The <scp>IL</scp>‐13–<scp>OVOL</scp>1–<scp>FLG</scp> axis in atopic dermatitis

Furue, Kazuhisa; Ito, Takamichi; Tsuji, Gaku; Ulzii, Dugarmaa; Vu, Yen Hai; Kido‐Nakahara, Makiko; Nakahara, Takeshi; Furue, Masutaka

doi:10.1111/imm.13120

Cited by 100 publications

(83 citation statements)

References 77 publications

(230 reference statements)

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“…These subtypes have different inciting factors and molecular compositions [7]. For example, IgE levels are only elevated in about 20-50% of patients, and loss-of-function mutations in the filaggrin (FLG) gene are only identified in a small subset of AD patients of European ancestry [1,4,9]. However, all subtypes of AD are characterized by a cycle of T cell mediated skin inflammation and disruption of the skin barrier [8,10].…”

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

“…Increased type 1 helper T cell (T H 1) activation along with T H 2 and T H 22 inflammation characterizes the chronic phase of the disease [10]. Cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 promote the maturation of skin resident T H 2 and group 2 innate lymphoid cells (ILC2s) [1,4]. ILC2s are tissue-resident lymphocytes that do not derive from either the T cell or B cell lineage.…”

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

“…ILC2s are tissue-resident lymphocytes that do not derive from either the T cell or B cell lineage. Along with T H 2 cells, ILC2s produce a large amount of the pro-inflammatory cytokine IL-13 [1,11].…”

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

“…Many proteins essential for skin-barrier function-including filaggrin, loricrin, involucrin, and ceramides-are downregulated or inhibited in this way through the effect of IL-4 and IL-13 on gene expression [4]. Additionally, activation of STAT6 results in increased gene expression of periostin, a pro-inflammatory extracellular matrix protein, trophic to keratinocytes that stimulates them to produce TSLP [1]. T H 2 cells also express IL-31, which acts on keratinocytes to potentiate the release IL-24.…”

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

“…Atopic dermatitis (AD) is a common inflammatory skin disease characterized by pruritus and skin barrier dysfunction [1][2][3]. Current mainstay treatments include topical moisturizers, topical corticosteroids, topical calcineurin inhibitors, phototherapy, and systemic immunotherapies [4].…”

Section: Introductionmentioning

confidence: 99%

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New and Emerging Systemic Treatments for Atopic Dermatitis

Newsom

Bashyam

Balogh

et al. 2020

Drugs

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Atopic dermatitis (AD) is a prevalent inflammatory skin condition that, depending on its severity, can cause enormous morbidity. Corticosteroids and systemic immunosuppression, traditionally standard of care for difficult-to-treat disease, have many undesirable side effects. The desire for targeted treatments along with an improved understanding of the pathophysiology of AD has spurred the development of novel treatments. In this article, we review promising new treatments and discuss how their targets-IL-13, IL-31, OX40 (CD134), and the Janus kinase family of proteins-participate in the pathogenesis of AD. We review the published phase II and III data for dupilumab, tralokinumab, lebrikizumab, nemolizumab, anti-OX40 antibody, baricitinib, abrocitinib, and upadacitinib. The introduction of new agents may offer new options, but it remains to be seen how narrow-acting agents, like single interleukin inhibitors, will compare in safety and efficacy to broad-acting agents such as JAK inhibitors. Key Points Our better understanding of the pathophysiology of AD has resulted in an explosion of research into new immunotherapies for this patient population. Multiple new agents targeting IL-13, IL-31, OX40 (CD134), and Janus kinase proteins may be effective for AD.

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Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

Section: Immunology Of Atopic Dermatitismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

New and Emerging Systemic Treatments for Atopic Dermatitis

Newsom

Bashyam

Balogh

et al. 2020

Drugs

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Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis

