PracticalDermatology

Some of us have a love/hate (more fear than hate in our case) with topical steroids. In a well written article in the Indian Journal of Dermatology in 2014, Abraham and Roga illuminate our relationship with topical steroids when they state that “topical steroids were introduced in 1951, when Sulzberger and Witten first used topical hydrocortisone. The anti-inflammatory and anti-proliferative actions of topical steroids result not only in their therapeutic effect but also in their side effects. In this way steroids act as a double-edged sword, which makes it important to use it with the utmost caution.” They list the cutaneous side effects of topical steroids to include atrophy, telangiectasia, striae, purpura, pseudo scars, ulceration, skin fragility, infections, steroid addiction, tachyphylaxis, acne, rosacea, perioral dermatitis, hirsutism, and dyspigmentation.¹

Pictured on the following pages are two of our patients who were being treated for many years by other providers with topical steroids. The first patient developed skin ulceration that was biopsy-proven squamous cell carcinoma on her left lateral neck. She also developed skin atrophy, pseudoscars, and purpura (Figure 1). The second patient developed steroid addiction, tachyphylaxis, and acne on her face that took many weeks and lots of extra care to resolve (Figure 2).

Figure 1: Epidermal and dermal atrophy with associated telangiectasias, purpura, and ulceration. A biopsy of the ulceration demonstrated squamous cell carcinoma.

Figure 2: Erythema, telangiectasias, and thinning of the skin as well as acneiform eruption in a patient who was using high-potency topical steroids on her face for years.

There are currently few FDA approved options for non-steroidal topicals to treat psoriasis or atopic dermatitis. Fortunately, there is abundant research being conducted to bring more non-steroidal topical treatment options to market. We have conducted an internet search of non-steroidal treatments and listed the FDA approved topical medications. We included the indications, precautions, and warnings. We also tabulated into chart form the data we felt was important for comparison. The topical treatments FDA approved to treat psoriasis include Vectical (calcitriol), Tazorac (tazarotene) Gel, Dovonex (calcipotriene) and Vtama (tapinarof). The topical treatments that are FDA approved to treat atopic dermatitis include Protopic (tacrolimus), Elidel (pimecrolimus), Eucrisa (crisoborale), and Opzelura (ruxolitinib). We also listed the associated precautions, warnings, or black boxes from the FDA that these topical medications have. Tapinarof is the only FDA approved topical medication that has no warnings or precautions.

Because we are involved with clinical trials, our interest is piqued when a novel therapeutic agent is added to our armamentarium. The therapeutic aryl hydrocarbon modulating agent, Vtama (tapinarof, Dermavant) is the most recently approved topical treatment for psoriasis. Tapinarof is special because it offers a mechanism of action that can treat both psoriasis and atopic dermatitis. It inhibits two pro-inflammatory pathways: one implicated in psoriasis (Th17 pathway with downregulation of the associated cytokines IL17A and F) and one implicated in atopic dermatitis (Th2 pathway with downregulation of the associated cytokines IL4, 5, and 13).² An article in Nature explains that the “aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that integrates environmental, dietary, microbial, and metabolic cues to control complex transcriptional programmes in a ligand-specific, cell-type-specific and context-specific manner.”³ Additionally, “It is believed that the AHR modulation by tapinarof also increases antioxidant activity via upregulation of Nrf2 and promotes skin barrier restoration through upregulation of a number of epidermal barrier genes, including filaggrin, hornerin, and involucrin. These characteristics illustrate tapinarof’s potential to pivot between these very distinct diseases.”²

Tapinarof is also unique because it is found naturally. It was discovered during research on metabolites of a gram-negative bacteria that live in the intestines of nematodes. When these nematodes enter an insect, they inhibit putrefaction. This knowledge led us to investigate its anti-inflammatory properties.⁴ On May 24, 2022, the FDA approved tapinarof for the once per day treatment of plaque psoriasis with no boxed warnings, safety warnings, precautions, or limitations on body surface, or duration of treatment. It can be applied to sensitive and intertriginous areas. Even more exciting, this is the first topical treatment that I am aware of that can provide a drug holiday or remittive effect of four months on average off therapy.⁵

This is a skintastic time to practice dermatology and be involved with dermatologic research. We are all thankful for the advances that biological medications have brought and continue to bring that improve the lives of people who suffer with all conditions, including psoriasis and atopic dermatitis. Even with these advances, 90 percent of people with psoriasis still use topical treatments alone or in combination with systemic therapies. Because of this, we are thankful to be able to offer our patients novel, non-steroidal topical therapies that are not only effective but also safe and offer remittive benefits.⁶

TABLE NOTES

(v) Vectical: Effects on Calcium metabolism: Risk of hypercalcemia. If aberrations in parameters of calcium metabolism are noted discontinue VECTICAL Ointment until these normalize. Increased absorption may occur with occlusive use. (5.1) VECTICAL Ointment should be used with caution in patients receiving medications known to increase the serum calcium level, such as thiazide diuretics, and in patients receiving calcium supplements or high doses of vitamin D.

