Sage Journals: Discover world-class research

Abstract

Rosacea is a chronic inflammatory skin condition that affects over 5% of individuals worldwide. Its clinical presentation is characterized by an array of features, including erythema, papules and pustules, phymatous changes, telangiectasia, and ocular manifestations. Specifically, the multifaceted manifestation of erythema varies widely in intensity and distribution. Factors contributing to pathogenesis include neurovascular dysregulation, increased levels of pro-inflammatory mediators, and aberrant vasodilation. Erythema management plays an important role in reducing the psychosocial burden associated with rosacea and improving overall quality of life. Cochrane CENTRAL, Medline, and Embase databases were searched from inception to September 2023 and included 33 clinical trials reporting on a total of 7411 rosacea patients (74.1% female) and 21 different topical or systemic treatments. The mean age was 48.8 years (range, 18-83 years), and the mean time to outcome assessment was 8.1 weeks (standard deviation, 4.1 weeks). Treatment efficacy was assessed by outcome measures including percent improvement from baseline on 4- and 5-point scales, clinician erythema assessment (CEA) success (improvement ≥1 point), and CEA and patient self-assessment success (improvement ≥1 point). Pooled effect sizes for each treatment were calculated as a weighted average based on the number of patients in each study. The most effective topical treatments for reducing erythema include sodium sulphacetamide and sulphur, praziquantel, metronidazole, and B244 spray (Nitrosomonas eutropha). The most effective systemic treatment was paroxetine. Our findings highlight the varying efficacy of treatments in addressing the erythema in rosacea, recognizing the nuances of clinical presentations.

Keywords

rosacea erythema treatment

Introduction

Rosacea is a common chronic inflammatory skin condition that affects more than 5% of the global population.^1,2 It is characterized by major features including facial flushing, persistent erythema, papules, pustules, telangiectasia, and phymatous changes.^1,3 In addition to the cutaneous features, ocular manifestations may also arise in up to 58% of patients.¹ It is important to note that the clinical presentation of rosacea is heterogeneous, where patients may present with different combinations of clinical features.

The erythema associated with rosacea in particular represents a complex clinical challenge and likely has a multifactorial etiology. Contributing factors include neurovascular dysregulation, increased levels of pro-inflammatory mediators, and aberrant vasodilation.^1,4
-6 The presence of persistent erythema in the central facial region may have a marked impact on the patient’s body image, resulting in psychological distress and comorbidities.⁷ Many patients experience heightened self-consciousness and diminished self-esteem due to their visible facial symptoms, which can result in social anxiety, withdrawal from social interactions, and an overall decreased quality of life.^7,8 The psychosocial impact of erythema underscores the importance of effective treatment and support for patients with rosacea.

A variety of therapies are currently available for treating rosacea, including topical, oral, and light-based modalities.⁹ The light-based therapies in rosacea are designed to target erythema (e.g., Pulsed dye laser, intense pulsed light), but these treatments are expensive, not covered by insurance, and yield temporary results. In addition, patients requiring access to clinics equipped with these treatment modalities typically need several sessions to achieve satisfactory clinical effect.¹⁰ Pharmaceutical treatment options are generally more accessible and have the additional benefit of being effective in reducing inflammatory lesions, a common feature observed in rosacea.¹¹ With consideration of the psychosocial distress rosacea patients experience, the objective of this systematic review is to determine the efficacy of topical and systemic treatments for reducing erythema in rosacea.

Methods

Literature Search

The literature search for this systematic review (PROSPERO CRD42023463880) was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.¹² Medline and Embase were searched using the following term combinations: rosacea and erythema, resulting in a total of 692 articles. The databases were searched from inception to September 2023, with no exclusions on language and patient demographics. The removal of 306 duplicates resulted in a total of 415 articles for screening. A PRISMA flow diagram is provided (Supplemental Figure 1). Full search strategies are provided in the supplemental material.

Inclusion and Exclusion Criteria

All published articles reporting on the change in erythema in rosacea patients after treatment with any topical or systemic pharmaceutical treatment within a 4- to 16-week timepoint were included. Animal studies and articles that do not provide quantitative data on the change in erythema post-treatment were excluded.

