 j), un autre avec atteinte muqueuse sévère par infliximab (5mg/kg puis 10mg/kg) tous les14jours. Le dernier patient a été traité par infliximab (7,5mg/kg) tous les14jours puis du fait d’une résistance secondaire à la présence d’anticorps anti-infliximab, par adalimumab (40mg/15j) avec une réponse complète. Aucun effet indésirable sous anti TNFα rapporté. Discussion Les DN pédiatriques peuvent être sévères, notamment en cas d’atteinte des voies aériennes supérieures (laryngées) pouvant se compliquer d’une détresse respiratoire. Nos cas sont originaux car l’atteinte ORL n’a été rapportée que chez les nourrissons et non chez les enfants. La résistance/dépendance aux stéroïdes systémiques est également inhabituelle chez les enfants, mais plus souvent rapportée que chez l’adulte. Dans ce cas, les anti-TNFα semblent, comme cela a été bien décrit chez l’adulte, efficaces et bien tolérés, à fortes doses en particulier en cas d’atteinte muqueuse. Une limite à leur utilisation pourrait être l’apparition d’anticorps anti-TNFα. Conclusion Les DN pédiatriques sont parfois difficiles à prendre en charge notamment lors d’une cortico-résistance ou dépendance. Les anti-TNFα apparaissent comme une option efficace et sûre dans ces situations.

Introduction Le psoriasis est une cause très fréquente de kératodermie palmoplantaire (KPP) inflammatoire acquise, quelle que soit la tranche d’âge. À l’inverse, cette dernière est très rarement l’expression d’un lymphome T épidermotrope. Chez l’adulte, une KPP est dans 0,6 % des cas une manifestation d’un lymphome T cutané, principalement des mycosis fongoïdes (MF) érythrodermiques ou des syndromes de Sézary. Nous rapportons 4 cas pédiatriques de KPP inflammatoires traitées comme des KPP psoriasiques, puis diagnostiquées MF après échec de plusieurs lignes de traitement systémique. Observations L’âge moyen des 4 enfants (2 garçons et 2 filles) était de 11 ans au diagnostic (de 6 à 15 ans). Trois patients étaient de phototype VI et un de phototype II. La KPP psoriasiforme était au premier plan. Tous les patients, très gênés sur le plan fonctionnel, recevaient plusieurs lignes de traitements systémiques : acitrétine (1 patient), méthotrexate (2 patients), anti-TNF (2 patients), anti-IL-12/23 (1 patient), anti-IL-17 (1 patient). Aucun de ces traitements ne permettait une rémission suffisante et le diagnostic de psoriasis était alors remis en question, d’autant que d’autres plaques étaient apparues à distance : le tronc et le cuir chevelu dans 3 cas, les ongles dans 2 cas, la zone péri-unguéale dans 4 cas. L’aspect histologique des biopsies alors réalisées (en zone palmoplantaire et/ou sur des lésions à distance) était évocateur de MF : épidermotropisme, alignement basal lymphocytaire et atypies lymphocytaires. L’immunohistochimie montrait un infiltrat CD4+ et CD8+ chez 3 patients et CD4+ et CD8- chez un autre. Un clone T dominant dans la peau était détecté chez 2 patients sur 4. Tous les patients étaient au stade Ia du MF. Le délai moyen entre l’apparition de la KPP et le diagnostic de MF était de 2,3 ans (de 1 à 4 ans). Les traitements proposés pour le MF comprenaient : photothérapie UVB puis UVA chez un patient, en échec et actuellement sous peginterféron, acitrétine chez un patient et méthotrexate chez 2 patients. Aucun patient n’a encore obtenu de rémission complète. Le suivi médian était de 2 ans (de 1 à 3 ans). Discussion Le diagnostic du MF chez l’enfant est rare et difficile du fait d’une présentation mimant souvent une dermatose fréquente et bénigne (eczématides folliculaires, eczématides achromiantes), la présentation la plus fréquente étant la forme hypopigmentée. Nous attirons l’attention sur le fait qu’une KPP psoriasiforme peut être la manifestation inaugurale d’un MF de l’enfant. La résistance à plusieurs lignes de traitement du psoriasis est un signe qui doit faire évoquer le diagnostic de MF devant une KPP inflammatoire de l’enfant et proposer une biopsie, car l’aspect sémiologique de la KPP semble assez proche dans les deux étiologies. Conclusion Le MF doit donc être rajouté aux étiologies des KPP de l’enfant avec le psoriasis et les formes génétiques.