Topical Calcineurin Inhibitors in Rosacea: Potential Benefit in Selected Clinical Settings and Risk of Rosaceiform Dermatitis

Abstract

Rosacea is a chronic inflammatory skin disorder characterized by persistent erythema, flushing, papules, pustules, and telangiectasia, predominantly affecting the central face. Topical calcineurin inhibitors (TCIs), including tacrolimus and pimecrolimus, are approved for atopic dermatitis(AD) but have also been used off-label in rosacea and other facial inflammatory dermatoses. Evidence for their use in rosacea is limited and mixed. Some small uncontrolled studies have reported clinical improvement, particularly with pimecrolimus. In contrast, rosaceiform dermatitis has been reported during treatment with both tacrolimus and pimecrolimus, including cases with increased Demodex density. These reports highlight the need to distinguish primary rosacea from steroid-induced rosacea-like dermatitis(SIRD) and other rosaceiform eruptions associated with topical therapies. Tacrolimus and pimecrolimus have also been studied in different clinical settings, and the available evidence does not support treating them as interchangeable. Current guidelines and consensus statements provide no consistent recommendation for TCI use in primary rosacea. This review summarizes the clinical evidence for the potential benefits and adverse effects of TCIs in rosacea and discusses their possible role in selected clinical settings.

Graphical Abstract

Introduction

Rosacea is a chronic inflammatory facial disorder with heterogeneous clinical manifestations. Current approaches favor a phenotype-based assessment rather than the historical subtype classification. However, terms such as erythematotelangiectatic rosacea (ETR) and papulopustular rosacea (PPR) are retained in this review when they reflect the terminology used in the original studies.¹

TCI use in rosacea remains off-label, and the available clinical evidence is limited.² Several conditions that may appear similar clinically should nevertheless be distinguished. Primary rosacea refers to the chronic inflammatory facial disorder itself, whereas SIRD describes a rosacea-like eruption associated with topical corticosteroid use.³ Rosaceiform dermatitis occurring during TCI treatment represents another clinical setting and should not automatically be considered newly developed primary rosacea. Topical corticosteroids may also worsen pre-existing rosacea, which is different from SIRD.

This distinction is relevant when interpreting reports of improvement after corticosteroids are replaced by TCIs. In patients with SIRD or other steroid-associated facial eruptions, improvement may result, from withdrawal of the corticosteroid rather than from a specific effect of TCI.^4–6 Similarly, a rosaceiform eruption that develops during TCI treatment may represent a drug-associated reaction rather than new-onset primary rosacea.^3,7–11 These possibilities need to be considered when the clinical history and treatment response are assessed.

Studies of TCIs in rosacea have involved different patient populations, clinical conditions and study designs. These make the available findings difficult to compare directly. In this narrative review, we summarize the clinical studies, case reports, expert consensus statements and guidelines on tacrolimus and pimecrolimus, focusing on both their reported clinical benefits and the occurrence of rosaceiform dermatitis. Particular attention is given to the distinction between primary rosacea, steroid-associated eruptions and TCI-associated rosaceiform dermatitis.

Literature Identification

This narrative review was based on a literature search of PubMed and manual screening of reference lists from relevant reviews, guidelines and consensus statements. The search covered publications available through August 2026. The main search terms included “rosacea”, “tacrolimus”, “pimecrolimus”, “topical calcineurin inhibitor”, “rosaceiform dermatitis”, “steroid-induced rosacea” and “Demodex” used alone or in combination. Clinical studies, case reports, case series, guidelines and expert consensus statements relevant to the use of tacrolimus or pimecrolimus in rosacea and rosaceiform dermatitis were considered.

Clinical Evidence

Pimecrolimus

Pimecrolimus in Rosacea and SIRD

Early clinical evidence suggested that pimecrolimus may improve some features of rosacea. Crawford et al¹² evaluated 12 patients with ETR or PPR who had failed conventional treatment. Patients applied pimecrolimus 1% cream twice daily for 12–18 weeks. Ten of the 12 patients showed marked improvement in erythema. Among the six patients with PPR, five had an ≥80% reduction in lesion counts, including one patient with complete clearance. Although these findings suggested a potential clinical benefit, the study was small, uncontrolled, and limited to patients with recalcitrant disease. Therefore, the results do not establish the efficacy of pimecrolimus for primary rosacea.

