Sage Journals: Discover world-class research

Abstract

This review summarizes the off-label applications of topical sirolimus (rapamycin) for dermatological conditions beyond its approved use for angiofibromas associated with tuberous sclerosis, focusing on efficacy, safety, and reported adverse effects. Off-label use of mammalian target of rapamycin inhibitors like sirolimus has shown promising potential in dermatology. We analyzed the literature on the efficacy and safety of topical sirolimus for a range of dermatological conditions, including inflammatory eruptions, genodermatoses, bullous disorders, neoplasms, and others. Publications on topical sirolimus for other vascular anomalies, such as lymphatic malformations, were excluded to maintain focus on other lesser-known dermatological uses, except for studies involving post-laser combination therapies for vascular lesions. Topical sirolimus demonstrated notable efficacy in several genetic and benign proliferative skin disorders, including pachyonychia congenita, trichilemmomas, trichoepitheliomas, and Kaposi sarcoma, with a generally favorable safety profile and minimal systemic absorption. However, variability in formulations, dosing regimens, and the predominance of small-scale studies limit definitive conclusions. Further research is warranted to standardize treatment protocols and validate these findings.

Keywords

off-label topical sirolimus off-label topical rapamycin topical mTOR inhibitor

Introduction

Sirolimus, or rapamycin, is an mammalian target of rapamycin (mTOR) inhibitor originally FDA-approved as an oral immunosuppressant for preventing organ rejection and treating lymphangioleiomyomatosis.¹ More recently, topical sirolimus – HYFTOR^® (Nobelpharma America, LLC, Bethesda, MD, USA) – was approved for the treatment of facial angiofibromas associated with tuberous sclerosis.² Beyond its immunosuppressive properties, sirolimus demonstrates antineoplastic effects by inhibiting cell proliferation and angiogenesis.^3,4

Mechanistically, sirolimus binds FKBP12 within target cells to form an immunosuppressive complex, which inhibits mTOR, a serine/threonine protein kinase central to pathways regulating cell growth, proliferation, survival, and angiogenesis, including the PI3K/Akt signaling cascade.^3,4 By disrupting this pathway, sirolimus prevents cytokine-driven T-cell proliferation and halts cell cycle progression from G1 to S phase.³ Additionally, sirolimus may reduce the production of nonfunctional keratin by downregulating genes such as KRT6 and KRT16, potentially alleviating symptoms in conditions like pachyonychia congenita (PC).⁵

While the registered topical formulation is the only commercially available topical sirolimus product, various compounded formulations (solutions, mouthwashes, creams, and ointments) ranging from 0.001% to 8% concentration are used in clinical practice.^6-10 Despite its expanding off-label use in dermatology, current literature lacks a comprehensive synthesis of efficacy, safety, and practical considerations across different dermatological indications.

This review aims to systematically summarize the off-label applications of topical sirolimus for dermatologic conditions beyond tuberous sclerosis-associated angiofibromas, with a focus on reported clinical outcomes, safety profiles, and limitations of current evidence.

Materials and Methods

A comprehensive literature search was conducted using PubMed, Scopus, and Embase to identify studies from the past 50 years on the off-label topical application of sirolimus for dermatological conditions beyond angiofibromas in tuberous sclerosis. Search terms included “topical sirolimus,” “topical rapamycin,” and “off-label application.” The search was limited to articles published in English.

Studies were included if they reported on the clinical use of topical sirolimus in human subjects for dermatologic conditions other than tuberous sclerosis-associated angiofibromas. Both monotherapy and combination therapy studies (eg, topical sirolimus combined with laser or other treatments) were considered. In contrast, studies focusing primarily on vascular or lymphatic malformations (eg, lymphangiomas) were excluded, to maintain the review’s focus on lesser-known dermatologic uses of topical sirolimus.

The initial search results were screened by title and abstract to exclude irrelevant studies. Full-text reviews were then performed to assess eligibility based on inclusion and exclusion criteria. Case reports, case series, retrospective and prospective studies, randomized controlled trials (RCTs), and literature reviews were included. Preclinical animal studies were excluded, except when used to support mechanistic insights in conditions with limited human data.

Study quality was assessed descriptively based on study design, sample size, and the level of evidence, following a simplified hierarchy adapted from the Oxford Centre for Evidence-Based Medicine. Level 1 evidence was assigned to RCTs, Level 2 to non-randomized prospective studies, Level 3 to retrospective studies, and Level 4 to case reports and case series. This assessment was intended to contextualize the strength of the available data rather than as a formal systematic review grading.

In total, 47 studies met the inclusion criteria and were included in this review.

Results

The off-label topical application of sirolimus has been reported for a broad range of dermatologic conditions. For clarity, results are organized by disease categories, including genodermatoses, skin tumors, bullous diseases, inflammatory dermatoses, vascular proliferative lesions, and other dermatologic conditions.

An overview of included conditions is presented in Table 1, and details of study interventions and clinical outcomes are summarized in Table 2.

Table 1.

Search Results: Off-Label Topical Sirolimus Applications.

N	Disease category	N	Reported dermatologic indications
1	Bullous diseases	1	Epidermolysis bullosa simplex
		2	Pemphigus vulgaris (oral)
2	Genodermatoses	3	Familial multiple discoid fibromas, fibrofolliculomas and Birt-Hogg-Dubé syndrome
		4	Pachyonychia congenita
		5	Trichilemmomas, mucocutaneous hamartomas (Cowden syndrome)
		6	Trichoepitheliomas (MFTs/trichoepithelioma papulosum multiplex
3	Histiocytoses	7	Benign cephalic histiocytosis
		8	Cutaneous Rosai-Dorfman disease
4	Inflammatory dermatoses	9	Chronic plaque psoriasis
		10	Erosive lichen planus (oral and genital)
		11	Keratosis rubra pilaris
		12	Rosacea
5	Non-vascular neoplasms	13	Basal cell carcinoma (Gorlin syndrome)
		14	Epidermal nevus
		15	Extramammary Paget’s disease
		16	Nevus sebaceous
		17	SCC (intraepidermal carcinoma, keratotic lesions as proxy for actinic keratoses)
6	Other dermatologic conditions	18	Acanthosis nigricans
		19	Aging skin (photoaging and dermal volume loss)
		20	CARP
		21	Lymphedematous verrucous changes (Crohn disease)
		22	Ulerythema ophryogenes (keratosis pilaris atrophicans faciei)
7	Vascular anomalies	23	APACHE
		24	Angiokeratomas
		25	BLAPs
		26	Kaposi sarcoma
		27	Post-laser vascular lesions (PDL-induced angiogenesis)
		28	Superficial KHE

Abbreviations: APACHE, acral pseudolymphomatous angiokeratoma of children; BLAPs, benign lymphangiomatous papules; CARP, confluent and reticulated papillomatosis; KHE, kaposiform hemangioendothelioma; MFT, multiple familial trichoepithelioma; PDL, pulsed dye laser; SCC, squamous cell carcinoma.

Table 2.

Reported Cases of Off-Label Topical Sirolimus Application for Dermatological Conditions.