Data Extraction and Analysis

Articles were screened based on titles and abstract content, followed by full-text screening to determine final eligibility. Data extraction was performed by NJH and JC individually, with disagreements mediated by a third author. Treatment efficacy was assessed by outcome measures including percent improvement from baseline on 4- and 5-point scales, clinician erythema assessment (CEA) success (improvement ≥1 point), and CEA and patient self-assessment (PSA) success (improvement ≥1 point). Pooled effect sizes for each treatment were calculated as a weighted average based on the number of patients in each study. The National Institute of Health quality assessment tool was used to assess methodological quality, which provides quality ratings of “good,” “fair,” or “poor.” Only reports with a “good” rating were included.

Results

A total of 415 unique articles were identified with the outlined search strategy (Supplemental Figure 1). Of the 33 articles included, all were Randomized Control Trials (RCTs) with the exception of 1 uncontrolled trial, reporting on 7411 rosacea patients (74.1% female) and 21 different topical or systemic treatments (Supplementary Table 1). Supplemental tables summarizing the efficacy of treatments in reducing erythema are provided (Supplemental Tables 1–4). Diagrams ranking the treatments by percent post-treatment erythema improvement are also provided (Figures 1 -4).

Figure 1.

Efficacy of treatment regimens in improving erythema when measured on a 4-point scale in rosacea patients. The mean percent improvement in erythema score is represented by the bullet for each treatment. Bars represent standard deviations. SS, sodium sulphacetamide.

Figure 2.

Efficacy of treatment regimens in improving erythema when measured on a 5-point scale in rosacea patients. The mean percent improvement in erythema score is represented by the bullet for each treatment. Bars represent standard deviations.

Figure 3.

Efficacy of treatment regimens in improving erythema when measured in terms of CEA success (≥1 point improvement) in rosacea patients. The mean percent of patients achieving CEA success is represented by the bullet for each treatment. Bars represent standard deviations. CEA, clinician erythema assessment.

Figure 4.

Efficacy of treatment regimens in improving erythema when measured in terms of CEA and PSA success (≥1 point improvement) in rosacea patients. The mean percent of patients achieving CEA and PSA success is represented by the bullet for each treatment. Bars represent standard deviations. CEA, clinician erythema assessment; PSA, patient self-assessment.

Erythema Assessed by 4-Point Scale

4-Ethoxybenzaldehyde [20 patients]

4-Ethoxybenzaldehyde was reported by 1 study in a 1% topical formulation applied twice daily.¹³ There was a mean 43.7% improvement in the 4-point scale score among the 20 patients, representing a 0.97-fold change compared to the topical placebo.

Artemether [62 patients]

Artemether was reported by 1 study in a 1% topical formulation applied twice daily.¹⁴ There was a mean 78.4% improvement in the 4-point scale score among the 62 patients, representing a 1.73-fold change compared to the topical placebo.

Azelaic acid [130 patients]

Azelaic acid was reported by 4 studies in either 15% or 20% topical formulations applied twice daily.^15
-18 For the 2 studies reporting on the 20% formulation, there was a mean 28.5% improvement in the 4-point scale score among the 53 patients, representing a 0.63-fold change compared to the topical placebo.^15,16 For the remaining 2 studies reporting on the 15% formulation, there was a mean 60.4% improvement in the 4-point scale score among the 607 patients, representing a 1.34-fold change compared to the topical placebo.^17,18

Isotretinoin [8 patients]

Isotretinoin was reported in 1 uncontrolled trial at a dose of 10 mg once daily. There was a mean 40.0% improvement in the 4-point scale score among the 8 patients.¹⁹

Metronidazole [344 patients]

Metronidazole was reported by 8 studies in 3%, 1%, or 0.75% formulations applied twice daily.^{14,15,16,18,20
-23} For the 1 study reporting on the 3% formulation, there was a mean 74.4% improvement in erythema measured on a 4-point scale among 60 patients, representing a 1.64-fold change compared to topical placebo.¹⁴ For the 2 studies reporting on the 1% formulation, there was a mean 45.7% improvement in erythema measured on a 4-point scale among 68 patients, representing a 1.01-fold change compared to topical placebo.^15,16 For the 5 studies reporting on the 0.75% formulation, there was a mean 39.2% improvement in erythema measured on a 4-point scale among the 216 patients, representing a 0.87-fold change compared to the topical placebo.^18,20
-23

