Topical tacrolimus topics
By Warren R. Heymann, MD
August 26, 2020
Vol. 2, No. 34
What were you doing in 2000? Worrying about counting chads in Florida? If you were a dermatologist, you were probably eagerly awaiting the release of topical tacrolimus (Protopic) and pimecrolimus (Elidel) two years later. These topical calcineurin inhibitors (TCIs) quickly became vital agents in dermatologists’ therapeutic repertoire for treating atopic dermatitis (AD) and other dermatoses off-label.
Hanna et al state: “Despite the demonstrated benefits of TCIs in treating atopic dermatitis (AD) in adult and pediatric populations, and notwithstanding the considerable evidence that had been collected on their safety and tolerability, use of TCIs decreased sharply in 2005, when national and international regulatory authorities, notably the U.S. FDA, took public action to inform patients and physicians of a potential risk for malignancy with TCIs as a result of postmarketing case reports of cancer (skin and lymphoma).” (1) According to Fiorillo et al: “Despite the large body of evidence and extensive clinical experience with these agents, there remain concerns among parents and clinicians regarding the long-term safety of this class of therapy, particularly with respect to the boxed warning about the potential risk of lymphoma and malignancy associated with TCIs.” (2)
In 2005 the iPhone was not yet invented, and Hurricane Katrina devastated the Big Easy. Fifteen years later we are glued to our smartphones, the great city of New Orleans is 90% rebuilt, but TCIs are still just indicated for AD and the black box warning persists. Why?
This commentary will focus on topical tacrolimus (although clearly applicable to both TCIs).
The mechanism of action of TCIs is by suppressing the production of inflammatory cytokines, by initially binding to macrophiln-12 (aka FKBP) in the cytoplasm of target cells. Additionally, TCIs inhibit mast cell and neutrophil activation, with pimecrolimus exerting its action on T cells and mast cells, while tacrolimus also reduces function of basophils and eosinophils, while inducing Langerhans cell apoptosis. This explains the broad anti-inflammatory effect of tacrolimus. (3)
Every seasoned dermatologist reading this commentary can discuss their experience using TCIs where there is good evidence for their efficacy — vitiligo, psoriasis of the face, genitals and intertriginous regions, seborrheic dermatitis, contact dermatitis, oral lichen planus, lichen sclerosus, morphea, and cutaneous lupus. Guenther et al detail scores of other dermatoses where TCIs have been touted to be of benefit, although with lower quality evidence. (4)
The literature continues to support TCI versatility. Recent examples of successful treatment with tacrolimus include a recalcitrant case of granuloma faciale in a 41-year-old man (5); superficial Kaposiform hemagioendotheliomas and tufted angiomas, presented in a series of 6 cases, in which all improved, with 3 demonstrating near complete remissions (6); and resolution of leg ulcers associated with the autosomal recessive disorder prolidase deficiency. (7) Topical tacrolimus has been demonstrated to prevent hypertrophic scars using a rabbit ear model. (8)
TCIs are remarkably well tolerated with cutaneous application-site reactions (burning, pruritus, and erythema) observed more commonly in adults than children. These are transient, and easily mitigated with a moisturizer to improve the skin barrier. (Placing the topical in the fridge beforehand and applying it cold can help prevent stinging.) Significant adverse reactions with TCIs are rare, including severe allergic reactions and acute renal failure. Patients on TCIs may be at greater risk of impetigo or eczema herpeticum. (1) Other dermatologic adverse reactions may include trichomegaly (as reported in a 17-year-old boy treated for years with tacrolimus for periocular vitiligo) (9), lentigines (10), and facial flushing following imbibing alcoholic beverages. (11) Regarding long-term risk, the incidence of lymphoma in TCI-treated patients is no higher than in the general population, and no causal relationship has been documented between TCIs and an increased lymphoma risk. (3)
When dermatologists in 2040 look back to the 2020 election year, I hope it is with a smile acknowledging that the worthy TCIs have many new approved indications without a black box warning.
Point to Remember: TCIs have an outstanding safety record and are useful in an ever-expanding list of off-label indications.
