The microbiome in patients with atopic dermatitis.

As an interface with the environment, the skin is a complex ecosystem colonized by many microorganisms that coexist in an established balance. The cutaneous microbiome inhibits colonization with pathogens, such as Staphylococcus aureus, and is a crucial component for function of the epidermal barrier. Moreover, crosstalk between commensals and the immune system is now recognized because microorganisms can modulate both innate and adaptive immune responses. Host-commensal interactions also have an effect on the developing immune system in infants and, subsequently, the occurrence of diseases, such as asthma and atopic dermatitis (AD). Later in life, the cutaneous microbiome contributes to the development and course of skin disease. Accordingly, in patients with AD, a decrease in microbiome diversity correlates with disease severity and increased colonization with pathogenic bacteria, such as S aureus. Early clinical studies suggest that topical application of commensal organisms (eg, Staphylococcus hominis or Roseomonas mucosa) reduces AD severity, which supports an important role for commensals in decreasing S aureus colonization in patients with AD. Advancing knowledge of the cutaneous microbiome and its function in modulating the course of skin disorders, such as AD, might result in novel therapeutic strategies

Crisaborole Ointment Improves Quality of Life of Patients with Mild to Moderate Atopic Dermatitis and Their Families.

IntroductionThe impact of crisaborole ointment, a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis (AD), on quality of life (QoL) was assessed in two identically designed phase 3 studies (AD-301: NCT02118766; AD-302: NCT02118792, both at http://www.clinicaltrials.gov ).MethodsIn both studies, patients aged ≥ 2 years with mild to moderate AD per the Investigator's Static Global Assessment were randomly assigned 2:1 to receive crisaborole or vehicle twice daily for 28 days. QoL was assessed using the Children's Dermatology Life Quality Index (CDLQI) (2-15 years), the Dermatology Life Quality Index (DLQI) (≥ 16 years), and the Dermatitis Family Impact Questionnaire (DFI) (parents/caregivers/family of patients aged 2-17 years). Established QoL score severity bands provided clinical context.ResultsGreater mean improvement in QoL was observed in crisaborole-treated patients than in vehicle-treated patients at day 29 [mean change from baseline (∆BL), CDLQI: - 4.6 vs. - 3.0; P < 0.001; DLQI: - 5.2 vs. - 3.5; P = 0.015]. At baseline, more than half the patients had a "moderate effect" or higher of AD on QoL. At day 29, there was a trend toward more crisaborole- than vehicle-treated patients having "small effect" to "no effect", The QoL of parents/caregivers/family improved more for crisaborole-treated than for vehicle-treated patients (∆BL, DFI: - 3.7 vs. - 2.7; P = 0.003).ConclusionCrisaborole treatment results in clinically meaningful improvement in QoL for patients and their parents/caregivers/families.Trial registrationAD-301: http://www.clinicaltrials.gov , NCT02118766; AD-302: http://www.clinicaltrials.gov , NCT02118792.FundingAnacor Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc., New York, NY

A Mouse Monoclonal Antibody Against a Newly Discovered Basement Membrane Component, the Epidermolysis Bullosa Acquisita Antigen

A mouse monoclonal antibody, H3a, directed against the newly described epidermolysis bullosa acquisita (EBA) antigen was obtained using hybridoma techniques. The distribution of the monoclonal antibody is identical to that of the polyclonal serum antibody of patients with EBA. By immunofluorescence, a linear band is seen at the dermal-epidermal junction and, by immunoelectron microscopy, immune reaction products are present in the lamina densa and sublamina densa regions. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western immunoblot analysis shows that the monoclonal antibody recognizes 290 and 145 kilodalton proteins present in the immunizing junctional extract, identical with the newly discovered EBA antigen. This monoclonal antibody should be useful in the further isolation and characterization of the EBA antigen

Pathogenesis of the cutaneous phenotype in inherited disorders of cholesterol metabolism: Therapeutic implications for topical treatment of these disorders

Molecular geneticists tend to conceptualize disease pathogenesis from the mutated gene outward, an approach that does not take into account the impact of barrier requirements in determining disease phenotype. An ‘outside-to-inside’ perspective has provided quite different explanations for the ichthyoses, including several of the disorders of distal cholesterol metabolism. Elucidation of responsible pathogenic mechanisms also is pointing to appropriate, pathogenesis (pathway)-based therapeutic strategies. In the case of the lipid metabolic disorders, it takes full advantage of new molecular, genetic and cellular pathogenesis information to correct or bypass the metabolic abnormality. This approach fully exploits the unique accessibility of the skin to a topical approach. Moreover, since it will utilize topical lipids and lipid-soluble, and often generic, lipid-soluble drugs, these treatments should be readily transported across the stratum corneum. If successful, this approach could initiate an entirely new departure for the therapy of the ichthyoses. Finally, because these agents are relatively safe and inexpensive, this form of treatment has the potential to be widely-deployed, even in the developing world

Characterization of CYP26B1-selective inhibitor, DX314, as a potential therapeutic for keratinization disorders