Permethrin [94 patients]

Permethrin was reported by 4 studies in either 5% or 2.5% topical formulations applied twice daily.^16,22,24,25 For the 3 studies reporting on the 5% formulation, there was a mean 47.8% improvement in the 4-point scale score among the 59 patients, representing a 1.06-fold change compared to the topical placebo.^16,22,24 For the 1 study reporting on the 2.5% formulation, there was a mean 68.9% improvement in the 4-point scale score among the 35 patients, representing a 1.52-fold change compared to the topical placebo.²⁵

Pimecrolimus [49 patients]

Pimecrolimus was reported by 2 studies in a 1% topical formulation applied twice daily.^21,26 There was a mean 47.6% improvement in the 4-point scale score among the 49 patients, representing a 1.05-fold change compared to the topical placebo.

Sodium sulphacetamide/sulphur [94 patients]

Sodium sulphacetamide 10%/sulphur 5% topical formulation applied twice daily was reported by 1 study.²⁷ There was a mean 83.0% improvement in the 4-point scale score among the 94 patients, representing a 1.84-fold change compared to the topical placebo.

Terbinafine [16 patients]

Terbinafine was reported by 1 study in a 1% topical formulation applied twice daily.²³ There was a mean 53.7% improvement in the 4-point scale score among the 16 patients, representing a 1.19-fold change compared to the topical placebo.

Tretinoin [8 patients]

Tretinoin was reported by 1 study in a 0.025% topical formulation applied once daily.¹⁹ There was a mean 26.7% improvement in the 4-point scale score among the 8 patients, representing a 0.59-fold change compared to the topical placebo.

Erythema Assessed by 5-Point Scale

CD06713 (Ondansetron) [24 patients]

CD06713 was reported by 1 study at a dose of 8 mg twice daily.²⁸ There was a mean 18.4% improvement in the 5-point scale score among the 20 patients, representing a 0.70-fold change compared to the topical placebo.

Metronidazole [105 patients]

Metronidazole was reported by 2 studies in both 1% or 0.75% formulations applied once daily or twice daily.^29,30 For the 1 study reporting on the 1% formulation, there was a mean 34.2% improvement in erythema measured on a 5-point scale among 65 patients, representing a 0.82-fold change compared to topical placebo.²⁹ For the 1 study reporting on the 0.75% formulation, there was a mean 48.2% improvement in erythema measured on a 5-point scale among the 65 patients, representing a 1.15-fold change compared to the topical placebo.³⁰

Minocycline [1009 patients]

Minocycline was reported by 1 study in a 1.5% topical formulation applied once daily.³¹ There was a mean 54.4% improvement in the 5-point scale score among the 1009 patients, representing a 1.30-fold change compared to the topical placebo.

Praziquantel [43 patients]

Praziquantel was reported by 1 study in a 3% topical formulation applied twice daily.³² There was a mean 71.9% improvement in the 5-point scale score among the 43 patients, representing a 1.72-fold change compared to the topical placebo.

Timolol [16 patients]

Timolol was reported by 1 study in a 0.5% topical formulation applied once daily.³³ There was a mean 47.6% improvement in the 5-point scale score among the 16 patients, representing a 1.14-fold change compared to the topical placebo.

Erythema Assessed by CEA Success (≥1 Point Improvement)

B244 (Nitrosomonas eutropha) [73 patients]

B244 was reported by 1 study in a 4 × 10E9 cells/ml topical formulation applied twice daily.³⁴ Of the 73 patients, 67.1% achieved CEA success, representing a 2.79-fold change compared to the topical placebo.

Brimonidine tartrate [161 patients]

Brimonidine tartrate was reported by 1 study in both 0.5% and 0.18% topical formulations applied once daily or twice daily.³⁵ There was a mean 37.7% rate of CEA success among 53 patients, representing a 1.57-fold improvement over topical placebo. The study also reported on the 0.18% formulation, noting a mean 32.4% rate of CEA success among 108 patients, representing a 1.35-fold improvement compared to the topical placebo.

