Novel Clinical Applications of Topical Ruxolitinib: A Case Series.

Topical ruxolitinib, a potent Janus kinase (JAK) inhibitor, has shown significant efficacy in treating inflammatory skin conditions. While its use has already been established in atopic dermatitis and vitiligo, recent reports suggest its potential efficacy in treating other dermatoses. Specifically, topical ruxolitinib may be an effective treatment option for refractory dermatological conditions that are inflammation-driven with dysregulated activity of cytokines implicated in the JAK/STAT pathway. In this case series, we present four novel clinical applications of topical ruxolitinib in treatment-resistant dermatological conditions. These cases include pediatric lichen sclerosus et atrophicus, morphea, perioral dermatitis, and notalgia paresthetica. All four patients reported noticeable symptomatic improvement and a significant improvement in the condition of their skin lesions. Our results suggest that ruxolitinib cream can successfully manage these conditions and may serve as supporting evidence for its formal evaluation.   J Drugs Dermatol. 2024;23(3): doi:10.36849/JDD.7696.

Alopecia Areata: A Complex Cytokine Driven Disease.

Alopecia areata (AA) has been recently shown to also include T-helper cell type 2/IL-23 activation, in addition to T-helper cell type 1/IFN-skewing. The success of Jak inhibition together with IL-4Rα antagonism and limited response to IL-17A and PDE4 (protein) inhibition in AA are increasing our understanding of the complex immune interplay in AA. Trials testing targeted therapeutics are needed to further elucidate the pathogenic contribution of various cytokines.

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (TH2/TH22/TH17/TH1) and epidermal differentiation. OBJECTIVE: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. METHODS: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. RESULTS: ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including TH2 (IL4 receptor [IL4R], IL13, CCL13/monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), TH17/TH22 (lipocalins, PI3/elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and TH1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. CONCLUSION: The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.

The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood.

The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4+/CD8+ and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+/CD8+ T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.

Hippocampal mGluR5 predicts an occurrence of helplessness behavior after repetitive exposure to uncontrollable stress.

An individual's behavior is generally based on genetic blueprint and previous experiences. A coping strategy, affected by personal interpretation of past events, can be determined by behavioral controllability of stress. In this study, we examined the relationship between the hippocampal mGluR5 expression and coping strategies to stress. Rats were exposed to stress via inescapable and unpredictable footshocks on PNDs 14 and 90. Coping strategies to stress were also measured. Hippocampal mGluR5 was found to be linked to the behavioral coping strategy, as it increased in rats that showed helplessness behavior (HL (+) group) and decreased in those that did not (HL (-) group). Also, the HL (+) group showed a lack of adaptation in a novel environment but the HL (-) group did not. The results suggest that mGluR5 has a pivotal role in the controllability-based coping strategy. Hippocampal mGluR5 could be a target molecule in the manipulation of neuropsychiatric conditions for which maladaptation is a part of behavioral consequences.