N	Disease category	N	Reported dermatologic indications	Author/year	Level of evidence	Number of patients (adult/peds)	Intervention	Clinical outcome
1	Bullous diseases	1	Epidermolysis bullosa simplex	Lee et al (2022)	4	2 adult F	Sirolimus 2% ung BID to the feet for 12 wk	Significant clinical improvement, reduced blistering and keratoderma, improved ambulation, and decreased foot pain
		2	Pemphigus vulgaris (oral)	Poot and Jonkman (2012)	4	3 adults	Sirolimus solution 1 mg/mL 5 mL as mouthwash BID for 2-3 wk	No improvements and even gradual worsening
2	Genodermatoses	3	Familial multiple discoid fibromas, fibrofolliculomas, and Birt-Hogg-Dubé syndrome	Gijezen et al (2014)Kim et al (2019)Wee et al (2013)	144	19 adults1 adult F1 adult F	Sirolimus solution 0.1% BID for 6 moSirolimus 1% ung BID for 6 mo to the right side of the face in addition to not ablative resurfacingSirolimus solution 1 mg/mL daily for 4 mo	No significant difference in fibrofolliculoma number or change in sizeOverall improvement, with a notably greater reduction in cutaneous lesions on the right sideNoticeable improvement in the redness and size of the fibromas after 8 wk with further improvement at 16 wk
		4	Pachyonychia congenita	Teng et al (2018)	4	2 adult F	Sirolimus ung 1% BID for 4 mo	Pain decreased within 4 wk and keratoderma thinned within 2 wk with a consistent clinical improvement over the 4 mo period. One patient experienced a recurrence of symptoms 2 wk after discontinuation
		5	Trichilemmomas (Cowden syndrome)	Bhanot et al (2023)	4	1 adult F	Sirolimus 0.2% gel applied daily to facial papules for 9 mo	Almost complete clearance of the multiple flesh-colored papules
			Mucocutaneous hamartomas (Cowden syndrome)	Botsali et al (2019)	4	1 adult F	Topical Sirolimus 0.5% daily in addition to ongoing laser therapy (q 3-6 mo) for 9 mo	Near clearance of the lesions with no recurrence
		6	MFT	Tu and Teng (2017)Dreyfus et al (2019)	44	1 girl (8 y old)1 boy (6 y old)5 adult F	Sirolimus 1% cream twice daily for 12 mo after CO₂ ablationSirolimus 1% cream BIDSirolimus 1% cream twice daily for 5 mo	Minimal regrowth and required no additional CO₂ laser ablationMinimal disease progression and did not require laser treatments4/5 reported improvement in the lesions and no new lesions appeared. 1/5—no improvementOne patient had recurrence 10 mo after DC
		6	Trichoepithelioma papulosum multiplex	Shimizu et al (2020)	4	1 girl (12 y old)	Sirolimus 0.2% gel applied daily for 3 mo	Dramatic decrease in the number of facial nodules
3	Histiocytoses	7	Benign cephalic histiocytosis	Habeshian et al (2019)	4	5 y old boy	Sirolimus 1% ung BID to the lesions for 5 mo	Fewer new lesions and flattening of existing lesions. Improvement persisted after a 6 wk unintended interruption in treatment
		8	Cutaneous Rosai-Dorfman disease	Balestri et al (2023)	4	1 adult F	Sirolimus 0.1% cream BID for 40 d	Marked improvement in the clinical appearance and the disappearance of some lesions, with only slight background erythema observed on dermoscopy
4	Inflammatory dermatoses	9	Chronic plaque psoriasis	Ormerod et al (2005)	1	24 adults	Sirolimus 2.2% cream for 6 wk, followed by Sirolimus 8% cream for 6 wk	Significant reduction in clinical scores, but no significant changes in plaque thickness or erythema
		10	Erosive LP (oral and genital)	Soria et al (2009)	4	7 adult F with oral and 6 of them also with genital erosive LP	Sirolimus solution 1 mg/mL BID for 3 mo	Four women experienced complete disappearance of oral and genital erosions resolvedTwo women had partial remissionOne DC due to local side effect
		11	Keratosis rubra pilaris	Eckburg et al (2022)	4	1 boy (15 y old)	Sirolimus 1% cream BID for 18 mo	Noticeable improvement after 2 mo, with near-complete resolution of erythema and burning after 18 mo. The results were sustained with once-daily application to the face over the following several mo
		12	Rosacea	Deng et al (2021)	1	18 adult F	Sirolimus 0.4% ung BID for 4 wk	Significant clinical improvement with reductions in CEA and IGA scores
5	Non-vascular neoplasms	13	Basal cell carcinoma (Gorlin syndrome)	Chang et al (2024)	4	1 girl (6 y old)	Sirolimus 1% cream 1-2 times a day for 2 y	Resolution of ~60%-70% of clinically suspicious BCCs (>40 lesions) and a lower incidence of new lesions. No additional treatment was required
		14	Epidermal nevus	Zhou and Antaya (2022)Dodds and Maguiness (2019)	44	2 kids (11-12 y old)1 boy (4 y old)	Sirolimus 1% cream BID for 2 ySirolimus 0.1% solution daily for 4 mo	Flattening and a decrease in papule size without any side effects in 1 patient, another DC after 1 mo due to local side effects but also noted lesions thinningReduction in the thickness of the nevus
		15	Extramammary Paget’s disease	Song et al (2020)	4	4 adults	Sirolimus 0.4% ung BID for 2 wk	Positive clinical response, reduced skin erythema and thickness
		16	Nevus sebaceous	Zhou and Antaya (2022)	4	4 kids (12-18 y old)	Sirolimus 1% cream BID for 1-5 y	4/4 observed thinning of the plaques (up to 90%) and decrease in size and flattening of the papules 2-3 mo after the initiation of therapy with stable results
		17	SCC (intraepidermal carcinoma, SCC) and keratotic lesions (proxy for actinic keratoses)	Chong et al (2022)	1	18 adults	Sirolimus 1% gel for 12 wk	31% ± 5% reduction in keratotic lesions (proxy for actinic keratoses) on the treated side at 12 wk; a 3-fold decrease in intraepidermal carcinomas at 24 mo; no significant difference in invasive SCC numbers at 24 mo
5	Other dermatologic conditions	18	Acanthosis nigricans	Coerdt et al (2021)	4	1 adult F	Sirolimus 1% cream BID for 13 mo	Significant lightening and thinning of the plaques starting 2 mo after initiation and results maintained for at least 6 wk after discontinuation
		19	Aging skin (photoaging and dermal volume loss)	Chung et al (2019)	2	36 adults	Sirolimus 10 μM (micromolar) or 0.001% cream q 1-2 d for 8 mo	Majority (11/13) demonstrated reduced fine wrinkles, increased dermal volume, brighter, and more even skin tone, less sagging, decreased prominence of veins and tendons, reduced expression of the p16INK4A protein (reduction in cellular senescence), and increased collagen VII
		20	CARP	Kurtyka et al (2021)	4	Adolescent male	Sirolimus 1% cream BID for 3 mo	Marked improvement in discoloration, no recurrence at the 7 mo follow-up with maintenance therapy of 1-2 times/wk
		21	Lymphedematous verrucous genital skin changes (an extraintestinal manifestation of Crohn disease)	Pei et al	4	17 y old girl	Sirolimus 1% cream daily for 2 wk	Reduction in pruritus and burning pain within 2 wk, further improvement but cannot be assessed as intralesional steroid injections were added
		22	Ulerythema ophryogenes (keratosis pilaris atrophicans faciei)	Bessis et al (2019)	4	1 adult	Sirolimus 1%	Unsuccessful
7.	Vascular anomalies	23	APACHE	Park et al (2020)	4	2 girls (12 and 3 y old)	First patient: Sirolimus 0.35% ung once daily for 5 moSecond patient: Sirolimus 0.2% ung once daily for 3 mo followed by BID for a total of 5 mo	Significant improvement, flattening of the existing lesions, and no new lesion developmentNotable reduction in erythema and flattening of the lesions
		24	Angiokeratomas	Farajzadeh et al (2023)Camacho et al (2020)Wataya-Kaneda et al (2023)Bell et al (2021)Ginés et al (2018)	44444	Boy (5 y old)1 adult F1 adult F1 adult F1 girl (12 y old)	Sirolimus 0.04% ung BID for 3 moSirolimus 1% ung BID for 4 moSirolimus 0.2% gel BID for 12 wkSirolimus 0.25% cream BID for 3 moSirolimus 0.4% ung daily for 1 y	Improvement—after 4 wk, >80% of the vascular component reduction by 3 mo; no recurrence at 6 mo follow-upLesion flattened, lightened, reduced in size; pruritus and pain resolved. No recurrence at 1 mo follow-upOnly 2 (the most recent) of the 9 lesions showed mild improvementPain and tenderness resolved; lesion size and appearance improved by 50% at 3 mo and 100% at 7 moImprovement (regression of the lesions) seen in the majority facial lesions
		25	BLAPs	Leducq et al (2021)	4	3 adults	Sirolimus 1% ung once daily for 3 mo	Vulvar lesions resolved completely in 1 patient and reduced by 50% in another. No significant changes were observed in the chest wall lesions
		26	Kaposi sarcoma	Díaz-Ley et al (2015)	4	1 adult M	Sirolimus 0.5% ung BID for 16 wk	Completely regressed with no recurrence after 2 y
		27	Post-laser vascular lesions (PDL-induced angiogenesis)	Musalem et al (2018)	4	4 kids (17 mo, 2, 9, 11 y old) and 1 adult	Sirolimus 0.5%-1% post PDL	Significant improvement in a shorter duration, subjective clearance ranging from 15% to 90%
		28	Superficial KHE	Liu et al (2021)Der Sarkissian et al (2022)Dang and Ren (2024)	444	15 kids1 adult1 boy(1 y old)	Sirolimus 0.1% ung BID for 6 moSirolimus 0.5% ung was switched later for 2 patients with enlarging tumorsSirolimus 1% ung daily for 5 wkSirolimus 0.1% gel BID for 1 y in addition to oral Propranolol (2 mg/kg/d)	13/15 improved (4 with near-complete regression, others with reduced induration and lighter lesions); 8/9 reported pain relief after 1-2 mo. One non-responder switched to oral sirolimus. No recurrence at 3 yNo responseLightening, resolution of induration, reduced cutaneous temperature, and decreased thickness on US

