Targeting the aryl hydrocarbon receptor as a strategy to expand the therapeutic armamentarium in atopic dermatitis

Figures & data

Table 1. Tapinarof cream 1% compared with treatments for atopic dermatitis approved by the US FDA since 2000: Regulatory restrictions, warnings, and common adverse events.

Drug (year approved) Mechanism of action Route of administration	FDA Label Indications
	AD Severity	Age	Boxed Warnings, Restrictions, Common^a Adverse Events (AEs)
SYSTEMIC MEDICATIONS
Dupilumab (2017) Interleukin-4 alpha antagonist SC injection	Moderate to severe	≥6 months	Restrictions: AD that is refractory to topical therapy^b AEs: Injection site reactions, conjunctivitis, blepharitis, oral herpes, keratitis, eye pruritus, other herpes simplex virus infection, dry eye
Tralokinumab-ldrm (2021) Interleukin-13 antagonist SC injection	Moderate to severe	≥12 years	Restrictions: AD that is refractory to topical therapy^b AEs: Upper respiratory tract infections, conjunctivitis, injection site reactions, eosinophilia
Abrocitinib (2022) Janus kinase (JAK) inhibitor Oral tablet, once daily	Moderate to severe	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Patients with refractory AD not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants. AEs: Nasopharyngitis, nausea, headache, herpes simplex, increased blood creatine phosphokinase levels, dizziness, urinary tract infection, fatigue, acne, vomiting, oropharyngeal pain, influenza, gastroenteritis, impetigo, hypertension, contact dermatitis, upper abdominal pain, abdominal discomfort, herpes zoster, thrombocytopenia
Upadacitinib (2022) JAK inhibitor Oral tablet, once daily	Moderate to severe	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Patients with refractory AD not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable AEs: Upper respiratory tract infections, acne, herpes simplex, headache, blood creatine phosphokinase levels increased, cough, hypersensitivity, folliculitis, nausea, abdominal pain, pyrexia, increased weight, herpes zoster, influenza, fatigue, neutropenia, myalgia, influenza-like illness
TOPICAL MEDICATIONS
Tacrolimus ointment 0.03% and 0.1% (2000) Calcineurin inhibitor Topical ointment, twice daily	Moderate to severe	≥2 years (0.03%) ≥16 years (0.1%)	Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable AEs ≥10%: Burning sensation, pruritus, flu-like symptoms, skin erythema, headache
Pimecrolimus cream 1% (2001) Calcineurin inhibitor Topical cream, twice daily^c	Mild to moderate	≥2 years	Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients who have failed to respond adequately to other topical prescription treatments for AD, or when those treatments are not advisable AEs ≥10%: Burning sensation, headache, fever, nasopharyngitis, cough, bronchitis, upper respiratory tract infection
Crisaborole ointment (2016) Phosphodiesterase-4 inhibitor Topical ointment, twice daily^d	Mild to moderate	≥3 months	AEs: Application site pain
Ruxolitinib cream 1.5% (2021) JAK inhibitor Topical cream, twice daily	Mild to moderate	≥12 years	Boxed warning: Serious infections, mortality, malignancy, major cardiovascular events, and thrombosis Restrictions: Short-term, non-continuous chronic treatment in non-immunocompromised patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable Do not use more than one 60 g tube/week or one 100 g tube/2 weeks. Do not use on >20% body surface area AEs: Nasopharyngitis, diarrhea, bronchitis, ear infection, eosinophil count increased, urticaria, folliculitis, tonsillitis, rhinorrhea
Tapinarof cream 1% Aryl hydrocarbon receptor agonist Topical cream, once daily^e	Mild to severe	≥2 years	Boxed warning: None expected. Restrictions: None expected. AEs ≥5%: Folliculitis, headache, and nasopharyngitis.

^aAEs with incidence ≥1% except where indicated.

^bPatients with AD that is refractory to topical therapy refers to patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.

^cPimecrolimus is approved by the FDA for twice-daily application. An evaluation of pimecrolimus twice daily versus once daily in the prevention of relapse of AD in pediatric patients demonstrated that during the double-blind maintenance period, the median time to first disease recurrence was 5 days for pimecrolimus twice daily and 6 days for pimecrolimus once daily (31).

^dCrisaborole is approved by the FDA for twice-daily application. Once-daily crisaborole ointment, 2%, demonstrated efficacy in reducing the mean number of flares versus vehicle when used as maintenance treatment in patients aged ≥3 months with mild-to-moderate AD in a 52-week trial (32). No effect was observed in maintenance of pruritus response.

^eTapinarof is not FDA approved for the treatment of AD; expected profile based on preliminary phase 3 data in AD and FDA prescribing information for the treatment of plaque psoriasis in adults (33–35).

AD: atopic dermatitis; BSA: body surface area; FDA: Food and Drug Administration; JAK: Janus kinase; SC: subcutaneous. Source: current FDA prescribing information (23–30,33).

Figure 1. Ligand-specific binding and activation of the aryl hydrocarbon receptor in the treatment of atopic dermatitis (36,38–44). Ligand-specific binding and activation of the aryl hydrocarbon receptor downregulates proinflammatory cytokines, reduces oxidative stress, upregulates expression of skin barrier components and inhibits the generation, persistence, and cytokine production of resident memory T cells in the skin. Some of the proposed downstream effects of tapinarof in AD are distinct from its mechanism of action in psoriasis. The proposed mechanism of action of tapinarof in psoriasis is described by Bissonnette et al. (36). AhR: aryl hydrocarbon receptor; ARNT: aryl hydrocarbon receptor nuclear translocator; DNA: deoxyribonucleic acid. Th2: T helper 2 cell; T_RM: resident memory T cell.

Ruer-Mulard M, Aberer W, Gunstone A, et al. Twice-daily versus once-daily applications of pimecrolimus cream 1% for the prevention of disease relapse in pediatric patients with atopic dermatitis. Pediatr Dermatol. 2009;26(5):551–558. doi:10.1111/j.1525-1470.2009.00981.x.

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Eichenfield LF, Gower RG, Xu J, et al. Once-daily crisaborole ointment, 2%, as a long-term maintenance treatment in patients aged ≥ 3 months with mild-to-moderate atopic dermatitis: a 52-week clinical study. Am J Clin Dermatol. 2023;24(4):623–635. doi:10.1007/s40257-023-00780-w.

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FDA. Tapinarof (VTAMA®) cream Prescribing Information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215272s000lbl.pdf

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Bissonnette R, Gold LS, Rubenstein DS, et al. Tapinarof in the treatment of psoriasis: a review of the unique mechanism of action of a novel therapeutic aryl hydrocarbon receptor–modulating agent. J Am Acad Dermatol. 2021;84(4):1059–1067. doi:10.1016/j.jaad.2020.10.085.

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