Drug-Induced Rosacea: A Systematic Review

To the Editor,

Rosacea is a common, chronic inflammatory skin condition characterized by a heterogenous mix of features including erythema, papules, pustules, phymatous changes, telangiectasias, and ocular manifestations. ¹ Onset of rosacea thought to be triggered by systemic or topical drug therapy have been documented, ² but summary evidence is lacking. We performed a systematic review to collate characteristics of reported cases of drug-induced rosacea.

Following PROSPERO registration (CRD42023483165), a search was conducted under the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using MEDLINE and EMBASE with the following keywords and variations: “rosacea,” “induce,” and “trigger.” The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence tool was used to assess quality of evidence. A total of 65 studies (publication date: 1986-2023) with 2205 participants were included (Supplemental Figure S1; Supplemental Files 1 and 2: https://data.mendeley.com/datasets/gvgg7724kk/1).

The median age of participants included was 55 years [interquartile range (IQR): 33 years], comprising of 784 females (35.5%) and 1401 males (64.5%). Triggering medications included topical and systemic corticosteroids (89.2%), immunosuppressive agents (1.5%; azathioprine, n = 1; pimecrolimus, n = 5; tacrolimus, n = 26), and biologic therapies (0.3%; cetuximab, n = 2; dupilumab, n = 2; ipilimumab, n = 1; nivolumab, n = 2). Drug-induced rosacea subtypes were documented in 6.3% (n = 140) of cases, from corticosteroid (n = 131; erythematotelangiectactic: 60.3%; papulopustular: 38.9%; periocular: 0.8%), tacrolimus (n = 5; papulopustular: 33.3%; granulomatous: 66.7%), pimecrolimus (n = 1; papulopustular: 100%), ipilimumab/nivolumab (n = 2; erythematotelangiectactic: 50%; papulopustular: 50%), and dupilumab (n = 1; papulopustular: 100%) therapy.

The median latency period to rosacea onset following drug therapy initiation was 1.4 months (IQR: 4.3 months). Mean documented latency period in patients receiving corticosteroid, immunosuppressive, and biologic therapy was 3.2 ± 2.7 months (systemic: 2.5 ± 0.7; topical: 3.9 ± 4.2), 2.9 ± 4.2 months (pimecrolimus: 12 ± 0; tacrolimus: 0.7 ± 0.5), and 3.2 ± 2.9 months (cetuximab: 0.75 ± 0; dupilumab: 6 ± 0; ipilimumab: 5 ± 0), respectively. Resolution of rosacea was reported in 25% of cases and categorized as complete (CR) or partial (PR) resolution. CR was documented in 56.3% (n = 311) of patients most commonly following treatment with erythromycin or clindamycin (n = 108), topical vitamin K (n = 32), doxycycline (n = 10), and ceasing of the offending agent (n = 5). PR was reported in 43.7% (n = 241) of patients most commonly following pimecrolimus therapy (n = 59), metronidazole (n = 50), topical vitamin K (n = 44), and doxycycline (n = 42). No cases documented PR following withdrawal of the offending agent alone (Supplemental Table S1: https://data.mendeley.com/datasets/gvgg7724kk/1).

Topical and systemic corticosteroids were the most common medications preceding rosacea in this review (n = 1966). Nonsteroidal immunosuppressive therapy, particularly tacrolimus and pimecrolimus, were the second most common medications preceding rosacea cases (n = 32). Steroid-induced rosacea has been implicated in rosacea pathogenesis. Most proposed mechanisms postulate that chronic intermittent steroid exposure leads to proinflammatory cytokine release and subsequent rebound vasodilation, inducing the characteristic erythema and flushing in rosacea, particularly erythematotelangiectatic rosacea. ³ It has been also proposed that immunosuppressive therapies in general may induce or exacerbate papulopustular features of rosacea in patients, as observed in our review, potentially due to overgrowth of bacteria and Demodex folliculorum mites.^4,5

These summary data suggest the involvement of immunosuppressants as plausible agents in drug-induced rosacea. Many rosacea cases resolved without discontinuation of the triggering agent. Limitations included the observational nature of the studies and lack of documented follow-up. Further studies of larger scale are needed to confirm these findings.

Supplemental Material

sj-docx-1-cms-10.1177_12034754241265719 – Supplemental material for Drug-Induced Rosacea: A Systematic Review

Supplemental material, sj-docx-1-cms-10.1177_12034754241265719 for Drug-Induced Rosacea: A Systematic Review by Hibo Rijal, Ryan Geng, Bethany Wilken, Jacqueline Slomovic and Cathryn Sibbald in Journal of Cutaneous Medicine and Surgery

Supplemental Material

sj-docx-2-cms-10.1177_12034754241265719 – Supplemental material for Drug-Induced Rosacea: A Systematic Review

Supplemental material, sj-docx-2-cms-10.1177_12034754241265719 for Drug-Induced Rosacea: A Systematic Review by Hibo Rijal, Ryan Geng, Bethany Wilken, Jacqueline Slomovic and Cathryn Sibbald in Journal of Cutaneous Medicine and Surgery

Supplemental Material

sj-docx-3-cms-10.1177_12034754241265719 – Supplemental material for Drug-Induced Rosacea: A Systematic Review

Supplemental material, sj-docx-3-cms-10.1177_12034754241265719 for Drug-Induced Rosacea: A Systematic Review by Hibo Rijal, Ryan Geng, Bethany Wilken, Jacqueline Slomovic and Cathryn Sibbald in Journal of Cutaneous Medicine and Surgery

Supplemental Material

sj-docx-4-cms-10.1177_12034754241265719 – Supplemental material for Drug-Induced Rosacea: A Systematic Review

Supplemental material, sj-docx-4-cms-10.1177_12034754241265719 for Drug-Induced Rosacea: A Systematic Review by Hibo Rijal, Ryan Geng, Bethany Wilken, Jacqueline Slomovic and Cathryn Sibbald in Journal of Cutaneous Medicine and Surgery