Doxycycline [30 patients]

Doxycycline was reported in 1 study at a dose of 100 mg once daily.³⁶ There was a mean 16.7% rate of CEA success among 108 patients, representing a 0.80-fold change compared to systemic placebo.

Hydroxychloroquine [28 patients]

Hydroxychloroquine was reported in 1 study at a dose of 200 mg twice daily.³⁶ There was a mean 21.4% rate of CEA success among 28 patients, representing a 1.03-fold change compared to the systemic placebo.

Metronidazole [65 patients]

Metronidazole was reported in 1 study in 0.75% of formulations applied once daily or twice daily.³⁰ There was a mean 78.5% rate of CEA success among the 65 patients, representing a 3.26-fold change compared to the topical placebo.

Oxymetazoline [446 patients]

Oxymetazoline was reported in 1 study in a 1% topical formulation applied once daily.³⁷ There was a mean 27.1% rate of CEA success among 446 patients, representing a 1.13-fold change compared to the topical placebo.

Paroxetine [49 patients]

Paroxetine was reported in 1 study at a dose of 25 mg once daily.³⁶ There was a mean 42.9% rate of CEA success among 446 patients, representing a 2.06-fold change compared to the systemic placebo.

TDT 068 [37 patients]

TDT 068 was reported in 1 study in a topical formulation applied twice daily.³⁸ There was a mean 44.8% rate of CEA success among the 37 patients, representing a 1.86-fold change compared to the topical placebo.

Erythema Assessed by CEA and PSA Success (≥1 Point Improvement)

Brimonidine tartrate [489 patients]

Brimonidine tartrate was reported by 4 studies in either 0.5% or 0.18% topical formulations applied once daily or twice daily.^35,39
-41 For the 4 studies reporting on the 0.5% formulation, there was a mean 39.9% rate of CEA and PSA success among the 381 patients, representing a 2.81-fold change compared to the topical placebo.^35,39
-41 For the study additionally reporting on the 0.18% formulation, there was a mean 12.1% rate of CEA and PSA success among the 108 patients, representing a 0.85-fold change compared to the topical placebo.³⁵

Oxymetazoline [868 patients]

Oxymetazoline was reported in 3 studies in 1% topical formulations applied once daily.^42
-44 For the 3 studies reporting on the 1% formulation, there was a mean 42.5% rate of CEA and PSA success among the 868 patients, representing a 2.98-fold change compared to the topical placebo.

Discussion

The therapeutic efficacy of 21 different topical or systemic therapies for improving erythema was assessed in 33 articles, covering a total of 7415 rosacea patients. All articles included were RCTs, with the exception of 1 uncontrolled trial.

Topical treatments generally achieved greater improvements in erythema reduction measured in both 4- and 5-point scales and CEA and CEA + PSA success rates over placebo compared to systemic treatments. The only exception was paroxetine, with a 2.06-fold improvement over the systemic placebo when assessed by CEA success. It should be noted that systemic isotretinoin was only given as a low-dose regimen of 10 mg once daily.

Paroxetine achieved the highest rate of CEA success among systemic treatments. Paroxetine may reduce flushing by decreasing blood flow to the skin, thus demonstrating efficacy against the vasodilatory aspect of erythema in rosacea.^45,46 Moreover, paroxetine has been shown to inhibit the production of pro-inflammatory cytokines such as interleukin 6 (IL-6) and interleukin 1β (IL-1β), which is elevated in rosacea patients.^47,48 In addition, paroxetine may promote the production of inducible nitric oxide synthase and nitric oxide which have anti-inflammatory effects.⁴⁸ Paroxetine also regulates complex inflammatory pathways including nuclear factor kappa-light-chain-enhancer of activated B cells, inflammasomes, toll-like receptor 4, and peroxisome proliferator-activated receptor gamma.⁴⁹ These pathways are critical components of the immunological response, and their modulation can help reduce inflammation and subsequent erythema in rosacea patients.⁴⁹ Paroxetine’s more common side effects include disturbances of sleep, drowsiness, loss of appetite, sweating, and sexual side effects.⁵⁰ It also functions as an anti-depressant and may potentially interact with other medications.⁵⁰

