Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features

Chan, Teh Sheng; Sanyal, R.D.; Pavel, Ana B.; Glickman, Jacob W.; Zheng, Xiuzhong; Xu, Hui; Cho, Yung-Tsu; Tsai, Tsen‐Fang; Wen, Huei‐Chi; Peng, Xiangyu; Cueto, Inna; Krueger, James G.; Guttman‐Yassky, Emma

doi:10.1016/j.jaci.2018.06.016

Cited by 81 publications

(95 citation statements)

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“…[41][42][43] Thus dual JAK-SYK inhibition might broaden the range of cytokines targeted to successfully resolve AD across the different disease subtypes. 9,10,12,21,[44][45][46][47][48] ASN002 is the first oral dual JAK/SYK inhibitor tested in patients with AD. A phase 1B clinical trial has been performed recently in patients with moderate-to-severe AD over 4 weeks (ClinicalTrials.gov: NCT03139981), 49 evaluating 3 daily doses (20,40, and 80 mg) compared with placebo.…”

Section: Abbreviations Usedmentioning

confidence: 99%

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

Pavel

Song

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

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101

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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.

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Section: Abbreviations Usedmentioning

confidence: 99%

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

Pavel

Song

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

Self Cite

101

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“…The ethnic background also plays a role in terms of differences in cytokine patterns among AD patients. In this context, it has been demonstrated that the expression of Th17 cytokines is greater and the levels of Th1 cytokines in the skin of Chinese AD patients are relatively lower than in European AD patients . Increased Th17 cytokine levels, associated with distinct parakeratosis, have also been found in AD patients from Japan and Korea.…”

Section: T‐helper Cellsmentioning

confidence: 98%

Pathophysiology of atopic dermatitis

Grobe

Bieber

Novak

2019

J Deutsche Derma Gesell

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ZusammenfassungWenige Erkrankungen wurden in den letzten Jahren so intensiv und vielfältig auf verschiedenen Ebenen erforscht wie die atopische Dermatitis (AD). Das liegt zum einen daran, dass es sich um die häufigste chronisch-entzündliche Hauterkrankung handelt, die bis zu 30 % der Kinder und 1-10 % der Erwachsenen betrifft. Zum anderen konnten zahlreiche komplexe Veränderungen auf genetischer Ebene sowie auf Ebene des angeborenen und erworbenen Immunsystems identifiziert werden, die für die Charakterisierung der Patienten und Entwicklung neuer diagnostischer und therapeutischer Ansätze wichtig sind. Trotz der komplexen Pathogenese und immunologischen Unterschiede in verschiedenen Krankheitsstadien, sowie der Heterogenität der Krankheitstrigger, war die Therapie der AD, vor allem der mittelschweren bis schweren Form, lange auf rein symptomatische bzw. unspezifische immunsup-Mit Zulassung des ersten Biologikums zur Behandlung der mittelschweren und schweren AD bei Erwachsenen und dessen Verfügbarkeit auf dem deutschen Markt seit Ende 2017, ist nun Bewegung in das Feld gekommen. In dieser Arbeit werden die aktuellen pathophysiologischen Erkenntnisse zur AD zusammengefasst. Durch die Fortschritte bei der Erforschung der Erkrankung wird eine verbesserte Charakterisierung von Patientensubgruppen und verschiedenen Krankheitsausprägungen möglich, was die Grundlage zukünftig zunehmend individuellerer Behandlungsmöglichkeiten darstellen wird. SummaryOnly few diseases have been studied as extensively and on as many different levels in recent years as atopic dermatitis (AD). One of the reasons why AD is the focus of interest is that it is one of the most common chronic inflammatory skin diseases, affecting up to 30 % of children and 1-10 % of adults. Numerous complex alterations both on the genetic level as well as on the level of innate and adaptive immunity have been identified and form the basis for the characterization of different patient groups and the development of novel diagnostic and therapeutic approaches. Despite the complex pathophysiological and immunological differences, which are closely related to disease stage and severity, as well as the heterogeneity of individual trigger factors, treatment of AD -in particular that of moderate-to-severe AD -was long limited to merely symptomatic and relatively nonspecific immunosuppressive approaches. Since the approval of the first biologic for the treatment of moderateto-severe adult AD (commercially available in Germany since late 2017), there has been some movement in the field of AD management.

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“…Remarkably, in the chronic stage, other Th cell subsets including IFN-γ-producing Th1, IL-17-producing Th17, and IL-22-producing Th22 are also infiltrating the skin lesions [11,15]. Depending on the AD subtypes, the relative frequency and contribution of these inflammatory Th cell subsets might vary significantly [11,35,36]. For example, in Asian AD patients as well as in some AD children subtypes, IL-17-producing Th17 cells might contribute to parakeratosis resembling typical features of psoriasis.…”

Section: Chronic Stagementioning

confidence: 99%

Atopic Dermatitis: From Physiopathology to the Clinics

Figueras‐Nart¹,

Palomares-Gracia²

2021

Atopic Dermatitis - Essential Issues

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Atopic dermatitis is a chronic, pruritic, relapsing inflammatory disease with a complex etiopathogenesis. Alterations of the epidermal barrier function together with a predominantly type 2 altered immune response are responsible for the heterogeneous clinical manifestation. Although pruritic eczematous plaques represent the most frequent phenotype, several others are also characteristic. The diagnostic of the disease relies on clinical aspects, and no complimentary tests are needed. In the literature, we can find a significant number of diagnostic and screening biomarkers; however, severity ones are the most reliable and applicable. Patient-tailored treatment is mandatory, as not all the patients equally respond to the same drugs. The newly released therapies, as well as those under investigation, give hope to AD patients.

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Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features

Cited by 81 publications

References 9 publications

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

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

Pathophysiology of atopic dermatitis

Atopic Dermatitis: From Physiopathology to the Clinics

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