Kim et al¹³ evaluated pimecrolimus 1% cream twice daily for 4 weeks in 30 patients with PPR and ETR. Among the 26 patients who completed treatment, both clinical scores and objectively measured erythema improved significantly. However, among the 18 patients available for long-term follow-up, 15 (83.3%) experienced recurrence at a mean of 10.4 months after treatment discontinuation. The frequent recurrence suggests that the improvement may not persist after treatment is stopped.

Pimecrolimus has also been studied in steroid-associated facial dermatoses, particularly SIRD. Chu et al⁵ reported improvement in erythema after 6 weeks of twice-daily pimecrolimus 1% cream in 40 patients with SIRD; localized burning, stinging, or pruritus occurred in 17.5% of patients. Lee et al⁶ conducted an investigator-blind, split-face study in 18 patients with SIRD, of whom 15 completed the 8-week study. Erythema, papules, papules or pustules, affected area and patient-reported symptoms improved during treatment, and adverse effects were generally mild and transient.

These studies suggest that pimecrolimus may improve SIRD. However, improvement in SIRD may also follow withdrawal of the offending corticosteroid. These findings therefore cannot be used as direct evidence that pimecrolimus is effective for primary rosacea.

Controlled Studies of Pimecrolimus in PPR

Two controlled studies have evaluated pimecrolimus in patients with PPR.

Weissenbacher et al¹⁴ conducted a randomized, vehicle-controlled, double-blind trial in 40 patients with PPR, with 20 patients assigned to pimecrolimus 1% cream and 20 to vehicle. After 4 weeks of treatment, no significant between-group differences were found in rosacea severity scores, subjective severity assessments or quality-of-life measures.

Karabulut et al⁷ conducted a randomized, single-blind, placebo-controlled, split-face study in 25 patients with PPR, of whom 24 completed the study. Pimecrolimus 1% cream was applied to one hemiface and vehicle cream to the other twice daily for 4 weeks, followed by a 2-week follow-up. At week 2, erythema and total rosacea severity scores improved significantly on the pimecrolimus-treated side. By week 4, however, most between-side differences were no longer significant. The authors concluded that pimecrolimus was not superior to placebo overall, although erythema appeared to improve earlier with pimecrolimus.

Overall, these controlled studies did not show a clear benefit of pimecrolimus over vehicle or placebo in PPR. Although an early improvement in erythema was observed in the study by Karabulut et al,⁷ the overall findings do not support pimecrolimus as a routine treatment for PPR.

Pimecrolimus-Associated Rosaceiform Dermatitis

Rosaceiform dermatitis has been reported during pimecrolimus treatment. Lübbe et al⁸ described a 43-year-old patient with facial AD who developed rosaceiform dermatitis after treatment with pimecrolimus 1% cream. Numerous follicular Demodex mites were identified and the eruption improved after treatment with oral doxycycline.

Yoon et al¹⁰ reported a patient with seborrheic dermatitis(SD) who developed rosacea-like demodicidosis during treatment with pimecrolimus 1% cream. Histopathological examination showed numerous follicular Demodex mites, and the eruption improved after pimecrolimus was discontinued and oral minocycline was given.

Both cases showed numerous Demodex mites on examination.

Tacrolimus

Tacrolimus in Rosacea and SIRD

Evidence for tacrolimus in rosacea is limited. Garg et al⁴ reported improvement in facial erythema and pruritus after 6 weeks of twice-daily treatment with 0.1% tacrolimus ointment in eight patients with rosacea and two with SIRD.

No randomized controlled trial has specifically evaluated tacrolimus for rosacea or SIRD.