Among the topical treatments, sodium sulphacetamide 10%/sulphur 5% and praziquantel at a 3% dosage were the most effective at improving erythema when measured on a 4-point and 5-point scale, respectively. Sodium sulphacetamide works by blocking bacterial dihydropteroate synthetase, preventing p-aminobenzoic acid from being converted to folic acid.^51,52 This mechanism inhibits the growth of various gram-negative and gram-positive organisms, including Propionibacterium acnes.⁵² Sulphur can also help reduce the production of sebum which may have pro-inflammatory effects and contribute to the development of erythema.⁵³ In addition, it demonstrates beneficial keratolytic effects by promoting dead skin cell exfoliation, assisting in the removal of surface contaminants, and leading to a smoother and more refined skin texture.⁵² Sulphacetamide-sulphur side effects typically present as dryness, erythema, itchiness, and general discomfort.⁵⁴

Praziquantel has been suggested to have immunomodulatory effects, possibly by influencing cytokine production and immune cell activity, specifically macrophages, causing an anti-inflammatory effect.^55-57

In terms of CEA success, metronidazole 0.75% and B244 (Nitrosomonas eutropha) applied as a 4 × 10E9 cells/ml topical formulation were the most effective in improving erythema. Metronidazole, also the most commonly studied topical treatment, acts by scavenging reactive oxygen species, inhibiting pro-inflammatory cytokine production, and displaying bactericidal activity against Bacillus oleronius.^58,59 This organism has been implicated in eliciting an inflammatory response in 73% of individuals with rosacea.^60,61 Ammonia and urea from sweat are converted by Nitrosomonas eutropha into nitrite, which has antibacterial qualities, and nitric oxide, which modulates inflammation and vasodilation.⁶² Topical metronidazole has common side effects such as burning, dryness, itching, and stinging.⁶³ Nitrosomonas eutropha’s most common side effects include gastrointestinal disorders, headaches, infections/infestations, and musculoskeletal and connective tissue disorders.⁶⁴

The study is subject to certain limitations, such as the heterogeneous patient population and sample sizes. It is important to note that the specific skin colour of patients was not consistently specified across included studies, and variations in baseline pigmentation may introduce a confounding factor in the accurate assessment of erythema improvement following treatment interventions. Moreover, the breadth of understanding may have been limited by limiting the scope to quantitative data on the change in erythema, which may have missed important qualitative insights or anecdotal material regarding treatment experiences. The use of different scales in assessing erythema and timing endpoints may limit the ability to compare all treatments included in this study. A consensus on the method of assessing erythema in clinical trials is required.

Conclusion

This systematic review comprehensively assessed the efficacy of various treatments in reducing erythema associated with rosacea, recognizing the imperative need for effective interventions to alleviate both the physical and psychosocial burden affecting over 5% of individuals worldwide. The findings underscore the multifaceted nature of rosacea, wherein the intricate interplay of vascular, inflammatory, and neurovascular mechanisms contributes to the development of erythema. The diverse array of treatments examined in this review, ranging from topical agents to laser therapies, has demonstrated varying degrees of success in addressing this challenging symptom. The most well-studied treatments addressing erythema in rosacea include metronidazole, azelaic acid, permethrin, oxymetazoline, and brimonidine tartrate. Sodium sulphacetamide and sulphur, praziquantel, metronidazole, and B244 (Nitrosomonas eutropha) emerge as the most effective treatments in reducing erythema associated with rosacea, showcasing their notable efficacy in targeting the underlying inflammatory and microbial factors that contribute to the condition.

Supplemental Material

sj-docx-1-cms-10.1177_12034754241287546 – Supplemental material for Efficacy of Treatments in Reducing Facial Erythema in Rosacea: A Systematic Review

Supplemental material, sj-docx-1-cms-10.1177_12034754241287546 for Efficacy of Treatments in Reducing Facial Erythema in Rosacea: A Systematic Review by Nicholas J. Hua, Jennifer Chen, Ryan S. Q. Geng, Ronald Gary Sibbald and Cathryn Sibbald in Journal of Cutaneous Medicine and Surgery

Footnotes

Acknowledgements

None.