Abbreviations: APACHE, acral pseudolymphomatous angiokeratoma of children; BCC, basal cell carcinoma; BLAPs, benign lymphangiomatous papules; CEA, Clinician’s Erythema Assessment; CARP, confluent and reticulated papillomatosis; IGA, Investigator’s Global Assessment; KHE, kaposiform hemangioendothelioma; LP, lichen planus; MFT, multiple familial trichoepithelioma; PDL, pulsed dye laser; SCC, squamous cell carcinoma.

Bullous Diseases

Epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a hereditary blistering disorder caused by mutations in keratin 5 or 14, leading to skin fragility and intraepidermal blistering in response to minor trauma.¹¹ Lee et al reported 2 adult female patients with plantar EBS and painful plantar keratoderma who were treated with sirolimus 2% ointment applied twice daily for 12 weeks.¹¹ Both patients experienced significant clinical improvement, including reduced blistering, thinning of keratoderma, improved ambulation, and decreased foot pain. No adverse events were reported. mTOR inhibition may reduce keratinocyte hyperproliferation and inflammatory signaling, thereby enhancing epidermal stability and reducing mechanical stress-induced injury.¹¹

Pemphigus vulgaris

Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and mucous membranes caused by autoantibodies against desmoglein 1 and 3, with desmoglein 3 being predominantly targeted in mucosal-dominant PV.¹² Poot and Jonkman treated 3 PV patients with painful oral erosions using sirolimus 1 mg/mL solution – Rapamune^® (Pfizer Inc., New York, NY, USA) – twice daily as a mouthwash. No improvements were observed, with gradual worsening noted, and treatment was discontinued in favor of high-dose steroids with azathioprine.¹³ No specific adverse events were observed. Pretel et al demonstrated that sirolimus protected keratinocytes from acantholysis by inhibiting apoptosis, suggesting a potential disease-specific mechanism of action.¹⁴

Genodermatoses

Familial multiple discoid fibromas, fibrofolliculomas, and Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant genodermatosis characterized by multiple fibrofolliculomas, trichodiscomas, and acrochordons. It is caused by mutations in the folliculin gene, impacting mTOR signaling.¹⁵ Gijezen et al conducted a RCT of 19 patients with BHD using 0.1% sirolimus solution twice daily for 6 months, which showed no significant reduction in fibrofolliculoma size or number.¹⁵ However, Kim et al reported improved cosmetic outcomes using 1% sirolimus ointment combined with 1540 nm nonablative laser.¹⁶ Wee et al also described a case of familial multiple discoid fibromas in a 27 year-old male who experienced improved size and redness of the fibromas after applying sirolimus 1 mg/mL solution daily for 4 months.¹⁷ No adverse events were reported.

In BHD syndrome, sirolimus may act by reducing abnormal follicular proliferation.^15,16

Pachyonychia congenita

PC is a rare autosomal dominant disorder of cornification caused by heterozygous mutations in keratin genes, most commonly KRT6A, and is characterized by painful palmoplantar keratoderma, blistering and maceration, nail dystrophy, oral leukokeratosis, and follicular keratosis.¹⁸ Teng et al described 2 adult female patients with PC who applied sirolimus 1% ointment twice daily for 4 months.⁵ Both reported reduced plantar pain within 4 weeks and thinning of plantar keratoderma. Clinical improvement was sustained during treatment, although 1 patient experienced symptom recurrence 2 weeks after discontinuation. No systemic adverse events were reported. Sirolimus is thought to reduce nonfunctional keratin production by downregulating keratin gene expression such as KRT6 and KRT16.⁵

Trichilemmomas, mucocutaneous hamartomas (Cowden syndrome)

Cowden syndrome is a rare autosomal dominant genodermatosis associated with PTEN mutations, characterized by mucocutaneous hamartomas including facial trichilemmomas, oral papillomas, and acral keratoses.¹⁹ In a 67 year-old woman with Cowden syndrome, sirolimus 0.2% gel was applied once daily for 9 months, resulting in near-complete clearance of facial trichilemmomas.¹⁹

