SummaryBackground ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate‐to‐severe AD. Methods A total of 36 patients with moderate‐to‐severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28‑day period (20 mg, 40 mg and 80 mg once daily).Results ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg −1·3 ± 2·1, P = 0·81; 40 mg −3·1 ± 2·7, P = 0·27; 80 mg −4·7 ± 2·1, P = 0·01; placebo −1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose‐dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis‐associated biomarker E selectin/SELE.ConclusionsIn patients with moderate‐to‐severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

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 (T H 2/T H 22/T H 17/T H 1) 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 T H 2 (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), T H 17/T H 22 (lipocalins, PI3/ elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and T H 1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrierrelated 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 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.

(AA) is a nonscarring hair loss disorder with a lifetime prevalence of approximately 2%. 1 Various studies attempted to profile the cytokine pathways involved in the pathogenesis of AA, with a recent shift from T H 1/IFN-g axis activation alone to potentially also include T H 2 skewing. 1-3 A link to atopy has been further observed by genetic linkage to IL-13 in genome-wide association studies, 1 increased IgE levels in patients with AA regardless of atopy, 4 and increases in T H 2-related serum measures (ie, IL-4, IL-13, and CCL17). 5 Nevertheless, extensive serum cytokine profiling, with appropriate correlations to clinical parameters and scalp biomarkers, is lacking. Because scalp tissues can be difficult to obtain, it is imperative to identify blood biomarkers that reflect both clinical severity and scalp expression to aid in therapeutic development. Our study evaluated both serum cytokines and scalp expression of lesional and nonlesional measures in patients with moderate-to-severe AA (n 5 30) compared with age-matched control subjects (n 5 10) to integrate circulating and tissue biomarkers that correlate with AA severity (Severity of Alopecia Tool [SALT]). This study included 30 patients with AA (21 female and 9 male patients; age range, 20-72 years old; mean age, 41.8 years old) and 10 age-matched control subjects (see Table E1 in this article's Online Repository at www.jacionline.org). Three (10%) of 30 patients had an atopic background, and all our control subjects lacked an atopic background. Fourteen (46.7%) of 30 patients had moderate-to-severe AA (>50% scalp involvement), 14 (46.7%) of 30 had alopecia universalis (AU), and 2 (6.6%) of 30 had alopecia totalis (AT). Severity was assessed by using the SALT score, 6 ranging from 50 to 100 (mean, 87.8). Blood, lesional, nonlesional, and control scalp biopsy specimens were obtained under an Institutional Review Board-approved protocol (see the Methods section in this article's Online Repository at www.jacionline.org for details). Electrochemiluminescence (ECL) immunoassays, which have greater sensitivity than standard ELISAs, were used in a multiplex format (Meso Scale Discovery, Rockville, Md) to analyze 9 serum chemokines (CCL2/CCL3/CCL4/CXCL10 for T H 1 and CCL11/CCL13/CCL17/CCL22/CCL26 for T H 2) and the cytokine IL-15. Because serum IFN-g and IL-13 cytokine levels are very low, we used Erenna immunoassays (EMD Millipore, St Louis, Mo), which have much lower quantification levels.