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CS has received honoraria from Abbvie, Leo, Pfizer, Miravo, Novartis, UCB, Sanofi/Regeneron unrelated to this work. RGS has received honoraria from Perfuse, Quart Medical, Novartis, Medexus Pharmaceuticals Canada along with Ontario Gov’t (Project ECHO Ontario Skin & Wound-Ministry of Health and Micro-credentials—through Ministry of Colleges and Universities and Sault College) all unrelated to this work. NJH, JC, and RSQG have no conflicts of interest to disclose.

Funding

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

Research Ethics

An ethics statement is not applicable because this study is based exclusively on published literature.

ORCID iDs

Nicholas J. Hua

Ryan S. Q. Geng

Research Data

The data underlying this article are available in the article and its online supplementary material.

Supplemental Material

Supplemental material for this article is available online.

References

Farshchian

Daveluy

S. Rosacea

. In: StatPearls. StatPearls Publishing; 2023:1-2. http://www.ncbi.nlm.nih.gov/books/NBK557574/

Huynh

TT.

Burden of disease: the psychosocial impact of rosacea on a patient’s quality of life. Am Health Drug Benefits. 2013;6(6):348-354.

Patel

Gupta

Shetty

Preferred practice patterns and review on rosacea. Indian J Ophthalmol. 2023;71(4):1382-1390. doi:10.4103/IJO.IJO_2983_22

Del Rosso

. Advances in understanding and managing rosacea: part 1. J Clin Aesthet Dermatol. 2012;5(3):16-25.

Gerber

Buhren

Steinhoff

Homey

Rosacea: the cytokine and chemokine network. J Investig Dermatol. Symp Proc. 2011;15(1):40-47. doi:10.1038/jidsymp.2011.9

Tao

Zhang

Pan

Neurogenic rosacea could be a small fiber neuropathy. Front Pain Res. 2023;4:1122134. doi:10.3389/fpain.2023.1122134

Heisig

Reich

Psychosocial aspects of rosacea with a focus on anxiety and depression. Clin Cosmet Investig Dermatol. 2018;11:103–107. doi:10.2147/CCID.S126850

Holas

Kowalczyk

Krejtz

Wisiecka

Jankowski

The relationship between self-esteem and self-compassion in socially anxious. Curr Psychol. 2023;42(12):10271-10276. doi:10.1007/s12144-021-02305-2

Zhang

Tang

Wang

Fang

Sun

Rosacea treatment: review and update. Dermatol Ther. 2020;11(1):13–24. doi:10.1007/s13555-020-00461-0

10.

Husein-ElAhmed

Steinhoff

(2021). Laser and light-based therapies in the management of rosacea: an updated systematic review. Lasers Med Sci. 2021;36(6):1151-1160. doi:10.1007/s10103-020-03200-1

11.

Culp

Scheinfeld

Rosacea: a review. P T. 2009;34(1):38.

12.

Page

McKenzie

Bossuyt

, et al The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71

13.

Draelos

Fuller

BB.

Efficacy of 1% 4-ethoxybenzaldehyde in reducing facial erythema. Dermatol Surg. 2005;31:881-886. doi:10.1111/j.1524-4725.2005.31735

14.

Wang

G-J

Gao

X-Y

, et al Evaluation of the efficacy and tolerance of artemether emulsion for the treatment of papulopustular rosacea: a randomized pilot study. J Dermatolog Treat. 2019;30:809-812. doi:10.1080/09546634.2019.1610549

15.

Maddin

A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol. 1999;40:961-965. doi:10.1016/s0190-9622(99)70085-x

16.

Mostafa

El Harras

Gomaa

Al Mokadem

Nassar

Abdel Gawad

Comparative study of some treatment modalities of rosacea. J Eur Acad Dermatol Venereol. 2009;23:22-28. doi:10.1111/j.1468-3083.2008.02940.x

17.

Draelos

Elewski

Harper

, et al A phase 3 randomized, double-blind, vehicle-controlled trial of azelaic acid foam 15% in the treatment of papulopustular rosacea. Cutis. 2015;96:54-61.

18.

Elewski

Fleischer

Pariser

DM.

