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Seven patients with pustular psoriasis, three with mutations in IL36RN , were treated with a monoclonal antibody against interleukin-36 receptor and had amelioration of their skin disease.

In a randomized trial involving patients with the rare but disabling disorder generalized pustular psoriasis, the anti–interleukin-36 monoclonal antibody spesolimab greatly curtailed disease activity as compared with placebo over a period of 1 week. Systemic drug reactions and infections occurred with spesolimab.

A study of families from southern Tunisia affected by general pustular psoriasis uncovered the genetic cause of their disease: a mutation affecting the function of the interleukin-36–receptor antagonist. Psoriasis is a chronic inflammatory skin disease affecting 2 to 3% of persons of European descent. 1 Psoriasis vulgaris, the most common form of the disease, accounts for 80% of cases and has a strong, albeit complex, genetic component. 2 Numerous chromosomal loci have been implicated in genomewide association studies, but analyses of these loci have yielded only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses. 3 – 5 The disease follows mendelian transmission in a small minority of families. Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are characterized by . . .

Background Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, resulting from genetic defects in the nucleotide excision repair (NER) pathway. It predisposes individuals to skin cancers, including melanoma. The melanoma microenvironment is enriched with inflammatory mediators, particularly macrophages, which may serve as prognostic biomarkers or therapeutic targets. While inflammation is linked to melanoma outcomes, its role in carcinogenesis among XP patients remains poorly understood. Methods We assessed the cytokine profiles in the sera of XP-melanoma patients, as well as the expression level of a pan-macrophage marker (CD68), M2-markers CD163, and M1-associated nitric oxide synthase (iNOS) expression. Results XP patients exhibited significantly reduced levels of iNOS, MIP-1β, MCP-1, and IL-33, indicating an impaired inflammatory and macrophage-mediated immune response. We also found that IL-33 and iNOS levels were positively correlated with the density of inflammatory infiltrates. Moreover, in vitro assays using G361 melanoma cells demonstrated that both pro-inflammatory macrophage-conditioned media and exogenous IL-33 suppressed tumor cell proliferation. Conclusion This study emphasizes the need for specific macrophage biomarkers and proposes local interleukin-33 delivery as a potential therapy for poorly infiltrated melanoma. This also suggests that NER-deficient patients may exhibit unique molecular profiles, warranting personalized treatment.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

IntroductionGeneralized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.Methods and analysisAt least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.Ethics and disseminationThe study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.Trial registration detailsClinicalTrials.gov identifier: NCT03782792; Pre-results.

An otherwise healthy 63-year-old man from a rural area in Tunisia presented with ulcerated paronychia, with a verrucous lesion at the base of the right thumb. Physical examination revealed seven crusty, ulcerated skin lesions on the limbs. An otherwise healthy 63-year-old man from a rural area in central Tunisia presented with a 1-month history of ulcerated paronychia, with a verrucous lesion at the base of the right thumb (Panel A). He was otherwise asymptomatic and reported having no pain, but physical examination revealed seven crusty, ulcerated skin lesions on the limbs (including a lesion on the left ankle, Panel B). Since the ulcerations and the presence of lesions on the limbs were not consistent with chronic paronychia, a skin smear was obtained. Optical examination of the smear after May–Grünwald–Giemsa staining revealed amastigote forms of the leishmania parasite, . . .

Morsicatio is caused by chronic self‐inflicted biting of the buccal mucosa that results in clinically whitish plaques. It is frequently confused with other dermatological mucosal disorders. To avoid needless invasive procedures, dermoscopy can help with differential diagnosis. Dermoscopy shows whitish and yellowish structureless areas and lines, small erosions, and some white scales. The lack of additional, more specific signs such as Wickham striae is crucial to guide the diagnosis. Dermoscopy can help to make the right diagnosis in front of whitish patches of the buccal mucosa avoiding unnecessary invasive procedures and inappropriate treatment.

Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 ( STAT3 ) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.

Cutaneous leishmaniasis is a major world health problem. Diagnosis is suspected on evocative clinical presentation in patients living in or coming from endemic areas. Several methods have been used. The smear is a simple investigation used in endemic regions. The culture enables to identify the specimen. PCR has a high sensitivity. Montenegro's reaction is used in the epidemiological study. Pentavalent antimony derivatives remain the mainstay of systemic treatment. Their efficiency is well established. Their toxicity should be researched. Other treatments can be utilized, such as miltefosine. Local therapy is used in uncomplicated lesions. Injections of the pentavalent antimony derivate, cryotherapy and paromomycin ointmentsis are important options and should be used more frequently in Old World leishmaniasis.