Management of Atopy with Dupilumab and Omalizumab in CADINS Disease.

The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity. We assessed the response of dupilumab in five patients and omalizumab in one patient with CADINS for the treatment of severe atopic symptoms. CARD11 mutations were validated for pathogenicity using a T cell transfection assay to assess the impact on activation-induced signaling to NF-κB. Three children and three adults with dominant-negative CARD11 LOF mutations were included. All developed atopic disease in infancy or early childhood. In five patients, atopic dermatitis was severe and recalcitrant to standard topical and systemic medications; one adult suffered from chronic spontaneous urticaria. Subcutaneous dupilumab was initiated to treat atopic dermatitis and omalizumab to treat chronic spontaneous urticaria. All six patients had rapid and sustained improvement in atopic symptoms with no complications during the follow-up period. Previous medications used to treat atopy were able to be decreased or discontinued. In conclusion, treatment with dupilumab and omalizumab for severe, refractory atopic disease in patients with CADINS appears to be effective and well tolerated in patients with CADINS with severe atopy.

Sclerotic-Type Cutaneous Chronic Graft-Versus-Host Disease Exhibits Activation of T Helper 1 and OX40 Cytokines.

Sclerotic-type cutaneous chronic graft-versus-host disease is a severe complication of allogeneic hematopoietic stem cell transplantation, with profound morbidity. A dearth of effective, targeted treatment options necessitates further investigation into the molecular mechanisms underlying this T-cell-mediated disease. In this study, we compared the transcriptome in skin biopsies from pediatric and young adult (aged <25 years) patients with sclerotic-type cutaneous chronic graft-versus-host disease (n = 7) with that in demographically matched healthy controls (n = 8) and patients with atopic dermatitis (n = 10) using RNA sequencing with RT-PCR and immunohistochemistry validation. Differential expression was defined as fold change > 1.5 and false discovery rate < 0.05. Sclerotic-type cutaneous chronic graft-versus-host disease exhibited strong and significant T helper (Th)1 skewing through key related cytokines and chemokines (CXCL9/10/11, IFNG/IFN-γ, STAT1/signal transducer and activator of transcription 1). Several markers related to the TSLP-OX40 axis were significantly upregulated relative to those in both controls and lesional atopic dermatitis, including TNFSF4/OX40L, TSLP, and IL33, as well as fibroinflammatory signatures characterized in a prior study in systemic sclerosis. Gene set variation analysis reflected marker-level findings, showing the greatest enrichment of the Th1 and fibroinflammatory pathways, with no global activation identified in Th2 or Th17/Th22. Cell-type deconvolution revealed a significant representation of macrophages and vascular endothelial cells. Sclerotic-type cutaneous chronic graft-versus-host disease in young patients may therefore be characterized by strong Th1-related upregulation with a unique TSLP-OX40 signature, suggesting new therapeutic avenues for this devastating disease.

Topical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions.

Acne vulgaris is a common neutrophil-driven inflammatory skin disorder in which Cutibacterium acnes (C. acnes) is known to play a key role. For decades, antibiotics have been widely employed to treat acne vulgaris, inevitably resulting in increased bacterial antibiotic resistance. Phage therapy is a promising strategy to combat the growing challenge of antibiotic-resistant bacteria, utilizing viruses that specifically lyse bacteria. Herein, we explore the feasibility of phage therapy against C. acnes. Eight novel phages, isolated in our laboratory, and commonly used antibiotics eradicate 100% of clinically isolated C. acnes strains. Topical phage therapy in a C. acnes-induced acne-like lesions mouse model affords significantly superior clinical and histological scores. Moreover, the decrease in inflammatory response was reflected by the reduced expression of chemokine CXCL2, neutrophil infiltration, and other inflammatory cytokines when compared with the infected-untreated group. Overall, these findings indicate the potential of phage therapy for acne vulgaris as an additional tool to conventional antibiotics.

Tumor necrosis factor-α inhibitor-induced follicular psoriasiform eruption.