Please see Dr. Heymann's "A Clinician's Perspective" in the August 2020 Journal of the American Academy of Dermatology, entitled "Topical tacrolimus and malignancy risk: Should the theory be put to rest?"
Our expert's viewpoint
Andrea Zaenglein, MD
Professor of Dermatology and Pediatric Dermatology
Penn State Hershey Dermatology
In the year 2000, I was a pediatric dermatology fellow at NYU. After being assured that the apocalyptic predictions of Y2K did not force me to finish out my training in a candlelit bunker, I served as a sub-investigator in my first clinical trial, “Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.”
It was with great anticipation that pediatric dermatologists looked forward to the FDA approval of a medication tested and labeled for use in children. Pediatricians too were sold as they tended to be quite cautious with using even low-potency steroids in babies. Fourteen percent of pimecrolimus prescriptions were for children under 2 years of age. Then the black box warning came. I do not think it dramatically changed how peds derms used the TCIs — infants with moderate to severe atopic dermatitis on their face need a steroid sparing agent — but the warning certainly increased counseling time, forced endless prior authorizations and impaired access.
As Dr. Heymann notes, the dire predictions of malignant risk have been quelled by long-term safety studies. And yet the FDA continues to mandate the black box warning, making TCIs still very difficult to get for those who need them, our little atopic dermatitis patients. But there is hope for the change we need. Crisaborole and dupilumab have both been studied in young infants and hopefully will be FDA approved for all.
As we enter 2020, I too hope the fake news regarding TCIs is recognized and the FDA and drug manufacturers increase their investment in clinical trials for infants and children with atopic dermatitis and other relevant disorders, rather than practicing trickle-down safety and testing.
By 2040, I am confident that all new medications will be rigorously tested in children and we will have medicines for all.
Dr. Zaengelin had disclosed financial relationships with the following to the AAD at the time of publication: AbbVie, Allergan, Inc, Astellas Pharma US, Inc, Cassiopea S.p.A., Incyte Corporation, Innovaderm Research Inc., Pfizer Inc., Ranbaxy Laboratories Limited, Verrica Pharmaceuticals Inc. Full disclosure information is available at coi.aad.org.
Hanna S, Zip C, Shear NH. What is the risk of harm associated with topical calcineurin inhibitors? J Cutan Med Surg 2019; 23: 19S-26S.
Fiorillo L, Marcoux D, Ramien M. Contemporary role of topical calcineurin inhibitors: A pediatric dermatology perspective. J Cutan Med Surg 2019; 23: 11S-18S.
Remitz A, De Pità O, Mota A, Serra-Baldrich E, et al. Position statement: Topical calcineurin inhibitors in atopic dermatitis. J Eur Acad Dermatol Venereol 2018; 32: 2074-2082.
Guenther L, Lynde C, Poulin Y. Off-label use of topical calcineurin inhibitors in dermatologic disorders. J Cutan Med Surg 2019; 23: 27S-34S.
Gil F, Parente J, Aranha J. Resolution of granuloma faciale with topical tacrolimus. Int J Dermatol 2019; Sep 30 [Epub ahead of print].
Zhang X, Yang K, Chen S, JI Y. Tacrolimus ointment for the treatment of superficial kaposiform hemangioendothelioma and tufted angioma. J Dermatol 2019; 46: 898-901.
Good AJ, Nielson CB, Schoch JJ. Topical tacrolimus therapy in the management of lower extremity ulcers due to prolidase deficiency. Pediatr Dermatol 2019; Oct 6 [Epub ahead of print].
Menezes MC, Vasconcellos LS, Nunes CB, Alberti LR. Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model. An Bras Dermatol 2019; 94: 164-171.
Molés-Poveda P, Cowen EW. Trichomegaly induced by topical tacrolimus for the treatment of periorbital vitiligo: A brief report of a new adverse effect. Pediatr Dermatol 2019; 36: e95-e96.
Gan EY, Taïeb A. Unwanted lentigines after topical tacrolimus for vitiligo. Australas J Dermatol 2017; 58: e59-e60.
Sabater-Arad J, Matellanes-Palacios M, Parrilla FM. Image gallery: Interaction between alcohol and topical tacrolimus as a cause of facial flushing. Br J Dermatol 2019; 180: 144.
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