Tacrolimus-Associated Rosaceiform Dermatitis

Antille et al⁹ described six patients who developed rosaceiform dermatitis during treatment with topical tacrolimus for facial inflammatory dermatoses. Four patients had pre-existing facial inflammatory diseases, including rosacea or SD, while the other two had contact dermatitis or AD. Some patients developed worsening papules and pustules within 2–3 weeks, whereas others developed telangiectasia and papules after several months of treatment. The eruptions improved after tacrolimus was discontinued, with anti-Demodex treatment or oral tetracycline antibiotics used in some patients.

Fujiwara et al¹¹ reported three patients who developed similar rosaceiform changes during treatment with topical tacrolimus. The eruptions improved after tacrolimus was discontinued and oral minocycline or roxithromycin was given.

Teraki et al¹⁵ retrospectively reviewed 44 patients with rosacea-like dermatitis, including 16 cases associated with tacrolimus exposure: eight after topical tacrolimus alone and eight after sequential treatment with topical corticosteroids followed by tacrolimus.

Comparison of the Clinical Evidence for Pimecrolimus and Tacrolimus

Pimecrolimus has been studied in more clinical settings than tacrolimus, including primary rosacea and SIRD, with both observational studies and randomized controlled trials.^{5–8,10,12–14} Evidence for tacrolimus in rosacea is more limited, while several case reports and case series have described rosaceiform dermatitis during treatment with topical tacrolimus.^9,11,15 The two agents have not been directly compared. The clinical findings are summarized in Table 1.

Table 1.

Clinical Evidence for Tacrolimus and Pimecrolimus in Rosacea and Rosaceiform Dermatitis

Study Reference	Treatment	Patient Count	Duration
Studies reporting clinical benefit
Garg et al4	0.1% tacrolimus ointment	10 patients: 8 rosacea, 2 SIRD	6 weeks
Crawford et al12	1% pimecrolimus cream	12 patients with ETR or PPR	12–18 weeks
Kim et al13	1% pimecrolimus cream	30 enrolled; 26 completed, PPR/ETR	4 weeks
Chu et al5	1% pimecrolimus cream	40 SIRD	6 weeks
Lee et al6	1% pimecrolimus cream	18 enrolled; 15 completed, SIRD	6–8 weeks
Controlled studies showing no clear benefit
Weissenbacher et al14	1% pimecrolimus cream	40 PPR (20/20)	4 weeks
Karabulut et al7	1% pimecrolimus cream	25 PPR enrolled; 24 completed	4 weeks
Reports of TCI-associated rosaceiform dermatitis
Lübbe et al8	1% pimecrolimus cream	1 facial AD	1 week
Antille et al9	0.1% tacrolimus ointment/0.03% tacrolimus ointment	6 patients with facial inflammatory dermatoses	10 days–5 months
Yoon et al10	1% pimecrolimus cream	1 SD	3 months
Fujiwara et al11	0.1% tacrolimus ointment/0.03%tacrolimus ointment	1 perioral erythema	14 months
		1 AD	4 months
		1 rosacea	2 months
Teraki et al15	Topical tacrolimus/topical steroid use	16 tacrolimus-associated rosacea-like dermatitis cases: 8 after tacrolimus alone and 8 after sequential corticosteroid/tacrolimus treatment	Variable

Abbreviations: ETR, erythematotelangiectatic rosacea; PPR, papulopustular rosacea; SIRD, steroid-induced rosacea-like dermatitis; AD, atopic dermatitis; SD, seborrheic dermatitis.

