Therapy outcomes of IL-17 and JAK inhibitors in rosacea: A systematic review

Dear Editor,

Rosacea is characterized by persistent or transient erythema, papules, pustules, telangiectasia and/or phymatous lesions^[1]. Although multiple treatments are available for rosacea, the advent of biological agents and small-molecule agents has significantly advanced our ability to target the disease more effectively^[2]. In the current review, we summarize the outcomes of targeted therapies in rosacea, mainly represented by interleukin (IL)-17 inhibitors and Janus kinase (JAK) inhibitors.

We performed a Pubmed search on March 9, 2024, identifying 168 studies (Supplementary Table 1, available online), of which 11 met the inclusion criteria, representing 72 patients with different targeted therapies. Of these patients, 43 received targeted therapy with IL-17 inhibitors (n = 17, 39.5%) or JAK inhibitors (n = 26, 60.5%), of which eight (18.6%) received concomitant medications (Table 1 and Supplementary Table 2 [available online]). The remaining 29 patients received a number of other targeted medications. Due to the small sample size of other medications, we mainly analyzed the IL-17 inhibitors therapy and JAK inhibitors therapy outcomes in patients with rosacea.

Table  1.  Summary of IL-17 and JAK inhibitors therapy outcomes in rosacea patients

Characteristics	IL-17 inhibitors therapy (n = 17)	JAK inhibitors therapy (n = 26)
Agent [n (%)]	Secukinumab, 17 (100.0)	Tofacitinib, 22 (84.6); Abrocitinib, 4 (15.4)
Therapy outcomes [n (%)]	Partial resolution, 17 (100.0)	CR, 3 (11.5); PR, 17 (65.4); no resolution, 6 (23.1)
Mean response time (months)	4.0	CR, 0.4; PR, 1.0
Recurrence [n (%)]	Not reported	Yes, 7 (35.0); no, 13 (65.0)
Mean follow-up period (months)	4.0	7.0
Adverse events [n (%)]	Hearing impaired, 1 (5.9); diarrhea, 3 (17.6); sinus disorder, 1 (5.9); vomiting, 1 (5.9); fatigue, 3 (17.6); injection site reaction, 1 (5.9); flu like symptoma, 1 (5.9); otitis externa, 1 (5.9); sinusitis, 1 (5.9); skin or nail infection, 4 (23.5); urinary tract infection, 1 (5.9); gastrointestinal infection, 1 (5.9); arthralgia, 1 (5.9); none, 6 (35.3); upper respiratory infection, 1 (5.9); sinus pain, 1 (5.9); sore throat, 2 (11.8); cough, 1 (5.9); dysuria, 1 (5.9); pruritus, 3 (17.6); allergic rhinitis, 1 (5.9); rash (eczema), 2 (11.8)	Not reported, 19 (73.1); none, 5 (19.2); elevated liver enzymes: 1 (3.8); elevated serum bilirubin: 1 (3.8)
Abbreviations: IL-17, interleukin-17; JAK, Janus kinase; CR, complete resolution; PR, partial resolution.

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IL-17 inhibitors showed the highest efficacy with partial resolution (PR) in 17 cases (100.0%). JAK inhibitors followed with complete resolution (CR) in three cases (11.5%) within 0.4 months, PR in 17 cases (65.4%) within 1.0 months, and no resolution in six cases (23.1%) (Table 1 and Supplementary Table 3 [available online]). There was no heterogeneity between concomitant medications and no concomitant medications.

The pathology of rosacea is linked to immune dysfunction dominated by the Th1/Th17-polarized immune cells^[1–2] . These T cells express elevated levels of IFN-γ, tumor necrosis factor-alpha (TNF-α), and IL-17A that associated with inflammation, angiogenesis, and the induction of matrix metalloproteinase-9 (MMP-9) and cathelicidin antimicrobial peptide LL37^[1–2]. Therefore, the inhibition of IL-17 and TNF-α showed some favorable outcomes. The importance of JAK-signal transducer and activator of transcription (STAT) signaling in the pathogenesis of rosacea is related to its effects on skin barrier and immune cell activation^[3], and the inhibitors of these pathways may play a role in a valid therapy for rosacea, given the upregulation of STAT transcription factors. There are also some individual and small-sample targeted medications in our search results, such as phosphodiesterase inhibitors that may reduce the production of TNF-α, IL-12 and IL-23 and the response of natural killer cells and keratinocytes^[4], anti-vascular endothelial growth factor agents that have an inhibitory effect on vascular maturation^[2,5], and calcitonin gene related peptide (CGRP) inhibition that may improve treatment outcomes in rosacea patients with migraine according to this analysis (Supplementary Table 4, available online).

Limitations include the small sample size, the lack of a unified evaluation system for rosacea resolution, and the difficulty in isolating the effects of targeted therapies due to concomitant treatment. Although additional larger studies are needed, the occurrence of adverse events also merits attention. Targeted therapies, especially IL-17 inhibitors and JAK inhibitors, may become an effective adjunctive treatment for rosacea.

Yours sincerely,Xinyi Dai^△, Chenxingyue Zhang^△, Zhiqiang Yin^✉△These authors contributed equally to this work.Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.^✉Corresponding author: Zhiqiang Yin, E-mail: yinzhiqiang@njmu.edu.cn.