A comparison of 15% azelaic acid gel and 0.75% metronidazole gel in the topical treatment of papulopustular rosacea: results of a randomized trial. Arch Dermatol. 2003;139:1444-1450. doi:10.1001/archderm.139.11.1444

19.

Ertl

GA.

A comparison of the efficacy of topical tretinoin and low-dose oral isotretinoin in Rosacea. Arch Dermatol. 1994;130(3):319-324. doi:10.1001/archderm.1994.01690030051008

20.

Koca

Altinyazar

Ankarali

Muhtar

Tekin

Cinar

A comparison of metronidazole 1% cream and pimecrolimus 1% cream in the treatment of patients with papulopustular rosacea: a randomized open-label clinical trial. Clin Exp Dermatol. 2010;35(3):251-256. doi:10.1111/j.1365-2230.2009.03427.x

21.

Tan

JKL

Girard

Krol

, et al Randomized placebo-controlled trial of metronidazole 1% cream with sunscreen SPF 15 in treatment of rosacea. J Cutan Med Surg. 2002;6(6):529-534. doi:10.1007/s10227-001-0144-4

22.

Koçak

Yağli

Vahapoğlu

Ekşioğlu

Permethrin 5% cream versus metronidazole 0.75% gel for the treatment of papulopustular rosacea. A randomized double-blind placebo-controlled study. Dermatology. 2002;205(3):265-270. doi:10.1159/000065849

23.

Serdar

Yaşar

Ş.

Efficacy of 1% terbinafine cream in comparison with 0.75% metronidazole gel for the treatment of papulopustular rosacea. Cutan Ocul Toxicol. 2011;30(2):124-128. doi:10.3109/15569527.2010.541398

24.

Raoufinejad

Mansouri

Rajabi

Naraghi

Jebraeili

. Efficacy and safety of permethrin 5% topical gel vs. placebo for rosacea: a double-blind randomized controlled clinical trial. J Eur Acad Dermatol Venereol. 2016;30(12):2105-2117. doi:10.1111/jdv.13801

25.

Ebneyamin

Mansouri

Rajabi

Qomi

Asgharian

Azizian

The efficacy and safety of permethrin 2.5% with tea tree oil gel on rosacea treatment: A double-blind, controlled clinical trial. J Cosmet Dermatol. 2020;19(6):1426-1431. doi:10.1111/jocd.13177

26.

Karabulut

Izol

Eksioglu

HM.

A randomized, single-blind, placebo-controlled, split-face study with pimecrolimus cream 1% for papulopustular rosacea. J Eur Acad Dermatol Venereol. 2008;22(6):729-734. doi:10.1111/j.1468-3083.2008.02589.x

27.

Sauder

Miller

Gratton

Danby

Griffiths

Phillips

The treatment of rosacea: the safety and efficacy of sodium sulfacetamide 10% and sulfur 5% lotion (Novacet) is demonstrated in a double-blind study. J Dermatolog Treat. 1997;8(2):79-85. doi:10.3109/09546639709160276

28.

EudraCT Number 2006-003707-40—Clinical trial results—EU Clinical Trials Register. Cited December 14, 2023. https://www.clinicaltrialsregister.eu/ctr-search/trial/2006-003707-40/results

29.

Nielsen

PG.

Treatment of rosacea with i% metronidazole cream. A double-blind study. Br J Dermatol. 1983;108(3):327-332. doi:10.1111/j.1365-2133.1983.tb03972.x

30.

Miyachi

Yamasaki

Fujita

Fujii

Metronidazole gel (0.75%) in Japanese patients with rosacea: a randomized, vehicle-controlled, phase 3 study. J Dermatol. 2022;49(3):330-340. doi:10.1111/1346-8138.16254

31.

Gold

Del Rosso

Kircik

, et al Minocycline 1.5% foam for the topical treatment of moderate to severe papulopustular rosacea: results of 2 phase 3, randomized, clinical trials. J Am Acad Dermatol. 2020;82(5):1166-1173. doi:10.1016/j.jaad.2020.01.043

32.

Bribeche

Fedotov

Gladichev

Pukhalskaya

Kolitcheva

NL.

Clinical and experimental assessment of the effects of a new topical treatment with praziquantel in the management of rosacea. Int J Dermatol. 2015;54(4):481-487. doi:10.1111/ijd.12552

33.