Botsali et al reported sustained improvement over 9 months in mucocutaneous hamartomas with sirolimus 0.5% ointment in combination with periodic erbium:YAG laser treatment in a 57 year-old female with Cowden syndrome.²⁰ No adverse events were reported. Sirolimus may be effective in Cowden syndrome through inhibition of the overactive PI3K/AKT/mTOR pathway driven by PTEN deficiency.¹⁹

Trichoepitheliomas (multiple familial trichoepitheliomas)/trichoepithelioma papulosum multiplex

Trichoepitheliomas are benign follicular neoplasms that may occur sporadically or in inherited patterns such as multiple familial trichoepitheliomas (MFT) or Brooke-Spiegler syndrome, typically presenting as skin-colored papules on the central face.⁶ Tu and Teng described 2 siblings with MFT, one of whom was treated with sirolimus 1% cream twice daily following CO₂ laser ablation, with minimal regrowth after 12 months, while the untreated sibling showed slower progression after 7 months of sirolimus without laser treatment.⁶

Dreyfus et al reported 5 adult females with MFT treated with sirolimus 1% cream twice daily for 5 months; 4 showed lesion improvement and no new lesion development.²¹

Shimizu et al described a 12 year-old girl with MFT who experienced dramatic reduction in facial nodules after using sirolimus 0.2% gel once daily for 3 months.²² No adverse events were reported. The suppression of abnormal follicular proliferation is thought to be how sirolimus may aid patients with trichoepitheliomas.⁶

Histiocytoses

Benign cephalic histiocytosis

Benign cephalic histiocytosis (BCH) is a self-limiting, non-Langerhans cell histiocytosis that typically affects infants and young children, presenting as asymptomatic red-yellow papules on the head and neck.²³ Habeshian et al treated a 5 year-old boy with BCH using sirolimus 1% ointment twice daily for 5 months, resulting in flattening and reduction of lesions.²³ Improvement persisted despite a 6 week treatment interruption. No adverse events were reported.

Cutaneous Rosai-Dorfman disease

Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by dermal or subcutaneous nodules composed of S100-positive histiocytes.²⁴ Balestri et al reported a 47 year-old woman with cutaneous RDD treated with sirolimus 0.1% cream applied twice daily for 40 days.²⁴ Clinical improvement included flattening of nodules and partial resolution of lesions. No adverse effects were observed.

The proposed mechanism involves inhibition of histiocytic proliferation through modulation of the mTOR signaling pathway.²⁴

Inflammatory Dermatoses

Chronic plaque psoriasis

Chronic plaque psoriasis is a common inflammatory skin disorder characterized by erythematous plaques with silvery scale, resulting from immune-mediated keratinocyte hyperproliferation.¹⁰ Ormerod et al conducted a randomized, double-blind study in 24 adult patients, applying 2.2% sirolimus for 6 weeks followed by 8% sirolimus for another 6 weeks.¹⁰ Significant improvements were observed in clinical scores (P = .03), with reduced CD4+ cell infiltration (P = .0054) and epidermal proliferation (P = .0153). Although efficacy was modest compared to topical steroids, sirolimus may benefit select patients with enhanced skin permeability. No adverse events were reported.

Erosive lichen planus (oral)

Erosive lichen planus (LP) is a chronic inflammatory mucocutaneous condition marked by painful erosions of the oral mucosa, often co-occurring with genital involvement.²⁵ Soria et al reported on 7 steroid-refractory female patients treated with sirolimus 1 mg/mL oral solution used twice daily for 3 months.²⁵ Oral lesions resolved completely in 4 patients, and genital lesions in all 6 with genital involvement. Mild local discomfort was noted initially and resolved in most cases, though 1 patient discontinued treatment. One patient had detectable systemic sirolimus levels, but no systemic adverse effects were observed.

Keratosis pilaris rubra

Keratosis pilaris rubra (KPR) is a rare inflammatory keratinization disorder characterized by facial erythema, follicular hyperkeratosis, and burning discomfort.²⁶ Eckburg et al described a 15 year-old boy with KPR treated with sirolimus 1% cream applied twice daily for 18 months.²⁶ The patient experienced near-complete resolution of erythema and burning. Sustained improvement was maintained with once-daily application for several additional months. No adverse events were reported.

Rosacea

Rosacea is a chronic inflammatory skin condition characterized by facial erythema, flushing, and inflammatory papules.²⁷ Deng et al identified hyperactivation of mTORC1 signaling in affected epidermis, contributing to disease exacerbation.²⁷ In a RCT of 18 female patients, 10 patients applied sirolimus 0.4% ointment twice daily for 4 weeks, resulting in significant improvement in Clinician’s Erythema Assessment (CEA) and Investigator’s Global Assessment scores. No adverse events were reported.

Although the included studies in inflammatory dermatoses did not directly investigate the mechanism of action, the observed therapeutic effects of sirolimus may be attributed to its ability to regulate T-cell activation, keratinocyte proliferation, and inflammatory cytokine signaling. These immunomodulatory and antiproliferative effects may contribute to clinical improvement in conditions such as psoriasis, LP, and rosacea.^10,25,27

Non-Vascular Neoplasms

Basal cell carcinoma

Basal cell carcinoma (BCC) is the most frequent skin cancer, often associated with dysregulation of the Hedgehog and mTOR signaling pathways.²⁸ Chang et al reported a 6 year-old girl with Gorlin syndrome who applied sirolimus 1% cream once or twice daily for 1 year.²⁸ Approximately 60% to 70% of over 40 clinically suspicious BCCs on the eyelids and shoulders resolved, and no new lesions developed over 2 years of continuous treatment. No adverse effects were reported. The therapeutic effect is thought to result from inhibition of basal cell proliferation.²⁸

Epidermal nevus

Epidermal nevus (EN) is a congenital hamartomatous proliferation of the epidermis, typically following Blaschko’s lines.⁷ Zhou and Antaya reported 2 adolescent patients with EN on the posterior neck treated with sirolimus 1% cream applied twice daily.⁷ One patient discontinued treatment after 1 month due to dryness, flakiness, and redness, though some lesion thinning was observed. The second patient used sirolimus for 2 years and experienced lesion flattening without adverse effects. Dodds and Maguiness described a 4 year-old boy with extensive EN on the torso, neck, and upper arms in a Blaschkoid distribution, associated with an FGFR3 mutation, who was treated with sirolimus 0.1% solution applied daily to the neck and axilla for 4 months.⁸ Treatment resulted in reduced nevus thickness. The therapeutic effect of sirolimus may stem from its inhibition of the FGFR3 pathway, contributing to decreased keratinocyte proliferation.⁸

Extramammary Paget’s disease

Extramammary Paget’s disease (EMPD) is a rare intraepithelial adenocarcinoma typically affecting apocrine gland-bearing areas.²⁹ Song et al reported 4 patients with EMPD treated with sirolimus 0.4% ointment applied twice daily for 2 weeks.²⁹ Histological evaluation revealed a reduction in PAS+, CEA+, and CAM5.2+ Paget cells and decreased mTOR activity, along with improved epidermal structure. No adverse events were reported. These findings suggest that sirolimus may reduce tumor cell proliferation and improve epidermal architecture in EMPD.²⁹

Nevus sebaceous

Nevus sebaceous (NS) is a congenital hamartomatous lesion, often located on the scalp, face, or neck, and associated with postzygotic mutations in the RAS/MAPK pathway.⁷ Sirolimus, acting downstream via mTOR inhibition, may reduce cellular proliferation in these lesions. Zhou and Antaya described 4 adolescents (ages 12-18) with NS treated with sirolimus 1% cream twice daily for 1 to 5 years.⁷ All patients experienced lesion thinning within 2 to 3 months, and 1 achieved 90% flattening of scalp lesions, maintaining results with reduced application frequency. Reported side effects included cracking, itching, bleeding, and folliculitis, which were managed with topical hydrocortisone.

