Aryl-hydrocarbon receptor agonist: A novel topical therapeutic approach for inflammatory skin diseases.

Abstract

The broadening of novel therapeutic options for chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis (PSO), known to be associated with dysregulation of the immune response, systemic comorbidities and a reduced quality of life for patients and caretakers, offers better chances for long-lasting disease control.1, 2 Recent advances in clarifying the mechanisms that lead to the immune imbalance in both diseases indicate a predominant IL-23/IL-17A/IL36 pathway in psoriasis, and a predominant Th2 IL-4/IL-13, with the participation of IL-17 and IL-22 axis in atopic dermatitis.1, 2 The development of targeted-oriented therapies such as biologics and small molecule inhibitors (SMIs) changed the traditional management of such inflammatory conditions, therefore optimizing the standard of care in both diseases.1, 2 One of the new foci of targeted therapies for inflammatory skin diseases is the aryl-hydrocarbon receptor (AhR)/AhR-nuclear translocator (ARNT) system, which works as a sensor for exogenous and endogenous molecules. It is expressed in the skin and has a relevant role in the skin barrier maintenance, upregulating filaggrin and loricrin and enhancing epidermal differentiation. Furthermore, the AhR complex modulates the T-helper 17/22 and T regulatory axis, and some AHR ligands also exert a role in the neutralization of oxidative stress through the activation of the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor and a ROS-scavenging structure.3 Bissonnette et al.4 present a review article on tapinarof (3,5-dihydroxy-4-isopropylstilbene), an AhR agonist from a historical perspective. His group has been working with this component since 2007, and the initial studies focused on psoriasis.5 Tapinarof 1% cream is a topical medication applied once daily, and the review shows the main outcomes of its use in clinical trials in patients with psoriasis and AD. The key point of this review indicates the profile of tapinarof in psoriasis and AD, as follows4: Psoriasis: A phase 2, single-centre clinical trial, showed a rapid start of action in topically applied bid tapinarof 1% group than vehicle. There was a 67.5% of improvement in PGA (physician global assessment) score to clear or almost clear against 4.8% in vehicle group at week 12 in psoriasis patients. In phase 2b (multicentre trial), tapinarof 0.5% and 1%, once or twice a day compared to vehicle was tested and reached the primary endpoints (PGA0/1) with 1%. The relevant finding of phase 2b was the sustained improvement during the 4-week follow-up. Subsequentially, the studies with tapinarof 1% once a day versus placebo including 1366 psoriasis patients, demonstrated an improvement of 35.4% and 40.2% for tapinarof group, versus 6% and 6.3% for vehicle in PGA score, and a PASI (Psoriasis Area Index Severity) 75 achievement in 36.1% in tapinarof group versus 10.2% for vehicle (at week 12). In the 1-year open-label extension study, the mean duration of effect remission (PGA0/1) off-therapy was 130.1 days. Atopic dermatitis: In one single-centre study, 34 AD patients randomized (1:1:1) to tapinarof 0.5%, 1% or vehicle were treated bid for 4 weeks, showing that 50% of AD patients in both treatment groups achieved an IGA of clear or almost clear compared to 8.3% for the vehicle group (at week 5). These findings were confirmed in a phase 2 study with AD patients. A randomized phase 2b study with 247 AD patients under bid or once daily application of tapinarof 0.5%, 1% or vehicle (12 weeks), assessing safety and efficacy in adolescents 12 years and older, indicated that at week 12, 53% of the AD patients with tapinarof 1% BID and 46% with once daily application achieved the primary endpoint (IGA of clear/almost clear with a 2-point decrease proportion) versus 24% and 28% for vehicle respectively. Tapinarof is currently undergoing phase 3 trials for AD patients in >2 years of age. The present study with topical tapinarof 1% cream in both psoriasis and AD opens unlimited field for more research and expansion of its use. One advantage for such medication is the long-lasting clearing of the skin lesions despite discontinuation, which could be very beneficial to patients with chronic conditions, impacting on the need for prolonged systemic therapies and therefore impacting on the patients' safety regarding adverse events and alleviating the economic impact of the disease. There are still more points to be addressed that may be clarified after more studies are conducted, such as whether the response to treatment will be effective and homogeneous depending on: stages of the disease (acute × chronic), age and ethnic/racial immune phenotypes (folliculitis5 is a clinical finding that may be more present in patients with AD of African descent, and was one of the reported initial adverse events of tapinarof). None declared. VA has participated in clinical trials for Lilli and Sanofi and as a consultant for Abbvie, Galderma and Leopharma. RLO has participated in clinical trials for Lilli, Sanofi and Amgen and as consultant for Bayer and Abbvie. Data sharing not applicable.