Atopic dermatitis: a review of evolving targeted therapies

Kalamaha, Kadra; Reis, Erin; Newton, Shauna; Roche, Conor; Julson, Janet; Fernandes, Hermina D; Rodrigues, J.

doi:10.1080/1744666x.2019.1560267

Cited by 18 publications

(21 citation statements)

References 151 publications

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“…However, in our colocalisation analyses the AD risk allele is linked to overall reduction in IL6R transcript levels, likely due to the complex balance of IL6 classical and trans-signalling. A range of anti-IL6 biologics are in clinical use and development for inflammatory diseases, including, tocilizumab, which inhibits both soluble and membrane-bound IL6R, and is approved for treatment of RA and juvenile idiopathic arthritis[151]. However, AD adverse events have been reported in tocilizumab trials[152], consistent with the opposing effects of this GWAS locus on RA and AD.…”

Section: Resultsmentioning

confidence: 99%

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

Sobczyk

Richardson

Zuber

et al. 2020

Preprint

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Background: Genome-wide association studies for atopic dermatitis (AD, eczema) have identified 25 reproducible loci associated in populations of European descent. We attempt to prioritise candidate causal genes at these loci using a multifaceted bioinformatic approach and extensive molecular resources compiled into a novel pipeline: ADGAPP (Atopic Dermatitis GWAS Annotation & Prioritisation Pipeline). Methods: We identified a comprehensive list of 103 accessible molecular resources for AD aetiology, including expression, protein and DNA methylation QTL datasets in skin or immune-relevant tissues. These were used to test for overlap with GWAS signals (including colocalisation testing where possible). This was combined with functional annotation based on regulatory variant prediction, and independent genomic features such as chromatin accessibility, promoter-enhancer interactions, splicing sites, non-coding RNA regions, differential expression studies involving eczema patients and fine-mapping of causal variants. For each gene at each locus, we condensed the evidence into a prioritisation score. Results: Across the 25 AD loci investigated, we detected significant enrichment of genes with adaptive immune regulatory function and epidermal barrier formation among the top prioritised genes. At 8 loci, we were able to prioritise a single candidate gene (IL6R, ADO, PRR5L, IL7R, ETS1, INPP5D, MDM1, TRAF3). At a further 2 loci, 2 candidate genes emerge (IL18R1/IL18RAP, LRRC32/EMSY). For the majority of these, the prioritised gene has been previously proposed as a plausible candidate, but the evidence we combine here, strengthens the case for many of these. In addition, at 6 of the 25 loci, our ADGAPP analysis prioritises novel alternative candidates (SLC22A5, IL2RA, MDM1, DEXI, ADO, STMN3), highlighting the importance of this comprehensive approach. Conclusions: Our ADGAPP analysis provides additional support for previously implicated genes at several AD GWAS loci, as well as evidence for plausible novel candidates at others. We highlight several genes with good/converging evidence of involvement in AD that represent potential new targets for drug discovery.

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Section: Resultsmentioning

confidence: 99%

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

Sobczyk

Richardson

Zuber

et al. 2020

Preprint

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“…Despite dupilumab, the need for alternative treatments remains. Only 40% of patients on dupilumab with background topical corticosteroids (TCS) achieved clear or almost clear skin (18). Other biologic drugs currently being studied include pitrakinra (that specifically blocks IL-4), tralokinumab and lebrikizumab (that selectively target IL-13), and nemolizumab (an IL-31 receptor inhibitor, the first biologic specifically targeting IL-31, also known as the 'pruritus cytokine').…”

Section: To the Editormentioning

confidence: 99%

The Changing Landscape of Atopic Dermatitis - Focusing on JAK Inhibitors

Rodrigues

Torres

2020

Eur Ann Allergy Clin Immunol

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“…Like AD, these other conditions involve a T H 2 effector phase at some point in their progression and have barrier dysfunction as a hallmark. Despite the evidence for an epidermal component of AD pathogenesis, most of the new therapies for AD target only the inflammatory component of the disease (7,14).…”

Section: Epidermal Barrier Dysfunction and The Atopic Marchmentioning

confidence: 99%

“…Despite its increasing commonality the etiology of AD is still not fully understood, and standard treatments are not curative. Although most new treatments target the inflammatory component of the disease (7), epidermal barrier dysfunction is an important aspect of AD pathogenesis. Herein, we review the epidermal wound healing mechanisms' (specifically epithelial mesenchymal transition; EMT) established role in allergic rhinitis (AR) and asthma to contrast with the knowledge gaps present in AD.…”

Section: Introductionmentioning

confidence: 99%

Epithelial-Mesenchymal Transition in Atopy: A Mini-Review

2020

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Atopic diseases, particularly atopic dermatitis (AD), asthma, and allergic rhinitis (AR) share a common pathogenesis of inflammation and barrier dysfunction. Epithelial to mesenchymal transition (EMT) is a process where epithelial cells take on a migratory mesenchymal phenotype and is essential for normal tissue repair and signal through multiple inflammatory pathways. However, while links between EMT and both asthma and AR have been demonstrated, as we outline in this mini-review, the literature investigating AD and EMT is far less well-elucidated. Furthermore, current studies on EMT and atopy are mostly animal models or ex vivo studies on cell cultures or tissue biopsies. The literature covered in this mini-review on EMT-related barrier dysfunction as a contributor to AD as well as the related (perhaps resultant) atopic diseases indicates a potential for therapeutic targeting and carry treatment implications for topical steroid use and environmental exposure assessments. Further research, particularly in vivo studies, may greatly advance the field and translate into benefit for patients and families.

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Atopic dermatitis: a review of evolving targeted therapies

Cited by 18 publications

References 151 publications

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

Triangulating molecular evidence to prioritise candidate causal genes at established atopic dermatitis loci

The Changing Landscape of Atopic Dermatitis - Focusing on JAK Inhibitors

Epithelial-Mesenchymal Transition in Atopy: A Mini-Review

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