(T) TAZORAC® Cream contains tazarotene, which is a teratogenic substance. TAZORAC® Cream is contraindicated in pregnancy. Females of child-bearing potential should have a negative pregnancy test within 2 weeks prior to initiating treatment and use an effective method of contraception during treatment. Local Irritation: Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, discontinue until the integrity of the skin has been restored, or reduce dosing interval, or in the case of psoriasis, may switch to the lower concentration. TAZORAC® Cream should not be used on eczematous skin, as it may cause severe irritation. · Photosensitivity and Risk for Sunburn: Avoid exposure to sunlight, sunlamps, and weather extremes. Wear sunscreen daily. TAZORAC® Cream should be administered with caution if the patient is also taking drugs known to be photosensitizers

(E)Elidel/pimecrolimus: Should not be used in immunocompromised adults and children, including patients on systemic immunosuppressive medications. (5.1) • Avoid treatment on malignant or pre-malignant skin conditions, as these can present as dermatitis. • Should not be used in patients with Netherton’s Syndrome or skin diseases with a potential for increased systemic absorption.

(D) Dovonex® Cream is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation. It should not be used by patients with demonstrated hypercalcemia or evidence of vitamin D toxicity. Dovonex® Cream should not be used on the face. WARNINGS Contact dermatitis, including allergic contact dermatitis, has been observed with the use of Dovonex®.

(EC) Eucrisa warning: Hypersensitivity reactions, including contact urticaria, have occurred in patients treated with EUCRISA. Hypersensitivity should be suspected in the event of severe pruritus, swelling and erythema at the application site or at a distant site

(O) OPZELURA is a Janus kinase (JAK) inhibitor indicated for the topical short term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Limitation of Use of OPZELURA in combination with therapeutic biologics, other JAK inhibitors or potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Warnings: Serious Infections: Serious bacterial, mycobacterial, fungal, and viral infections have occurred. Regularly monitor patients for infection and manage it promptly. • Non-melanoma Skin Cancers. Basal cell and squamous cell carcinoma have occurred. Perform periodic skin examinations during treatment and following treatment as appropriate. • Thrombosis. Thromboembolic events have occurred. • Thrombocytopenia, Anemia and Neutropenia: Thrombocytopenia, anemia and neutropenia have occurred. Perform CBC monitoring as clinically indicated.

(V) Tapinarof has no warnings or precautions in the package insert.

(R) Topical roflumilast is not currently FDA approved however oral roflumilast has the following warnings listed in the package insert: Acute bronchospasm: Do not use for the relief of acute bronchospasm. • Psychiatric Events including Suicidality: Advise patients, their caregivers, and families to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Carefully weigh the risks and benefits of treatment with DALIRESP in patients with a history of depression and/or suicidal thoughts or behavior. • Weight Decrease: Monitor weight regularly. If unexplained or clinically significant weight loss occurs, evaluate weight loss, and consider discontinuation of DALIRESP. • Drug Interactions: Use with strong cytochrome P450 enzyme inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin) is not recommended. Most common adverse reactions (≥ 2%) are diarrhea, weight decrease, nausea, headache, back pain, influenza, insomnia, dizziness, and decreased appetite.

Relevant Disclosures: Sandra Marchese Johnson MD, FAAD has served as an investigator, consultant, and speaker for Fujisawa (tacrolimus); a speaker for Novartis (pimecrolimus). She is currently an investigator, advisor, and speaker for Dermavant (tapinarof); an investigator and advisor for Arcutis (Roflumilast); and an editor for Practical Dermatology®.

1. Abraham A, Roga G. Topical Steroid-Damaged Skin. Indian J Dermatol. 2014 Sep-Oct; 59(5): 456–459.

2. https://practicaldermatology.com/articles/2020-july/in-the-pipeline-what-to-know-about-tapinarof

3. Rothhammer, V., Quintana, F.J. The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 19, 184–197 (2019). https://doi.org/10.1038/s41577-019-0125-8.

4. Bissonnette R, Gold L, Rubenstein D, Tallman A, Armstrong A. Tapinarof in the treatment of psoriasis: a review of the unique mechanism of action of a novel therapeutic AhR modulating agent (TAMA). J Am Acad Dermatol. 2021; 84: 1059-1067.

5. https://www.dermatologytimes.com/view/tapinarof-cream-1-is-fda-approved

6. Murage MJ, Kern DM, Chang L, Sonawane K, Malatestinic WN, Quimbo RA, Feldman SR, Muram TM, Araujo AB. Treatment patterns among patients with psoriasis using a large national payer database in the United States: a retrospective study. J

7 Med Econ. 2018 Oct 25:1-9. doi: 10.1080/13696998.2018.1540424. Epub ahead of print. PMID: 30358465.)

8. file://jdc-fs01/Users/sjohnson/Downloads/20210918_a1567da9-af74-4afd-9ac5-8b53ec5d7cbf.pdf

9. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021184s007lbl.pdf

10. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/50777lbl.pdf

11. https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/50777lbl.pdf

12. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020273s013,020554s012lbl.pdf

13. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/207695s007s009s010lbl.pdf

14. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/215309Orig1s000ltr.pdf

15. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215272s000lbl.pdf

16. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf

17. Lebwohl MG, Papp KA, Stein Gold L, Gooderham MJ, Kircik LH, Draelos ZD, Kempers SE, Zirwas M, Smith K, Osborne DW, Trotman ML, Navale L, Merritt C, Berk DR, Welgus H; ARQ-151 201 Study Investigators. Trial of Roflumilast Cream for Chronic Plaque Psoriasis. N Engl J Med. 2020 Jul 16;383(3):229-239. doi: 10.1056/NEJMoa2000073. PMID: 32668113.