For more than 2,000 years, topical coal tar has been used to reduce inflammation in atopic dermatitis (AD) and psoriasis. Although its mechanism of action has been poorly understood, current evidence—including elegant knockout studies— points to aryl hydrocarbons as being responsible for coal tar’s therapeutic effect (Citation1). Coal tar contains a wide range of polycyclic aromatic hydrocarbons (PAHs), which activate aryl hydrocarbon receptors (AHRs) (Citation2). AHRs are cytoplasmic transcription factors that translocate to the nucleus upon ligand recognition, where they bind to xenobiotic response elements (XREs) in the DNA (Citation3). AHRs induce CYP450 enzymes that detoxify PAHs in keratinocytes (Citation4).
AHRs are widely expressed in skin, where they are involved in developing and maintaining the skin barrier. AHR activation directly enhances epidermal differentiation by restoring epidermal barrier proteins— such as filaggrin, hoernerin, and involucrin— and by blocking the effects of Th2 cytokines, such as the IL-4/STAT6 signaling pathway (Citation2). AHRs are crucial in regulating the development of lymphoid cells and the induction of regulatory T cells (Citation5,Citation6). These anti-inflammatory effects of AHR activation have been proposed as a mechanism of coal tar therapy (Citation2). The AHR pathway is a promising pharmacological target for developing a tidier alternative to messy coal tar.
Tapinarof is a AHR agonist with clinical efficacy for AD and psoriasis patients, reducing erythema, epidermal thickening, and tissue cytokine levels (Citation7,Citation8,Citation9). Tapinarof reduces IL-17A levels, which is a key player in psoriasis. Moreover, tapinarof also demonstrates efficacy in AD, which is largely driven by Th2 cytokines (Citation8). While AHR activation may be driving tapinarof’s efficacy in psoriasis and AD, tapinarof also has antioxidant properties that may derive from Nrf2 pathway activation (Citation9). NrF2 is a leucine zipper protein that regulates antioxidant proteins which protect against oxidative damage triggered by injury and inflammation. AHR/Nrf2 dual activation is thought to drive the efficacy of coal tar and may also play a role in tapinarof’s mechanism of action (Citation2).
Tapinarof is moving onto a phase 3 trial for AD after successfully meeting its primary and secondary efficacy endpoints in a large international, phase 2, dose-ranging study. Tapinarof is also scheduled for a phase 3 study for mild-to-moderate plaque psoriasis after a strong showing in a phase 2 study (Citation10). Tapinarof represents a potential new topical therapy that would be able to treat both psoriasis and atopic dermatitis.
Therapeutic use of AHR agonists may be controversial because toxic effects of dioxin (one of which is chloracne) are also mediated by AHR activation (Citation11,Citation12). However, AHR activation itself may not lead to toxic effects as several studies report diverse downstream effects by different exogenous and endogenous ligands. Several prescription medications (e.g., leflunomide, prednisolone, omeprazole) also activate AHRs, although AHR activation is not their primary mechanism of action (Citation13). These compounds are not associated with dioxin-related adverse events. Thus, although endogenous ligands, some marketed compounds, and dioxin share AHR as a target, their effects differ (Citation14). Topical tapinarof appears to have a good safety profile, though folliculitis was observed, perhaps echoing concerns about chloracne.
For future AHR agonist development, it is crucial to understand alternative AHR signaling mechanisms and distinct downstream biology. The emerging evidence of a more physiological role of AHR and the therapeutic effect of AHR activation suggest that it might be time to consider AHR agonists as a pharmacological target to treat inflammatory diseases.
Augusta University Medical Center, Augusta, Georgia
[email protected]
Steven R. Feldman, MD, PhD
Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, North Carolina
Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina
Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
Disclosure statement
Dr Abigail Cline has no conflict of interest to disclose.
Dr. Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. Dr. Feldman is the founder and holds stock in Causa Research and holds stock and is majority owner in Medical Quality Enhancement Corporation.
Contents of the manuscript have not been previously published and are not currently submitted elsewhere.
References
- Sekhon S, Jeon C, Nakamura M, et al. Review of the mechanism of action of coal tar in psoriasis. J Dermatolog Treat. 2017:1–3.
- van den Bogaard EH, Bergboer JG, Vonk-Bergers M, et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J Clin Invest. 2013;123:917–927.
- Burbach KM, Poland A, Bradfield CA. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc Natl Acad Sci USA. 1992;89:8185–8189.
- Du L, Hoffman SM, Keeney DS. Epidermal CYP2 family cytochromes P450. Toxicol Appl Pharmacol. 2004;195:278–287.
- Qiu J, Heller JJ, Guo X, et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity. 2012;36:92–104.
- Apetoh L, Quintana FJ, Pot C, et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol. 2010;11:854–861.
- Bissonnette R, Bolduc C, Maari C, et al. Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial. J Eur Acad Dermatol Venereol. 2012;26:1516–1521.
- Bissonnette R, Poulin Y, Zhou Y, et al. Efficacy and safety of topical WBI‐1001 in patients with mild to severe atopic dermatitis: results from a 12‐week, multicentre, randomized, placebo‐controlled double‐blind trial. Br J Dermatol. 2012;166:853–860.
- Smith SH, Jayawickreme C, Rickard DJ, et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans. J Invest Dermatol. 2017;137:2110–2119.
- Topical tapinarof heads for phase 3 in atopic dermatitis and psoriasis [press release]. Parsippany, NJ: Frontline Medical Communications Inc. 2017.
- Bradshaw TD, Bell DR. Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology. Clin Toxicol (Phila). 2009;47:632–642.
- Birnbaum LS. The mechanism of dioxin toxicity: relationship to risk assessment. Environmental Health Perspectives. 1994;102:157–167.
- Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR. Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol. 2007;71:1475.
- Farmahin R, Crump D, O’Brien JM, Jones SP, Kennedy SW. Time-dependent transcriptomic and biochemical responses of 6-formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are explained by AHR activation time. Biochem Pharmacol. 2016;115:134–143.