Squamous cell carcinoma

Squamous cell carcinoma is a common skin cancer derived from epidermal keratinocytes, particularly in immunosuppressed individuals.⁹ In a 12 week RCT involving 18 adult solid organ transplant recipients, each patient applied 1% sirolimus gel to the dorsum of 1 hand and forearm, while vehicle alone was applied to the contralateral side.⁹ The sirolimus-treated side showed a 31% reduction in keratotic lesions at 12 weeks and an 81% decrease in intraepithelial carcinomas over 24 months. One participant developed contact dermatitis. Sirolimus may exert antineoplastic effects by downregulating keratinocyte proliferation and may suppress premalignant transformation.⁹

Other Dermatologic Conditions

Acanthosis nigricans

Acanthosis nigricans (AN) is a velvety hyperpigmented thickening of the skin, often associated with insulin resistance or seen in familial cases caused by FGFR3 mutations.³⁰ Coerdt et al described an 18 year-old female with Fitzpatrick type IV/V skin and an FGFR3 mutation, who applied sirolimus 1% cream twice daily for 13 months.³⁰ She experienced significant lightening and thinning of plaques, with results maintained for at least 6 weeks after discontinuation. No adverse effects were reported.

Aging skin

Aging skin is characterized by dermal atrophy, fine wrinkles, pigment irregularities, and loss of elasticity, partly due to cellular senescence and reduced collagen integrity.^31,32 Chung et al conducted a placebo-controlled trial involving 36 participants over age 40 with photoaged dorsal hands, who applied sirolimus 0.001% cream every 24 to 48 hours for 8 months.³¹ Nineteen participants discontinued or were lost to follow-up, but among the 13 who completed the study, 11 showed clinical improvements by 4 months. These included reduction in fine wrinkles, increased dermal volume, more even skin tone, less sagging, and decreased visibility of veins and tendons. Histologic analysis demonstrated reduced expression of p16INK4A (a marker of cellular senescence) and increased collagen VII. Blagosklonny proposed the broader use of topical sirolimus for skin aging, based on its ability to potentially slow the aging process and enhance skin structure.³²

Confluent and reticulated papillomatosis

Confluent and reticulated papillomatosis (CARP) is a rare dermatosis characterized by hyperpigmented, reticulated plaques on the trunk.³³ Kurtyka et al described an adolescent male with CARP and AN who was treated with sirolimus 1% cream twice daily for 3 months.³³ The patient showed marked improvement in discoloration, and results were maintained with 1 to 2 times weekly application for 7 months. No adverse events were noted.

Lymphedematous verrucous changes of the genital skin

Lymphedematous verrucous changes of the genital skin are chronic, thickened, wart-like lesions often associated with inflammation or secondary lymphedema.³⁴ Pei et al described a 17 year-old female with Crohn’s disease and persistent erythema, swelling, and verrucous papules on the mons pubis and labia.³⁴ She was treated with sirolimus 1% cream for 2 weeks, resulting in a reduction in pruritus and burning. However, intralesional triamcinolone was added, limiting attribution of long-term improvement to sirolimus alone. No adverse events were reported.

Ulerythema ophryogenes

Ulerythema ophryogenes (UO), or keratosis pilaris atrophicans faciei, is a rare condition causing eyebrow and facial follicular atrophy and erythema and may occur as part of genetic syndromes such as cardiofaciocutaneous (CFC) syndrome.³⁵ Bessis et al reported a case of UO in CFC syndrome treated with sirolimus 1% cream without clinical improvement.³⁵

Vascular Anomalies

Acral pseudolymphomatous angiokeratoma of children

Acral pseudolymphomatous angiokeratoma of children (APACHE) is a rare, benign dermatosis characterized by multiple, asymptomatic, erythematous papules in acral regions.³⁶ Park et al described 2 pediatric patients with APACHE treated with sirolimus 0.2% and 0.35% ointment twice a day for 5 months, leading to significant flattening of the lesions and reduction in erythema.³⁶ No adverse effects were reported.

Angiokeratomas

Angiokeratomas are benign vascular neoplasms characterized by dilated capillaries in the superficial dermis with an overlying hyperkeratotic surface. They may present as solitary lesions or as multiple lesions in the context of genetic disorders such as Fabry disease.³⁷ Farajzadeh et al described a 5 year-old boy with a 5 × 6 cm angiokeratoma on the proximal thigh treated with sirolimus 0.04% ointment twice daily for 3 months.³⁸ Over 80% of the vascular component resolved, with sustained improvement and no complications at 6 months. Camacho et al reported an 18 year-old woman with a painful and pruritic 1.4 × 1.4 cm angiokeratoma on the right buttock, who achieved complete resolution of symptoms and lesion flattening after 4 months of sirolimus 1% ointment twice daily.³⁹ Wataya-Kaneda et al treated a 47 year-old woman with Fabry disease and 9 angiokeratomas on the trunk, head, and upper extremities using sirolimus 0.2% gel twice daily for 12 weeks; only 2 lesions showed mild improvement.³⁷ Bell et al treated a 61 year-old man with Fordyce-type angiokeratomas using sirolimus 0.25% cream twice daily, reporting a 50% subjective improvement after 3 months and complete resolution of pain with 100% improvement in lesion appearance after 7 months.⁴⁰ Ginés et al also reported a 12 year-old boy with facial angiofibromas treated with 0.4% sirolimus ointment once daily for 1 year, with improvement noted in the malar and infraorbital areas, but no change in the nasal region.⁴¹ These cases suggest sirolimus may have a role in reducing vascular proliferation and associated inflammation.^37-40

Benign lymphangiomatous papules

Benign lymphangiomatous papules (BLAPs) are benign lymphatic proliferative lesions that typically arise due to lymphatic obstruction, often following surgery or radiotherapy for malignancy.⁴² Leducq et al reported 3 adult patients with BLAPs after radiotherapy for endometrial or breast cancer.⁴² Two patients had vulvar lesions and 1 had lesions on the anterior chest wall, associated with oozing, pruritus, and lymphorrhea. All were treated with sirolimus 1% ointment once daily for 3 months. The vulvar lesions resolved completely or partially, whereas chest wall lesions showed minimal improvement. The authors suggested this difference may reflect regional variations in epidermal thickness, occlusion, and local humidity. No adverse effects were reported. The therapeutic effect of sirolimus in BLAPs may be attributed to its ability to suppress abnormal lymphatic endothelial proliferation and local inflammatory responses, as observed in other lymphatic disorders.⁴²