Inhibition of cytochrome P450 (CYP)-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents (RAMBAs) increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RAMBAs (i.e. liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study we use RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA (atRA) in healthy and diseased reconstructed human epidermis (RHE). We unexpectedly discovered that DX314, but not atRA or previous RAMBAs, appears to protect epidermal barrier integrity. Additionally, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, results indicate that DX314 inhibits atRA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a previously unreported promising candidate compound for further study and development in the context of keratinization disorders

Ichthyosis

[EN]The ichthyoses are a large, heterogeneous group of skin cornification disorders. They can be inherited or acquired, and result in defective keratinocyte differentiation and abnormal epidermal barrier formation. The resultant skin barrier dysfunction leads to increased transepidermal water loss and inflammation. Disordered cornification is clinically characterized by skin scaling with various degrees of thickening, desquamation (peeling) and erythema (redness). Regardless of the type of ichthyosis, many patients suffer from itching, recurrent infections, sweating impairment (hypohidrosis) with heat intolerance, and diverse ocular, hearing and nutritional complications that should be monitored periodically. The characteristic clinical features are considered to be a homeostatic attempt to repair the skin barrier, but heterogeneous clinical presentation and imperfect phenotype–genotype correlation hinder diagnosis. An accurate molecular diagnosis is, however, crucial for predicting prognosis and providing appropriate genetic counselling. Most ichthyoses severely affect patient quality of life and, in severe forms, may cause considerable disability and even death. So far, treatment provides only symptomatic relief. It is lifelong, expensive, time-consuming, and often provides disappointing results. A better understanding of the molecular mechanisms that underlie these conditions is essential for designing pathogenesis-driven and patient-tailored innovative therapeutic solutions. [ES]Las ictiosis son un grupo heterogéneo de desórdenes de la cornificación. Pueden ser hereditarios o adquiridos y resultan en una diferenciación defectuosa de los queratinocitos y una formación anormal de la barrera epidérmica. Esta disfunción de la barrera cutánea incrementa la perdida de agua transepidérmica y la inflamación. La cornificación desorganizada se caracteriza clínicamente por piel escamosa con diferentes grados de hiperqueratosis (engrosamiento cutáneo), descamación y eritema (rojez) Independientemente del tipo de ictiosis, muchos pacientes presentan prurito (picor), infecciones recurrentes, hipohidrosis (defectos en la sudoración) con intolerancia al calor y diversas complicaciones oculares, auditivas y nutricionales que deben ser controladas periódicamente. Se considera que las características clínicas comunes a estas enfermedades son un intento homeostático de reparar la barrera cutánea, pero la heterogeneidad en la presentación clínica y la baja correlación fenotipo-genotipo dificulta el diagnóstico. Un diagnóstico molecular es por ello, crucial para predecir el pronóstico y realizar un consejo genético apropiado. La mayoría de las ictiosis afectan gravemente a la calidad de vida del paciente y las formas más graves pueden causar discapacidad o incluso muerte. Hasta ahora, el tratamiento sólo proporciona alivio sintomático y es crónico, caro, laborioso y no proporciona resultados en todos los pacientes. Un mejor conocimiento de los mecanismos moleculares que subyacen a estas enfermedades es esencial para diseñar estrategias terapéuticas innovadoras

GLI1 genotypes do not predict basal cell carcinoma risk: a case control study

<p>Abstract</p> <p>Background</p> <p>Susceptibility to basal cell carcinoma results from complex interactions between ultraviolet radiation exposure and genetic factors. The <it>GLI1 </it>oncogene is believed to play a role in the genesis of these tumors. We determined whether <it>GLI1 </it>polymorphisms were risk factors for developing basal cell carcinoma, either alone or in combination with patterns of past sun exposure, and whether there were functional differences among different <it>GLI1 </it>haplotypes.</p> <p>Results</p> <p><it>GLI1 </it>genotypes at c.2798 and c.3298 from 201 basal cell carcinoma patients were compared to 201 age and sex-matched controls. Neither genotype nor haplotype frequencies differed between cases and controls. However, the odds of developing basal cell carcinoma on the trunk compared to the head/neck appeared somewhat lower with carriers of the c.3298GC than the CC genotype. There was no evidence for interactions between skin type, childhood sunburning, average adult sun exposure, adult sunbathing, or intermittency of sun exposure and <it>GLI1 </it>haplotype. Additionally, we found no significant differences in transcription activation or cell transforming ability among the four <it>GLI1 </it>haplotypes.</p> <p>Conclusion</p> <p>These results suggest that different <it>GLI1 </it>genotypes alone or in combination with past sun exposure patterns as assessed in this study do not affect basal cell carcinoma risk.</p

The histological and immunohistochemical features of the skin lesions in CANDLE syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous and often annular, cutaneous eruption. While the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 CANDLE syndrome patients by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathologic and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder as well as further insight into the pathogenesis of this severe, life-threatening conditionThis work was supported in part by the NIAMS Intramural Research Program (IRP) at the National Institutes of Health (NIH); The Authority for Research and Development, Hebrew University of Jerusalem (to A.Z.), and the Young clinician’s grant, Hadassah – Hebrew University Medical Center (to Y.R.