Therapeutic targeting of the IL-13 pathway in skin inflammation

ABSTRACT

Introduction: Atopic dermatitis (AD) is a heterogeneous, chronic, inflammatory skin disease with a non-negligible prevalence at present. Its pathogenesis is complex, but mainly characterized by constitutive T helper type 2 (Th2)-cell activation. Systemic therapies for moderate-to-severe AD can be associated with adverse events that encumber their satisfactory long-term use. Several drugs targeting relevant molecules in the immunopathogenesis of AD have been approved or are under clinical development for the treatment of moderate to severe AD. To elaborate this review, literature searches were performed in PubMed on 29 August 2020.

Areas covered: This narrative literature review is focused on the pivotal role of IL-13 in the immunopathogenesis of AD and other skin diseases.

Expert opinion: Dupilumab has demonstrated the central role of IL-13 and IL-4 in the pathogenesis of AD, asthma, and other diseases in the atopic spectrum. In addition, phase III randomized clinical trials (RCTs) evaluating specific blockade of IL-13 with tralokinumab for treatment of AD also demonstrated favorable results, and phase III RCT evaluating lebrikizumab are ongoing. The role of IL-13 in other skin diseases should be further investigated.

Keywords:

• Atopic dermatitis
• dupilumab
• interleukin-4
• interleukin-13
• lebrikizumab
• skin barrier dysfunction
• tralokinumab

Article highlights

• Atopic dermatitis is an inflammatory skin disease characterized by skin barrier dysfunction, immune abnormalities, skin dysbiosis and pruritus.

• Patients with AD show activation of type 2 immune response with variable involvement of Th1 and Th17/IL-23 pathways, depending on the AD phenotype.

• IL-13 has a key role in AD pathogenesis. It contributes to barrier dysfunction, decreases the production of AMP by keratinocytes contributing to skin dysbiosis, induces itch, and participates in the local alteration of the immune response.

• IL-13 is also involved in the pathogenesis of other skin conditions such as urticaria, alopecia areata, systemic sclerosis, keloids and hypertrophic scars.

• Dupilumab, targeting the IL-4Rα subunit of IL-4 and IL-13 receptors and blocking their signaling pathways, is the only monoclonal antibody approved for treatment of moderate to severe AD, as well as moderate to severe eosinophilic or corticosteroid-dependent asthma, and chronic rhinosinusitis with nasal polyps.

• Recently, phase III clinical trials evaluating the efficacy and safety of the IL-13 antagonist tralokinumab in the treatment of AD have shown promising results. Early-phase clinical trials of lebrikizumab have also shown favorable results, with phase III trials ongoing.

• Some other drugs targeting IL-13 are currently being developed for the treatment of AD and other skin disorders.

Declaration of interest

L. Puig has perceived consultancy/speaker’s honoraria from and/or participated in clinical trials sponsored by Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro, Janssen, JS BIOCAD, Leo-Pharma, Lilly, Merck-Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi, and UCB.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.