Kaposi sarcoma

Kaposi sarcoma (KS) is a vascular neoplasm linked to human herpesvirus 8 and characterized by endothelial proliferation and inflammation.⁴³ Díaz-Ley et al described a 73 year-old man with classic (Mediterranean) KS localized to the right foot and ankle who was treated with sirolimus 0.5% ointment twice daily for 16 weeks.⁴³ Complete regression was achieved, with no recurrence noted after 2 years of follow-up. Mild pruritus occurred during early treatment but resolved spontaneously. This case suggests sirolimus may offer a well-tolerated topical option for localized KS via inhibition of endothelial proliferation.⁴³

Post-laser vascular lesions (pulsed dye laser-induced angiogenesis)

Port-wine stains (PWS) are congenital capillary malformations that are often treated with pulsed dye laser (PDL). Despite PDL’s effectiveness, treatment outcomes are limited by post-laser angiogenesis and vascular regeneration, which may reduce blanching.^44-46 Musalem et al retrospectively reviewed 5 patients with PWS who were treated with PDL followed by sirolimus 0.5% to 1% cream.⁴⁵ Subjective clearance ranged from 15% to 90%, with minimal adverse effects—1 case of transient burning. Several patients showed marked improvement when sirolimus was introduced after a plateau in PDL response, suggesting a potential role for sirolimus in enhancing laser outcomes. Although direct mechanistic data in humans are limited, preclinical studies have shown that sirolimus may inhibit angiogenic pathways, including VEGF and HIF-1α expression, supporting its proposed effect in this setting.⁴⁴

Superficial kaposiform hemangioendothelioma

Superficial kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor that may present in infancy or adulthood.⁴⁷ In a retrospective study of 15 children with KHE treated with sirolimus 0.1% ointment twice daily for 6 months, 13 patients improved, and 4 achieved near-complete regression.⁴⁸ Two additional patients responded to a higher concentration (0.5% ointment), and no relapses occurred after 3 years. In contrast, Der Sarkissian et al described a 65 year-old man with neck KHE who failed to respond to 1% sirolimus ointment after 5 weeks.⁴⁷ Dang and Ren presented a 1 year-old boy with a 10 month history of KHE on the left mandible and prothorax, treated with sirolimus 0.1% gel twice daily plus oral propranolol (2 mg/kg/day) for 1 year.⁴⁹ The child showed noticeable improvement in induration, thickness, and lesion color. Across all cases, topical sirolimus was well tolerated, with no adverse effects reported. These reports suggest sirolimus may be most effective in pediatric superficial KHE, particularly when initiated early or combined with adjunctive therapies.^47-49

Topical formulation and adverse effects

Formulation concentrations of sirolimus ranged from 0.001% to 8% and were compounded into creams, ointments, and gels,^6-10 in addition to the commercially available HYFTOR^® 0.2% gel.² Dosing was typically once or twice daily. Notably, no comparative studies have evaluated the relative efficacy or adverse effects of different concentrations or dosing frequencies.^7-9,43

Topical sirolimus was typically well tolerated, with skin irritation as the most common side effect, which often resolved with continued use, temporary discontinuation, or adjunctive use of topical hydrocortisone.^7,9,31 Less frequent side effects included superficial mucosal erosions, mild facial acne (with facial application), folliculitis, and allergic contact dermatitis.^9,16,34 Two patients reported headaches that resolved with simple analgesia,⁹ but no significant systemic adverse events were noted.^7,9,31 Blood levels, when measured, remained below the immunosuppressive threshold (4 ng/mL), minimizing concerns about systemic immunosuppression.^9,41 In vascular and lymphatic lesions, topical sirolimus was also well tolerated, including in pediatric populations with long-term use.^20,27,41

Discussion

The application of topical sirolimus for various dermatologic conditions demonstrates a wide spectrum of efficacy, with outcomes largely dependent on the underlying pathology and treatment parameters. Sirolimus, an mTOR inhibitor, has shown therapeutic potential through modulation of the cell growth, proliferation, angiogenesis, lymphangiogenesis, and inflammation.^3,4

Topical sirolimus appears particularly effective for genetic and benign proliferative skin disorders such as PC,^5,18 trichilemmomas,¹⁹ trichoepitheliomas,^6,21,22 and epidermal nevi.^7,8 In these conditions, it reduced lesion size, discomfort, and recurrence, with enhanced outcomes reported when combined with adjunctive laser therapy.^16,20 For example, patients with trichilemmomas and trichoepitheliomas showed minimal regrowth following laser-assisted sirolimus delivery, and those with PC experienced reduced keratoderma thickness and pain, improving quality of life.

Encouraging results were also observed in vascular anomalies—including angiokeratomas,^9,27-29,30 superficial KHE,^48,49 and port-wine stains^44-46—especially when sirolimus was used in conjunction with PDL therapy. In such cases, sirolimus likely exerts its benefit through inhibition of angiogenic and endothelial proliferative pathways.^44,46 Conditions characterized by vascular proliferation and inflammation, such as KS,⁴³ also responded well, with 1 report noting complete lesion regression sustained for 2 years.

While sirolimus has shown positive outcomes in several inflammatory conditions such as psoriasis,¹⁰ oral LP,²⁵ and CARP,³³ results have been mixed in disorders like PV^13,14 and BLAPs.⁴² These differences may reflect the degree to which the mTOR pathway contributes to disease pathogenesis.

Variability in reported outcomes also stems from the lack of standardized formulations and dosing regimens. Concentrations ranged from 0.001% to 8%,^6-10 delivered in various vehicles and applied at different frequencies,^7-9,43 complicating cross-study comparisons. Although preclinical (murine) studies were not included for efficacy assessment, they were selectively referenced to support proposed mechanisms—such as the inhibition of post-laser angiogenesis⁴⁴ and lymphatic endothelial proliferation⁴²—in settings where human mechanistic data were lacking. Overall, topical sirolimus maintains a favorable safety profile, with most adverse effects being mild and localized. Systemic absorption was minimal, with measured blood levels consistently below the immunosuppressive threshold.^9,41 This favorable safety profile makes topical sirolimus an appealing option for localized dermatologic treatment, particularly in patients who are unsuitable for systemic immunosuppressive therapies.

Conclusion

Topical sirolimus demonstrates promising off-label therapeutic potential across a wide range of dermatologic conditions, particularly in genetic and benign proliferative disorders, vascular anomalies, and select inflammatory dermatoses. Its mechanism of action—via mTOR inhibition—enables targeted modulation of keratinocyte proliferation, angiogenesis, lymphangiogenesis, and immune responses. Reported outcomes include lesion size reduction, symptom control, and high local tolerability, with minimal systemic absorption and a low incidence of adverse effects. Although most of the current evidence is derived from case reports and small series, the consistency of reported clinical benefits supports its potential utility in dermatology, especially in patients who may not tolerate systemic immunosuppressive therapies. However, the heterogeneity of formulations, dosing regimens, and outcome measures hinders direct comparison and generalizability.

Further research is essential to establish standardized treatment protocols, assess long-term safety, and better understand disease-specific mechanisms of action. Larger, controlled studies are needed to define optimal concentrations, formulations, and dosing schedules. With a stronger evidence base, topical sirolimus may become an accepted and effective treatment option for a range of complex cutaneous conditions.

