Atopic dermatitis: pathogenesis

Guttman‐Yassky, Emma; Waldman, Andrea; Ahluwalia, Jusleen; Ong, Peck Y.; Eichenfield, Lawrence F.

doi:10.12788/j.sder.2017.036

Cited by 81 publications

(80 citation statements)

References 28 publications

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“…Although AD is primarily T H 2/T H 22 driven, it is a heterogeneous disease with variable contributions of T H 1 and T H 17 immune pathways in distinct disease subtypes. [6][7][8][13][14][15]66,93 For example, AD in both pediatric and Asian adult populations have strong T H 2 and T H 17 polarization, whereas AD in European American adults has mainly T H 2/T H 22 activation. 10,12,94 The broader range of cytokines targeted by JAK/SYK inhibition might make this class of therapeutics applicable across all AD subtypes as to patients with AD with concomitant allergic contact dermatitis, which often involves T H 1/T H 17 activation.…”

Section: Discussionmentioning

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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106

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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: Discussionmentioning

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

106

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“…Atopic dermatitis (AD) is a common chronic inflammatory skin disease affecting approximately 20% of children and 7–10% of adults in western countries . AD is characterized by dry skin and recurrent flares of pruritic, eczematous skin lesions with great variability in the clinical presentation . Treatment with emollients and topical anti‐inflammatory agents comprises the cornerstone in the management of mild AD, while systemic treatment with immunosuppressive drugs (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…1 AD is characterized by dry skin and recurrent flares of pruritic, eczematous skin lesions with great variability in the clinical presentation. 2 Treatment with emollients and topical anti-inflammatory agents comprises the cornerstone in the management of mild AD, while systemic treatment with immunosuppressive drugs (i.e. methotrexate, ciclosporin and azathioprine) is frequently required to ensure adequate disease control in patients with moderate-to-severe AD, although these drugs are not always effective and associated with frequent side-effects.…”

Section: Introductionmentioning

confidence: 99%

Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre

Olesen

Holm

Nørreslet

et al. 2019

Acad Dermatol Venereol

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Background Management of moderate‐to‐severe atopic dermatitis (AD) frequently requires treatment with systemic therapies. Dupilumab is the first biological agent approved for treatment of moderate‐to‐severe AD. Although promising results have appeared in clinical trials, real‐life data on efficacy and safety are lacking. Objectives To assess effectiveness and safety of treatment with dupilumab in the real‐life clinical setting at a Danish tertiary referral centre. Methods All patients with AD treated with dupilumab from October 2017 to October 2018 at Bispebjerg Hospital, Denmark, were included in the study. Patients were evaluated three times: at treatment initiation and at 1 and 3 months after first dupilumab injection. At each visit, disease activity was assessed by severity score (Eczema Area and Severity Index, EASI), patient‐reported outcomes (Dermatology Life Quality Index, DLQI, pruritus and sleep score) and serological markers [immunoglobulin (Ig)E, eosinophil count and lactate dehydrogenase (LDH)]. Results A total of 43 patients were included in the study. The mean reduction in EASI score from baseline was 19.6 points (72.4%) at 1‐month and 22.6 points (76.7%) at 3‐month follow‐up. EASI, DLQI, pruritus score, sleep score, IgE and LDH were all statistically significantly reduced between baseline and 1‐ and 3‐month follow‐up. Mean reductions in EASI score and LDH at 3‐month follow‐up were significantly correlated (P = 0.003). One patient (2.3%) discontinued treatment due to side‐effects, and seven patients (18.4%) developed conjunctivitis during the study period. Conclusion The effectiveness and safety of dupilumab treatment in a real‐life clinical setting are comparable to that of phase 3 clinical trials. LDH is suggested as a potential serological marker predictive of treatment response.

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“…Inflammatory skin disorders, including atopic dermatitis (AD), psoriasis and associated pruritus, and sensitive skin, are characterized by immune-mediated inflammation and epidermal barrier dysfunction, which has a complex multifactorial pathogenesis. 1,2,3,4,5,6 Many specific changes in skin neurobiology and neurophysiology have been described in inflammatory and sensitive skin disorders including neurogenic inflammation and neurosensibility, which involves the release in blood and skin of neurotransmitters such as substance P (SP) and calcitonin gene-related peptide (CGRP). [6][7][8] Substance P is a neuropeptide localized mainly in cutaneous nociceptive nerve terminals and is also found in human skin mast cells stored after uptake.…”

Section: Introductionmentioning

confidence: 99%

Cutaneous sensitivity modulation by Aquaphilus dolomiae extract‐G3 on in vitro models of neuro‐inflammation

Lestienne

Viodé

Ceruti

et al. 2020

Acad Dermatol Venereol

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Background Inflammatory skin disorders, including atopic dermatitis (AD), associated pruritus and sensitive skin, have a complex multifactorial pathogenesis including neurogenic inflammation involving the release in blood and skin of neurotransmitters such as substance P (SP). Aims and Methods In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae extract‐G3 (ADE‐G3) on cutaneous neurogenic inflammation. Results ADE‐G3 significantly inhibited SP‐stimulated release of IL‐1β and TNF‐α from normal human epidermal keratinocytes; significantly and dose‐dependently inhibited SP‐stimulated activation of human mast cells; significantly inhibited veratridine‐stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine‐sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL‐8 and histamine release. Conclusions Topically applied ADE‐G3, once formulated, may improve neuro‐inflammation in patients with inflammatory skin disorders.

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Atopic dermatitis: pathogenesis

Cited by 81 publications

References 28 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

Treatment of atopic dermatitis with dupilumab: experience from a tertiary referral centre

Cutaneous sensitivity modulation by Aquaphilus dolomiae extract‐G3 on in vitro models of neuro‐inflammation

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