Congenital deficiency reveals critical role of ISG15 in skin homeostasis.

Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteinases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-ß1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets.

Superficial cryotherapy using dimethyl ether and propane mixture versus microneedling in the treatment of alopecia areata: A prospective single-blinded randomized clinical trial.

To verify and compare the therapeutic efficacy and safety of superficial cryotherapy using dimethyl ether and propane (DMEP) mixture vs. microneedling in the treatment of mild scalp alopecia areata (AA). In a prospective randomized single-blinded clinical trial, 80 patients with clinically evident scalp mild AA were randomly assigned into two groups of 40 patients each. Group (1) was treated by superficial cryotherapy using DMEP in three freeze-thaw cycles of 5 s each. Group (2) was treated by microneedling. Both groups were treated every 2 weeks for 6 sessions and followed up for 3 months after the last session. Patients were assessed by photographic documentation, trichoscopic evaluation, severity of alopecia tool (SALT) score, and alopecia areata symptom impact scale (AASIS). An excellent response was achieved in 15 (37.5%) of group (1) compared with 14 (35%) of group (2) patients, while a good response was achieved in 23 (57.5%) of group (1) compared with 21 (52.5%) of group (1) patients, with a statistically insignificant difference. The mean SALT score change percentage was a statistically significantly higher in group (2) patients. The mean AASIS change percentage was higher in group (1) patients, but this was a statistically insignificant. In both groups, the mean numbers of trichoscopic signs of AA significantly decreased from baseline to the end of follow-up period. Both therapeutic modalities were well-tolerated, with no recurrence after the follow-up period. Both superficial cryotherapy using DMEP mixture, and microneedling are simple, effective, and safe therapeutic options for mild scalp AA, however, microneedling showed higher efficacy.