Limitations

There are several limitations in this literature review. A key limitation is that many included studies are case reports or case series without a comparator group, which increases the risk of publication bias and limits the strength of the conclusions. There was considerable heterogeneity in treatment protocols, including sirolimus concentrations, formulations, frequency, and duration of application, as well as variability in outcome reporting. These differences make direct comparisons between studies difficult and limit the generalizability of findings.

Furthermore, sirolimus topical therapy was often combined with surgical or laser modalities, making it challenging to isolate its independent therapeutic effect. Although preclinical (murine) studies were excluded from clinical efficacy analysis, they were referenced selectively to support proposed mechanisms of action, particularly in vascular and lymphatic proliferative conditions where human mechanistic data are limited.

Additionally, standardized clinical scoring tools were rarely used, and long-term follow-up was often lacking, particularly for assessing safety and sustained response. A detailed assessment of individual study quality and methodological limitations was beyond the scope of this review due to its broad coverage. Future research should aim to address these gaps through prospective, controlled studies with uniform endpoints and extended follow-up periods to better evaluate the long-term efficacy and safety of topical sirolimus.

Footnotes

Author Contributions

Tatiana Lapa: data curation, writing—original draft preparation. Matt Sandre: conceptualization, methodology, supervision, writing—review and editing.

Data Availability Statement

Data sharing not applicable—no new data generated.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical Considerations

Not applicable.

ORCID iD

Tatiana Lapa

References

Rapamycin. U.S. Food and Drug Administration. Rapamune (sirolimus) tablets and oral solution (Internet). 2017. Accessed May 22, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021083s059,021110s076lbl.pdf

U.S. Food and Drug Administration. Hyftor (sirolimus) gel, 0.2% for topical use (Internet). 2022. Accessed May 22, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213478s000lbl.pdf

Sun

Rosenberg

Wang

, et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005;65(16):7052-7058. doi:10.1158/0008-5472.CAN-05-0917

Chan

. Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004;91(8):1420-1424. doi:10.1038/sj.bjc.6602162

Teng

JMC

Bartholomew

Patel

Sun

. Novel treatment of painful plantar keratoderma in pachyonychia congenita using topical sirolimus. Clin Exp Dermatol. 2018;43(8):968-971. doi:10.1111/ced.13686

Teng

. Use of topical sirolimus in the management of multiple familial trichoepitheliomas. Dermatol Ther. 2017;30(2):e12458. doi:10.1111/dth.12458

Zhou

Antaya

. Topical sirolimus therapy for nevus sebaceus and epidermal nevus: a case series. J Am Acad Dermatol. 2022;87(2):407-409. doi:10.1016/j.jaad.2021.08.029

Dodds

Maguiness

. Topical sirolimus therapy for epidermal nevus with features of acanthosis nigricans. Pediatr Dermatol. 2019;36(4):554-555. doi:10.1111/pde.13833

Chong

Wong

Althabteh

, et al. Chemoprevention of cutaneous squamous cell carcinoma and its precursors in solid organ transplant recipients using topical sirolimus: a randomized, double-blind, placebo-controlled pilot trial. J Am Acad Dermatol. 2022;87(5):1163-1166. doi:10.1016/j.jaad.2022.02.039

10.

Ormerod

Shah

Copeland

Omar

Winfield

. Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial. Br J Dermatol. 2005;152(4):758-764. doi:10.1111/j.1365-2133.2005.06438.x

11.

Lee

Lekwuttikarn

Tafoya

Martin

Sarin

Teng

. Transcriptomic repositioning analysis identifies mTOR inhibitor as potential therapy for epidermolysis bullosa simplex. J Invest Dermatol. 2022;142(2):382-389. doi:10.1016/j.jid.2021.07.170

12.

Schmitt

Waschke

. Autoantibody-mediated disruption of desmosomal adhesion in pemphigus: from pathophysiology to therapeutic targets. Front Med. 2021;8:701809. doi:10.3389/fmed.2021.701809

13.

Poot

Jonkman

. Topical sirolimus for oral pemphigus vulgaris: 3 unresponsive cases. J Am Acad Dermatol. 2012;67(5):e228-e229. doi:10.1016/j.jaad.2012.04.032

14.

Pretel

España

Marquina

Pelacho

López-Picazo

López-Zabalza

. An imbalance in Akt/mTOR is involved in the apoptotic and acantholytic processes in a mouse model of pemphigus vulgaris. Exp Dermatol. 2009;18(9):771-780. doi:10.1111/j.1600-0625.2009.00893.x

15.

Gijezen

Vernooij

Martens

, et al. Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PLoS One. 2014;9(6):e99071. doi:10.1371/journal.pone.0099071

16.

Kim

Wysong

Teng

Rahman

. Laser-assisted delivery of topical rapamycin: mTOR inhibition for Birt-Hogg-Dube syndrome. Dermatol Surg. 2019;45(12):1713-1715. doi:10.1097/DSS.0000000000001778

17.

Wee

Chong

Natkunarajah

Mortimer

Moosa

. Familial multiple discoid fibromas: unique histological features and therapeutic response to topical rapamycin. Br J Dermatol. 2013;169(1):177-180. doi:10.1111/bjd.12315

18.

Zieman

Coulombe

. Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment. Br J Dermatol. 2020;182(3):564-573. doi:10.1111/bjd.18033

19.

Bhanot

Harrell

Levin

. Treatment of trichilemmomas with topical sirolimus. JAMA Dermatol. 2023;159(3):340-342. doi:10.1001/jamadermatol.2022.5701

20.

Botsali

Caliskan

Eşme

Dündar

. Oral hamartomatous lesion of Cowden’s disease treated with the combination of erbium:YAG laser and topical sirolimus. Dermatol Ther. 2019;32(5):e13002. doi:10.1111/dth.13002

21.

Dreyfus

Onnis

Tournier

Dereure

Mazereeuw-Hautier

. Effect of topical rapamycin 1% on multiple trichoepitheliomas. Acta Derm Venereol. 2019;99(4):454-455. doi:10.2340/00015555-3116

22.

Shimizu

Toyoda

Motegi

Yasuda

Ishikawa

. First Japanese case of trichoepithelioma papulosum multiplex successfully treated with sirolimus gel. J Dermatol. 2020;47(5):e197-e198. doi:10.1111/1346-8138.15271

23.

Habeshian

Silverman

DeKlotz

CMC

. Treatment of benign cephalic histiocytosis with topical 1% rapamycin ointment. Pediatr Dermatol. 2019;36(3):411-413. doi:10.1111/pde.13800

24.

Balestri

Magnano

Pedrolli

Girardelli

Rech

. Treatment of purely cutaneous Rosai-Dorfman disease with topical rapamycin. Clin Exp Dermatol. 2023;48(5):545-547. doi:10.1093/ced/llad018

25.

Soria

Agbo-Godeau

Taïeb

Francès

. Treatment of refractory oral erosive lichen planus with topical rapamycin: 7 cases. Dermatology. 2009;218(1):22-25. doi:10.1159/000172830

26.

Eckburg

Kazemi

Maguiness

. Keratosis pilaris rubra successfully treated with topical sirolimus: report of a case and review of the literature. Pediatr Dermatol. 2022;39(3):429-431. doi:10.1111/pde.14963

27.

