Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Guttman‐Yassky, Emma; Bissonnette, Robert; Ungar, Benjamin; Suárez‐Fariñas, Mayte; Ardeleanu, Marius; Esaki, Hideo; Suprun, Maria; Estrada, Yeriel; Xu, Hui; Peng, Xiangyu; Silverberg, Jonathan I.; Menter, Alan; Krueger, James G.; Zhang, Rick; Chaudhry, Usman; Swanson, Brian N.; Graham, Neil M.H.; Pirozzi, Gianluca; Yancopouloš, George D.; Hamilton, Jennifer D.

doi:10.1016/j.jaci.2018.08.022

Cited by 475 publications

(644 citation statements)

References 157 publications

(293 reference statements)

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“…It also restored the down‐regulation of FLG and loricrin and reduced epidermal acanthosis in the lesional skin of AD patients . In addition, dupilumab normalized the type 2 serum biomarkers CCL17, CCL18 and periostin …”

Section: Anti‐il‐13 Biologics For the Treatment Of Admentioning

confidence: 88%

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The IL‐13–OVOL1–FLG axis in atopic dermatitis

et al. 2019

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Summary Despite sharing interleukin‐4 receptor α (IL‐4Rα) in their signaling cascades, IL‐4 and IL‐13 have different functions in atopic inflammation. IL‐13 preferentially participates in the peripheral tissues because tissue‐resident group 2 innate lymphoid cells produce IL‐13 but not IL‐4. In contrast, lymph node T follicular helper cells express IL‐4 but not IL‐13 to regulate B‐cell immunity. The dominant microenvironment of IL‐13 is evident in the lesional skin of atopic dermatitis (AD). The IL‐13‐rich local milieu causes barrier dysfunction by down‐regulating the OVOL1–filaggrin (FLG) axis and up‐regulating the periostin–IL‐24 axis. Genome‐wide association studies also point to the crucial involvement of the IL‐13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL‐13, such as the anti‐IL‐4Rα antibody dupilumab and the anti‐IL‐13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL‐13 in the pathogenesis of AD.

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Section: Anti‐il‐13 Biologics For the Treatment Of Admentioning

confidence: 88%

“…Dupilumab therapy significantly reduced the lesional expression of IL‐13 and IL‐13‐regulated Th2 signature genes, such as CCL17 , CCL18 and CCL26 , in AD patients . It also restored the down‐regulation of FLG and loricrin and reduced epidermal acanthosis in the lesional skin of AD patients .…”

Section: Anti‐il‐13 Biologics For the Treatment Of Admentioning

confidence: 94%

The IL‐13–OVOL1–FLG axis in atopic dermatitis

et al. 2019

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“…Precision immunology data mining combined with pathway analysis underlined the hypothesis. [72,73] The rationale for multi-targeting Th2 cytokines can be demonstrated in vivo using murine airway inflammation models with surrogate antibodies. [68,69] At the same time the central role of the Th2 cytokines for atopic dermatitis became increasingly obvious for various key processes in the course of the disease.…”

Section: Atopic Dermatitis and The Role Of Type 2 Immunologymentioning

confidence: 99%

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

Florian

Flechsenhar

Bartnik

et al. 2019

Experimental Dermatology

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Due to the clinical development of drugs such as secukinumab, ustekinumab and dupilumab, major changes have been achieved in the treatment of patients diagnosed with psoriasis and atopic dermatitis. In academia and the pharmaceutical industry, research is increasingly moving towards the development of bispecific antibodies and multi‐specific nanobodies, as there is a compelling need for new treatment modalities for patients suffering from autoimmune or malignant disease. The purpose of this review is to discuss aspects of translational drug development with a particular emphasis on indications such as psoriasis and atopic dermatitis. The identification of biomarkers, the assessment of target organ pharmacokinetic and pharmacodynamics interactions and a wide range of in vitro, ex vivo and in vivo models should contribute to an appropriate prediction of a biological effect in the clinical setting. As human biology may not be perfectly reflected by approaches such as skin equivalents or animal models, novel approaches such as the use of human skin and dermal microperfusion assays in healthy volunteers and patients appear both reasonable and mandatory. These models may indeed generate highly translationally relevant data that have the potential to reduce the failure rate of drugs currently undergoing clinical development.

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“…The essential involvement of IL‐4 and IL‐13 in AD pathogenesis is strongly supported by the therapeutic effectiveness of anti‐IL‐4Rα antibody dupilumab, which block IL‐4 binding to type I and type II IL‐4 receptors and IL‐13 binding to type II receptor (Figure ). Dupilumab depresses Th2‐centered inflammatory axis and exerts a high clinical efficacy. Dupilumab was approved in Japan in 2018, and the number of patients treated with this biologic has been increasing.…”

Section: Therapies For Immunomodulation Of Admentioning

confidence: 99%

Atopic dermatitis as Th2 disease revisited

Tokura

Phadungsaksawasdi

Ito

2018

J Cutaneous Imm & Allergy

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T helper 1 (Th1) and T helper 2 (Th2) populations are a classical dichotomy to understand the immunological disorders, and this concept remains vital in atopic dermatitis (AD). While IL‐4 and IL‐13 are produced mainly by Th2 cells, mast cells, and basophils, these cytokines target these producers, indicating the presence of autocrine and paracrine stimulation. There are two types of receptors for IL‐4 and IL‐13, type I and type II. IL‐4 binds to both type I and II receptors, while IL‐13 has affinity to type II. Dupilumab is an IL‐4Rα‐antagonist that inhibits IL‐4 and IL‐13 signaling through blockade of the shared IL‐4α subunit. The Th2‐stimulating effect of thymic stromal lymphopoietin (TSLP) is triggered by its binding to TSLP receptor (TSLPR) on Th2 cells. The frequency of TSLPR+CD4+ T cells correlates with disease activity. CD4+ T cells directly interact with TSLP to produce a high amount of IL‐4. Conversely, IL‐4 induces TSLPR expression in T cells. Moreover, TSLP and IL‐4 promote CCR4 expression, which is a chemokine receptor for CCL17/TARC. Langerhans cells initiate epicutaneous sensitization with protein antigens and induce Th2 cell–mediated immune responses via TSLP signaling. Filaggrin deficiency, which cornified layer‐damaged skin allows protein antigens to penetrate through the stratum corneum, leads to allergy where IL‐4 and IL‐13 are overproduced. Subsequently, IL‐4 and IL‐13 further depress filaggrin expression with vicious cycle. AD is generally a Th2 disease, but there exist several exceptional and undeniable facts to be considered, including Th1‐activated intrinsic AD, Th1‐infiltrating chronic AD skin lesions, and Th17 involvement.

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Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Cited by 475 publications

References 157 publications

The IL‐13–OVOL1–FLG axis in atopic dermatitis

The IL‐13–OVOL1–FLG axis in atopic dermatitis

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

Atopic dermatitis as Th2 disease revisited

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