et al. 2023

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ImportanceSafe and effective long-term treatments for adolescents with moderate to severe atopic dermatitis (AD) are limited.ObjectiveTo evaluate the efficacy and safety of interleukin-13–targeted treatment with tralokinumab monotherapy in adolescents with AD.Design, Setting, and ParticipantsThe 52-week, randomized, double-blinded, placebo-controlled, phase 3 ECZTRA 6 trial was conducted from July 17, 2018, through March 16, 2021, at 72 centers across 10 countries in North America, Europe, Asia, and Australia. Enrolled patients were 12 to 17 years old with moderate to severe AD (Investigator’s Global Assessment [IGA] score ≥3; Eczema Area and Severity Index [EASI] ≥16).InterventionsPatients were randomized (1:1:1) to tralokinumab (150 or 300 mg) or placebo every 2 weeks for 16 weeks. Patients with an IGA score of 0 (clear) or 1 (almost clear) and/or 75% or higher improvement in EASI (EASI 75) at week 16 without rescue medication received maintenance treatment; other patients switched to open-label tralokinumab, 300 mg, every 2 weeks.Main Outcomes and MeasuresPrimary end points at week 16 were an IGA score of 0 or 1 and/or achieving EASI 75. Key secondary end points were a reduction of Adolescent Worst Pruritus Numeric Rating Scale of 4 or more, change in SCORing AD, and change in Children’s Dermatology Life Quality Index from baseline to week 16. Safety end points were the number of adverse events and serious adverse events.ResultsOf 301 patients randomized, 289 comprised the full analysis set (median [IQR] age, 15.0 [13.0-16.0] years; 149 [51.6%] male). More patients receiving tralokinumab, 150 mg, (n = 98), and tralokinumab, 300 mg (n = 97), achieved an IGA score of 0 or 1 without rescue medication at week 16 (21 [21.4%] and 17 [17.5%], respectively) vs placebo (n = 94; 4 [4.3%]) (adjusted difference, 17.5% [95% CI, 8.4%-24.6%]; P &lt; .001 and 13.8% [95% CI, 5.3%-22.3%]; P = .002, respectively). More patients receiving tralokinumab, 150 mg (28 [28.6%]), and tralokinumab, 300 mg, (27 [27.8%]) vs placebo (6 [6.4%]) achieved EASI 75 without rescue at week 16 (adjusted difference, 22.5% [95% CI, 12.4%-32.6%]; P &lt; .001 and 22.0% [95% CI, 12.0%-32.0%]; P &lt; .001, respectively). Proportions of patients with Adolescent Worst Pruritus Numeric Rating Scale reduction of 4 or more from baseline were greater with tralokinumab, 150 mg (23.2%), and tralokinumab, 300 (25.0%), vs placebo (3.3%), and adjusted mean changes were greater in SCORing AD with tralokinumab, 150 mg (–27.5%), and tralokinumab, 300 mg (–29.1%), vs placebo (–9.5%) and in Children’s Dermatology Life Quality Index with tralokinumab, 150 mg (–6.1%), and tralokinumab, 300 mg (–6.7%), vs placebo (–4.1%) at week 16. At week 52, tralokinumab efficacy was maintained without rescue in more than 50% of patients meeting primary end point(s) at week 16. In the open-label phase, IGA score of 0 or 1 and EASI 75 were achieved in 33.3% and 57.8%, respectively, at week 52. Tralokinumab was well tolerated, without frequency of conjunctivitis increasing through week 52.Conclusions and RelevanceIn this randomized clinical trial, tralokinumab was efficacious and well tolerated, supporting its value for treating adolescents with moderate to severe AD.Trial RegistrationClinicalTrials.gov Identifier: NCT03526861

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Development of a mammalian neurosensory full‐thickness skin equivalent and its application to screen sensitizing stimuli

Freer

Darling

Goncalves

et al. 2023

Bioengineering & Transla Med

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Human skin equivalents (HSEs) are an increasingly popular research tool due to limitations associated with animal testing for dermatological research. They recapitulate many aspects of skin structure and function, however, many only contain two basic cell types to model dermal and epidermal compartments, which limits their application. We describe advances in the field skin tissue modeling to produce a construct containing sensory-like neurons that is responsive to known noxious stimuli.Through incorporation of mammalian sensory-like neurons, we were able to recapitulate aspects of the neuroinflammatory response including secretion of substance P and a range of pro-inflammatory cytokines in response to a well-characterized neurosensitizing agent: capsaicin. We observed that neuronal cell bodies reside in the upper dermal compartment with neurites extending toward the keratinocytes of the stratum basale where they exist in close proximity to one another. These data suggest that we are able to model aspects of the neuroinflammatory response that occurs during exposure to dermatological stimuli including therapeutics and cosmetics. We propose that this skin construct can be considered a platform technology with a wide range of applications including screening of actives, therapeutics, modeling of inflammatory skin diseases, and fundamental approaches to probe underlying cell and molecular mechanisms.

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

Cited by 100 publications

References 77 publications

New and Emerging Systemic Treatments for Atopic Dermatitis

New and Emerging Systemic Treatments for Atopic Dermatitis

Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis

Development of a mammalian neurosensory full‐thickness skin equivalent and its application to screen sensitizing stimuli

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