Deng

Chen

Liu

, et al. A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea. EMBO Mol Med. 2021;13(5):e13560. doi:10.15252/emmm.202013560

28.

Chang

ALS

Brown

Betancourt

Teng

. Assessment of mammalian target of rapamycin pathway activation in basal cell carcinoma as a new therapeutic approach. Am J Dermatopathol. 2024;46(9):588-592. doi:10.1097/DAD.0000000000002718

29.

Song

Guerrero-Juarez

Chen

, et al. The Msi1-mTOR pathway drives the pathogenesis of mammary and extramammary Paget’s disease. Cell Res. 2020;30(10):854-872. doi:10.1038/s41422-020-0334-5

30.

Coerdt

Todd

DeKlotz

CMC

. Topical rapamycin for acanthosis nigricans in the Fitzpatrick IV/V adolescent population. Pediatr Dermatol. 2021;38(1):296-298. doi:10.1111/pde.14404

31.

Chung

Lawrence

Hoffman

, et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Geroscience. 2019;41(6):861-869. doi:10.1007/s11357-019-00113-y

32.

Blagosklonny

. Rapamycin for the aging skin. Aging. 2019;11(24):12822-12826. doi:10.18632/aging.102664

33.

Kurtyka

Burke

DeKlotz

CMC

. Use of topical sirolimus (rapamycin) for treating confluent and reticulated papillomatosis. JAMA Dermatol. 2021;157(1):121-123. doi:10.1001/jamadermatol.2020.4083

34.

Pei

Fischer

Yan

, et al. Lymphedematous verrucous changes of the genital skin: an extraintestinal manifestation of Crohn disease. J Cutan Pathol. 2021;48(4):465-468. doi:10.1111/cup.13723

35.

Bessis

Morice-Picard

Bourrat

, et al. Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients. Br J Dermatol. 2019;180(1):172-180. doi:10.1111/bjd.17077

36.

Park

Lara-Corrales

Pope

. Use of topical rapamycin in acral pseudolymphomatous angiokeratoma of children (APACHE): a report of two cases and review of the literature. Pediatr Dermatol. 2020;37(5):877-880. doi:10.1111/pde.14240

37.

Wataya-Kaneda

Maeda

Nakamura

Hayashi

Fujimoto

. Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study. J Dermatol. 2023;50(12):1619-1624. doi:10.1111/1346-8138.16930

38.

Farajzadeh

Pardakhty

Afshar

Abtahi-Naeini

. Clinical and dermoscopic improvement of angiokeratoma in a child with topical rapamycin. Indian J Dermatol Venereol Leprol. 2023;90(1):136. doi:10.25259/IJDVL_1008_2022

39.

Camacho

Scott

DeKlotz

. Topical sirolimus for treatment of a solitary angiokeratoma. Dermatol Ther. 2020;33(6):e13907. doi:10.1111/dth.13907

40.

Bell

Guo

DeKlotz

CMC

. Treatment of angiokeratomas of Fordyce with topical rapamycin 0.25% cream. JAAD Case Rep. 2021;8:50-52. doi:10.1016/j.jdcr.2020.12.007

41.

Ginés

Rodríguez-Cuadros

González

Guindo

. 4CPS-143 Topical application of rapamycin 0.4% for treatment of facial angiokeratomas in a paediatric patient. Eur J Hosp Pharm. 2018;25(suppl 1):A108. doi:10.1136/ejhpharm-2018-eahpconf.234

42.

Leducq

Gabeff

Zaragoza

Poiraud

Tallegas

Maruani

. Topical sirolimus 1% for benign lymphangiomatous papules after radiotherapy for endometrial and breast cancers: a report of three cases. Eur J Dermatol. 2021;31(2):252-254. doi:10.1684/ejd.2021.4000

43.

Díaz-Ley

Grillo

Ríos-Buceta

, et al. Classic Kaposi’s sarcoma treated with topical rapamycin. Dermatol Ther. 2015;28(1):40-43. doi:10.1111/dth.12182

44.

Tan

Jia

Sun

Mihm

Jr Nelson

. Topical rapamycin suppresses the angiogenesis pathways induced by pulsed dye laser: molecular mechanisms of inhibition of regeneration and revascularization of photocoagulated cutaneous blood vessels. Lasers Surg Med. 2012;44(10):796-804. doi:10.1002/lsm.22101

45.

Musalem

Alshaikh

Tuleimat

Alajlan

. Outcome with topical sirolimus for port wine stain malformations after unsatisfactory results with pulse dye laser treatment alone. Ann Saudi Med. 2018;38(5):376-380. doi:10.5144/0256-4947.2018.376

46.

Jia

Sun

Tran

, et al. Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: implications for effective port wine stain treatment. Lasers Surg Med. 2010;42(2):105-112. doi:10.1002/lsm.20890

47.

Der Sarkissian

Wong

Kossard

Hong

Sebaratnam

. Kaposiform haemangioendothelioma in an adult: lack of response to topical sirolimus and response to radiotherapy. Clin Exp Dermatol. 2022;47(1):192-193. doi:10.1111/ced.14928

48.

Liu

Zhang

Nie

Chen

Wang

. The effect of topical sirolimus on superficial kaposiform haemangioendothelioma. Australas J Dermatol. 2021;62(2):e329-e331. doi:10.1111/ajd.13499

49.

Dang

Ren

. A case of superficial kaposiform hemangioendothelioma treated with oral propranolol combined with topical sirolimus. Vasc Health Risk Manag. 2024;20:251-254. doi:10.2147/VHRM.S461505

Off-Label Topical Application of Sirolimus (Rapamycin) for Dermatological Conditions

Abstract

Keywords

Introduction

Materials and Methods

Results

Bullous Diseases

Epidermolysis bullosa simplex

Pemphigus vulgaris

Genodermatoses

Familial multiple discoid fibromas, fibrofolliculomas, and Birt-Hogg-Dubé syndrome

Pachyonychia congenita

Trichilemmomas, mucocutaneous hamartomas (Cowden syndrome)

Trichoepitheliomas (multiple familial trichoepitheliomas)/trichoepithelioma papulosum multiplex

Histiocytoses

Benign cephalic histiocytosis

Cutaneous Rosai-Dorfman disease

Inflammatory Dermatoses

Chronic plaque psoriasis

Erosive lichen planus (oral)

Keratosis pilaris rubra

Rosacea

Non-Vascular Neoplasms

Basal cell carcinoma

Epidermal nevus

Extramammary Paget’s disease

Nevus sebaceous

Squamous cell carcinoma

Other Dermatologic Conditions

Acanthosis nigricans

Aging skin

Confluent and reticulated papillomatosis

Lymphedematous verrucous changes of the genital skin

Ulerythema ophryogenes

Vascular Anomalies

Acral pseudolymphomatous angiokeratoma of children

Angiokeratomas

Benign lymphangiomatous papules

Kaposi sarcoma

Post-laser vascular lesions (pulsed dye laser-induced angiogenesis)

Superficial kaposiform hemangioendothelioma

Topical formulation and adverse effects

Discussion

Conclusion

Limitations

Footnotes

Author Contributions

Data Availability Statement

Declaration of Conflicting Interests

Funding

Ethical Considerations

ORCID iD

References