Guidelines and Consensus Statements

Earlier guidelines and consensus statements included TCIs among the treatment options for selected patients with rosacea. The German Rosacea – S1 Guideline described topical tacrolimus 0.03% or 0.1% ointment and pimecrolimus 1% cream as effective for steroid-induced rosacea. It also noted that tacrolimus could reduce erythema in papulopustular rosacea (PPR), although it did not improve papulopustular lesions.¹⁶ The Chinese Rosacea Diagnosis and Treatment Expert Consensus (2016) recommended TCIs for rosacea aggravated by topical corticosteroids or accompanied by pruritus. It advised stopping treatment once pruritus improved and generally limiting treatment to no more than 2 weeks.¹⁷

The 2017 Swiss S1 guideline made a distinction between the two TCIs and between rosacea subtypes. Tacrolimus could be considered for subtype I rosacea (ETR) but was not recommended for subtype II rosacea (PPR). Pimecrolimus could be considered for subtype II rosacea, and could also be considered in therapy-resistant subtype I disease, although direct evidence for ETR was limited. The guideline also cited case reports describing possible benefit of pimecrolimus in granulomatous rosacea.¹⁸

Several later guidelines and consensus statements did not specifically address topical TCIs. These included the Canadian Clinical Practice Guidelines for Rosacea (2016),¹⁹ the ROSCO recommendations published in 2017²⁰ and updated in 2019,²¹ the Rosacea Treatment Guideline for the Netherlands (2020),²² and the Guidelines for the Diagnosis and Treatment of Rosacea in China (2021 Edition).²³

The 2022 German S2k guideline concluded that the available evidence was not sufficient to either recommend or reject the use of calcineurin inhibitors for rosacea.²⁴ The recently published Japan Rosacea Consensus (2026) discussed the differential diagnosis of rosacea and rosacea-like dermatitis in greater detail.³ It noted that topical glucocorticoids, tacrolimus and other drugs may trigger rosacea-like symptoms. When such an exposure is present, the suspected drug should be discontinued and the clinical course followed. Patients whose symptoms resolve after withdrawal may be classified as having steroid-induced rosacea-like dermatitis, whereas persistent or recurrent symptoms after withdrawal may raise the possibility of underlying or previously unrecognized rosacea. Although the consensus retains the term “steroid-induced rosacea-like dermatitis”, its framework for differential diagnosis and classification also encompasses similar rosaceiform eruptions caused by other agents, including tacrolimus.

The recommendations are summarized in Table 2. Overall, some earlier documents allowed the use of TCIs in selected patients with rosacea, although with certain cautions. In more recent recommendations, TCIs are often not specifically addressed, or the available evidence is considered insufficient to make a clear recommendation.

Table 2.

Guideline and Consensus Statements for Tacrolimus and Pimecrolimus in Rosacea and Rosaceiform Dermatitis

Consensus/Guideline	Relevant Statement
May be considered in selected clinical settings
Rosacea - S1 guideline (2013)16	Tacrolimus 0.03%/0.1% and pimecrolimus 1% may be used for steroid-induced rosacea; tacrolimus may improve erythema in PPR.
Swiss S1 guideline for the treatment of rosacea (2017)18	Tacrolimus may be considered for ETR but is not recommended for PPR; pimecrolimus may be considered for PPR and selected therapy-resistant ETR.
Diagnosis and treatment of rosacea in China: an expert consensus statement (2016)17	TCIs may be used for steroid-aggravated rosacea or rosacea with pruritus; usually for ≤2 weeks.
Not specifically addressed
Canadian Clinical Practice Guidelines for Rosacea (2016)19	N/A
Rosacea treatment update: recommendations from the global ROSacea COnsensus (ROSCO) panel (2017)20	N/A
Recommendations for rosacea diagnosis, classification and management: update from the global ROSacea COnsensus 2019 panel21	N/A
Rosacea treatment guideline for the Netherlands (2020)22	N/A
Guidelines for the Diagnosis and Treatment of Rosacea in China (2021 Edition)23	N/A
Insufficient evidence to recommend or reject
S2k guideline: Rosacea (2022)24	Evidence insufficient to recommend or reject calcineurin inhibitors.
Potential risk/diagnostic caution
Japan Rosacea Consensus (2026)3	Tacrolimus and topical corticosteroids may trigger or worsen rosacea-like symptoms; clinical course after withdrawal should be assessed.

Abbreviations: TCI, topical calcineurin inhibitor; ETR, erythematotelangiectatic rosacea; PPR, papulopustular rosacea; N/A, not available.

