Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.

Mast cells have traditionally been associated with allergic inflammatory responses; however, they play important roles in cutaneous innate immunity and wound healing. The Hidradenitis Suppurativa tissue transcriptome is associated with alterations in innate immunity and wound healing-associated pathways; however, the role of mast cells in the disease is unexplored. We demonstrate that mast cell-associated gene expression (using whole tissue RNAseq) is upregulated, and in-silico cellular deconvolution identifies activated mast cells upregulated and resting mast cells downregulated in lesional tissue. Tryptase/Chymase positive mast cells (identified using IHC) localize adjacent to epithelialized tunnels, fibrotic regions of the dermis and at perivascular sites associated with Neutrophil Extracellular Trap formation and TNF-alpha production. Treatment with Spleen Tyrosine Kinase antagonist (Fostamatinib) reduces the expression of mast cell-associated gene transcripts, associated biochemical pathways and the number of tryptase/chymase positive mast cells in lesional hidradenitis suppurativa tissue. This data indicates that although mast cells are not the most abundant cell type in Hidradenitis Suppurativa tissue, the dysregulation of mast cells is paralleled with B cell/plasma cell inflammation, inflammatory epithelialized tunnels and epithelial budding. This provides an explanation as to the mixed inflammatory activation signature seen in HS, the correlation with dysregulated wound healing and potential pathways involved in the development of epithelialized tunnels.

A systematic review and critical evaluation of reported pathogenic sequence variants in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a severe chronic inflammatory disorder characterized by recurrent painful deep-seated nodules with a predilection to the apocrine-bearing areas of skin. A minority of cases of HS are due to mutations in the γ-secretase complex. Contention exists surrounding the pathogenicity of sequence variants and their effects upon Notch signalling. This systematic review was registered with PROSPERO (CRD42016041425) and was conducted in line with the PRISMA statement. Eligibility criteria for this review included published case reports, case series and reviews that identified sequence variants or protein or functional studies from patients with HS. Sixty-two articles were identified reporting a total of 41 sequence variants - heterozygous missense (nine), splice site (nine), insertion resulting in frameshift (one), premature termination codon (19) and promoter region PSTPIP1 (three) - with 18 associated protein or functional studies. The American College of Medical Genetics and Genomics standards and guidelines on the interpretation of sequence variants were applied to each identified variant to assess evidence for pathogenicity. Twenty-three variants were assessed as likely pathogenic, 17 of uncertain significance and one benign. The large number of variants of 'uncertain significance' is largely due to the variable number of functional studies. Four studies used Notch as a proxy for γ-secretase function, with conclusions of nonpathogenicity based on the assumption of Notch signalling as the sole pathogenic process. The role of Notch-independent signalling mechanisms requires further research. Limitations to this study include identification of variants of Mendelian inheritance and not complex polygenic traits.

Systemic treatment of severe psoriasis.

Severe psoriasis presents a difficult therapeutic challenge. Some modalities such as synthetic retinoids, phototherapy and methotrexate have been available for many years and need reappraisal, cyclosporin has only recently become available and requires careful administration. In this article we focus on the therapeutic modalities available to the dermatologist in Australia.

Safety and efficacy of mometasone furoate cream in the treatment of steroid responsive dermatoses.

The safety and efficacy of once daily application of mometasone furoate cream 0.1% was determined by comparison with twice daily applications of betamethasone dipropionate cream 0.05% in a single blind, dual centre, randomized study in patients with a variety of steroid-responsive inflammatory dermatoses, the most common of which was psoriasis. Morning plasma cortisol levels revealed little adrenal suppression in either of the two study groups and there was no significant difference between the two groups. Routine laboratory investigations showed no trends in values outside the normal ranges that were of clinical significance. Less skin atrophy was seen in the group treated with mometasone furoate. In comparison to the betamethasone dipropionate treated group, those treated with mometasone furoate exhibited only slight evidence of skin atrophy, and this was not observed before four to twelve weeks of treatment. Eighteen percent of patients using mometasone reported adverse reactions but all were of limited duration and did not persist despite continued application of the drug. Nine percent of patients using betamethasone dipropionate reported adverse effects. Both drugs were found to be highly effective with no significant difference between the two groups at the termination of the treatment period. Of importance is the fact that whilst mometasone furoate is found to be a highly effective treatment for a variety of steroid-responsive dermatoses, this drug has only a limited potential for production of local and systemic side effects. Thus, a high margin of safety can be expected for patients using this drug.

Diagnosis by Frozen Section Examination, II: Results in Skin Lesions.

A series of 910 frozen section examination of skin lesions is presented, and the results are analysed in detail and compared with others in the literature. The difficulties in histological diagnosis are discussed and contrasted with those of clinical diagnosis especially of pigmented lesions. SUMMARY: In 910 consecutive frozen section examinations of skin lesions nine false positive reports were submitted, but only two were of major importance. False negative reports occurred with malignant melanomas when the lesion was small or heavily pigmented, and with other malignant lesions when the specimens were large (sampling error). Frozen section examination accurately identifies lesions that tend to be mistaken for malignant melanoma on clinical examination.