Tumor necrosis factor-α inhibitor-associated adverse cutaneous reactions are common in patients with inflammatory bowel disease. Infection-related dermatoses and psoriasiform eruptions are seen most frequently. We describe a follicular psoriasiform eruption that appeared during treatment with infliximab in two adolescents with Crohn's disease.

LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1.

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience.

Background: Autosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features. Objectives: To describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants. Methods: The medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis. Results: Three adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients. Discussion: Dupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.

Acrofacial necrotic ulcers in an infant: An undiagnosed presentation.

Acral necrotic ulcers in infancy are rare but have been described in type I interferonopathies. Herein, we present a case of an 8-year-old child who presented at the age of one month with severe ulceronecrotic lesions on the face and limbs with exacerbations following exposure to cold weather. Despite extensive investigation the case remains undiagnosed to this day. We hypothesize that this case represents a novel and yet unknown autoinflammatory disease.

Acral peeling skin syndrome resulting from a novel homozygous mutation in the CSTA gene-A report of two cases.

Acral peeling skin syndrome is a rare genodermatosis characterized by asymptomatic peeling of the acral skin. It is usually caused by biallelic mutations in the gene TGM5. However, biallelic mutations in the CSTA gene have also been described to cause APSS with exfoliative ichthyosis, so far in only five pedigrees. Here, we report two new pedigrees, each with one patient having APSS, due to a novel CSTA mutation.

Cutaneous Adverse Events to Targeted Therapies and Immuno-therapies in Children: A Retrospective Study of 103 Patients from Two Tertiary Haemato-Oncology Referral Centres.

Targeted medications and immunotherapies are being developed to specifically target the pathways involved in tumours. There is limited experience with these new medications and their cutaneous side-effects in the paediatric population. A retrospective study of all paediatric oncological patients treated with targeted therapies and immunotherapies between 1 January 2013 and 1 August 2020 was carried out in 2 haemato-oncological referral centres. A total of 103 children were included in the study. The median (interquartile range) age was 13 years (8.4-16.9), male:female ratio 1.5:1, median (interquartile range) follow-up was 7 months (2-18). Fifty (48%) of the children developed cutaneous adverse events. Treatment was discontinued in only 3 (6%) cases and was altered in only (2%) 1 case due to a cutaneous adverse event. When targeted therapies and immunotherapies for tumours in children are used, there is an increased incidence of cutaneous adverse events. Nevertheless, treatment modification or discontinuation due to cutaneous side-effects is rarely needed.

Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function.

Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.

Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.

Dupilumab for pediatric prurigo nodularis: A case report.

Herein we report on a 9-year-old girl with recalcitrant prurigo nodularis unresponsive to multiple standard treatments. She was started on dupilumab therapy with rapid improvement in pruritus within 2 weeks and near complete regression of lesions at 3 months. Dupilumab should be considered as an off-label treatment for refractory prurigo nodularis in children.

Antibiotic Susceptibility of Cutibacterium acnes Strains Isolated from Israeli Acne Patients.

Antibiotic-resistant Cutibacterium acnes has been reported worldwide, but data from Israeli patients with acne is currently lacking. This study evaluated the antibiotic susceptibility of C. acnes, isolated from 50 Israeli patients with acne to commonly prescribed antibiotics, using the Epsilometer test (E-test). Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis, 16S rRNA sequencing and single locus sequence typing (SLST) molecular typing were used to identify and characterize C. acnes. Among 36 strains isolated, phylotype IA1 was most common. Resistance to at least one antibiotic was found in 30.6% of tested strains. Resistance rates were highest for erythromycin (25.0%), followed by doxycycline (19.4%), clindamycin (16.7%), minocycline (11.1%) and tetracycline (8.3%). Significant correlation was found between resistance to multiple antibiotics, with 5.6% of isolates resistant to all antibiotics tested. When reviewing resistances rate worldwide antibiotic resistance was found to be prevalent in Israel. Measures to limit the emergence of antibiotic-resistant strains of Cutibacterium acnes should be taken and alternative treatments should be sought.