Discussion

Based on the available clinical studies, case reports and guideline recommendations, the role of TCIs in rosacea remains uncertain. Pimecrolimus has been studied more extensively than tacrolimus, but controlled studies have not shown a consistent benefit in primary rosacea, whereas rosaceiform dermatitis has been reported during treatment with both agents. The available evidence does not support their routine use for primary rosacea.

Rosacea is a multifactorial inflammatory disorder involving innate immune activation, neurovascular dysregulation, and changes in the skin microbiome.²⁵ Increased Toll-like receptor 2 expression and aberrant cathelicidin expression and processing have been demonstrated in rosacea.^26,27 Histopathologic studies have also shown increased macrophage and mast cell infiltration across rosacea subtypes, with neutrophils particularly prominent in papulopustular rosacea.²⁸

Demodex mites are also found more frequently and at higher densities in patients with rosacea.²⁹ Experimental studies suggest that mite-associated bacterial antigens may stimulate inflammatory responses, although the exact contribution of Demodex to rosacea remains uncertain.³⁰

Adaptive immunity also appears to contribute to rosacea. Although innate immune abnormalities are prominent, changes in T cell populations and Th1/Th17 related pathways have been reported in rosacea, with evidence of Th1/Th17 polarized T cell responses in lesional skin.^25,28 B cells have also been identified in rosacea lesions, although their role remains less well defined.²⁸

Tacrolimus binds FKBP-12 and inhibits calcineurin-dependent signaling, thereby suppressing T-cell activation and cytokine production.^31,32 It can also affect the function of epidermal Langerhans cells and other inflammatory cells.³³ Pimecrolimus acts through a similar calcineurin-dependent pathway and inhibits inflammatory cytokine production by T cells and mast cells.^34,35 These pharmacologic effects may help explain the improvement reported with TCIs in some inflammatory facial dermatoses, but they do not provide direct evidence of efficacy in primary rosacea.

The relationship between TCI treatment and Demodex remains unclear. Increased numbers of follicular Demodex mites were reported in some patients who developed rosaceiform dermatitis during pimecrolimus or tacrolimus treatment.^7,9 However, these observations are based mainly on individual case reports, and there is no clinical evidence that long-term TCI treatment directly causes Demodex overgrowth. Demodex-associated inflammation may therefore be relevant in some patients, but a causal link between TCI use and Demodex proliferation has not been established.

Tacrolimus may also affect cutaneous sensory nerve responses. In an in vitro model, tacrolimus initially increased substance P release but subsequently reduced capsaicin-induced substance P release.³⁶ Facial flushing, particularly after alcohol consumption, has also been reported during topical tacrolimus treatment.³⁷

Overall, the mechanisms underlying the relationship between TCIs and rosacea remain unclear. The pharmacologic effects of TCIs may help explain some of their clinical effects and adverse reactions, but current evidence does not establish that TCI treatment promotes Demodex overgrowth or worsens primary rosacea. In selected settings, particularly steroid-associated facial dermatoses, TCIs may still have a role. Improvement in these patients may partly reflect withdrawal of the offending corticosteroid rather than a specific effect of the TCI.^4–6 These situations should be considered separately from the use of TCIs in primary rosacea.

Conclusion

In summary, the role of TCIs in rosacea remains uncertain. Current evidence does not support their routine use for primary rosacea, although they may have a role in selected cases of steroid-associated facial inflammation. The mechanisms underlying TCI-associated rosaceiform dermatitis remain to be clarified.

Funding Statement

This work was supported by the Special Research Program in Dermatology, Dermatology and Cosmetic Dermatology Branch, China Association of Medical Equipment (Grant No.20260101).

Abbreviations

AD, atopic dermatitis; ETR, erythematotelangiectatic rosacea; GR, granulomatous rosacea; PPR, papulopustular rosacea; ROSCO, ROSacea Consensus; SIRD, steroid-induced rosacea-like dermatitis; TCI, topical calcineurin inhibitor.

Data Sharing Statement

No datasets were generated or analyzed during the current study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.