in skin-barrier integrity are associated with inflammation and immune-cell infiltration, alongside alterations in the expression of epithelial barrier proteins, such as filaggrin.
More than 30 risk loci for AD have been identified, including genes involved in epidermal differentiation, innate immunity, and T-cell function.39,52 The strongest genetic risk for AD involves the filaggrin gene,53,54 which plays a role in skin-barrier integrity.52 Th2 cytokine genes, such as those encoding IL-4 and IL-13, are also associated with AD.52
Oxidative stress is also implicated in AD, resulting in increased dermal inflammation and skin-barrier dysfunction.55 Environmental factors implicated in the etiology of AD include pollutants, irritants, and microbial dysbiosis.56 Pollutants, including polyaromatic hydrocarbons, induce oxidative stress, skin-barrier dysfunction, and immune dysregulation, and are linked to the development and exacerbation of AD and asthma.22-25,57,58
Th2 cytokines, such as IL-4, IL-5, and IL-13, are associated with AD pathogenesis.59 Increased expression of IL-4 induces immunoglobulin E production, inflammation, and pruritus in vivo59,60 and suppresses expression of the terminal keratinocyte differentiation proteins, filaggrin, loricrin, and involucrin.60 IL-5 contributes to eosinophilia, which is characteristic of lesions in AD.59,61 IL-13 is an inflammatory mediator of pruritus, skin-barrier dysfunction, and inflammation in AD.62
Tapinarof in the Treatment of Psoriasis and AD
Tapinarof is a first-in-class, non-steroidal, topical AhR agonist approved by the US Food and Drug Administration for the treatment of plaque psoriasis in adults,16 and under investigation for the treatment of psoriasis in children down to 2 years of age, and for AD in adults and children down to 2 years of age. Tapinarof cream 1% QD demonstrated significant efficacy versus vehicle and was well tolerated in adults with mild to severe plaque psoriasis in two identical, 12-week, pivotal phase 3 trials.63 Efficacy improved beyond 12-weeks in the long-term extension trial, with a high rate of complete disease clearance (Physician Global Assessment [PGA]=0; 40.9% [n=312]), an approximately 4-month remittive effect defined as off-treatment maintenance of a PGA score of 0 (clear) or 1 (almost clear), and durability of response when on therapy for up to 52 weeks.64 The efficacy of tapinarof is attributed to its specific binding and activation of AhR, resulting in downregulation of pro-inflammatory cytokines, normalization of skin-barrier function, and antioxidant effects.14 The remittive effect off therapy in psoriasis may be attributed in part to an observed reduction in the activity and persistence of pathogenic resident memory T cells (TRM).65,66