Wei

Hamblin

Wen

A randomized, controlled, split-face study of topical timolol maleate 0.5% eye drops for the treatment of erythematotelangiectatic rosacea. J Cosmet Dermatol. 2021;20(12):3968-3973. doi:10.1111/jocd.14347

34.

AOBiome

LLC

. A vehicle-controlled, double-blind, randomized phase II study of B244 delivered as a topical spray to determine safety and efficacy in subjects with mild to moderate rosacea. clinicaltrials.gov; 2022.

35.

CTG Labs—NCBI. Cited December 14, 2023. https://clinicaltrials.gov/study/NCT01174030

36.

Wang

Yuan

Huang

, et al Efficacy and safety of hydroxychloroquine for treatment of patients with rosacea: a multicenter, randomized, double-blind, double-dummy, pilot study. J Am Acad Dermatol. 2021;84(2):543-545. doi:10.1016/j.jaad.2020.05.050

37.

Stein-Gold

Kircik

Draelos

, et al WITHDRAWN: efficacy and safety of topical oxymetazoline cream 1.0% for treatment of persistent facial erythema associated with rosacea: findings from the 2 phase 3, 29-day, randomized, controlled REVEAL trials. J Am Acad Dermatol. Published online January 31, 2018. doi:10.1016/j.jaad.2018.01.028

38.

Luger

Peukert

Rother

A multicentre, randomized, placebo-controlled trial establishing the treatment effect of TDT 068, a topical formulation containing drug-free ultra-deformable phospholipid vesicles, on the primary features of erythematotelangiectatic rosacea. J Eur Acad Dermatol Venereol. 2015;29(2):283-290. doi:10.1111/jdv.12520

39.

Fowler

Jackson

Moore

, et al Efficacy and safety of once-daily topical brimonidine tartrate gel 0.5% for the treatment of moderate to severe facial erythema of rosacea: results of two randomized, double-blind, and vehicle-controlled pivotal studies. J Drugs Dermatol. 2013;12(6):650-656.

40.

EudraCT Number 2012-001044-22—Clinical trial results—EU Clinical Trials Register. Cited December 14, 2023. https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-001044-22/results

41.

Phase 3 efficacy and safety study of CD07805/47 topical gel in subjects with facial erythema associated with rosacea. Cited December 14, 2023. https://clinicaltrials.gov/ct2/show/NCT01355471

42.

Gold

Lebwohl

Biesman

, et al Daily oxymetazoline cream demonstrates high and sustained efficacy in patients with persistent erythema of rosacea through 52 weeks of treatment. J Am Acad Dermatol. 2018;79(3):e57-e59. doi:10.1016/j.jaad.2018.05.037

43.

Efficacy and safety of AGN-199201 in patients with persistent erythema associated with rosacea. Cited December 14, 2023. https://clinicaltrials.gov/ct2/show/NCT02131636

44.

Safety and efficacy of oxymetazoline HCl cream 1.0% in patients with persistent erythema associated with rosacea. Cited December 14, 2023. https://clinicaltrials.gov/ct2/show/NCT02132117

45.

Carroll

Lisenby

Carter

TL.

Critical appraisal of paroxetine for the treatment of vasomotor symptoms. Int J Womens Health. 2015;7:615. doi:10.2147/IJWH.S50804

46.

David

Smith

Nordhues

Kling

JM.

A clinical review on paroxetine and emerging therapies for the treatment of vasomotor symptoms. Int J Womens Health. 2022;14:353-361. doi:10.2147/IJWH.S282396

47.

Liu

Peng

, et al Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation. J Neuroinflammation. 2021;18(1):1-14. doi:10.1186/s12974-021-02097-z

48.

Geng

RSQ

Bourkas

Sibbald

. Biomarkers in rosacea: a systematic review. J Eur Acad Dermatol Venereol. 2024;38:1048-1057. doi:10.1111/jdv.19732

49.

Dionisie

Filip

Manea

Riga

The anti-inflammatory role of SSRI and SNRI in the treatment of depression: a review of human and rodent research studies. Inflammopharmacology. 2020;29(1):75-90. doi:10.1007/s10787-020-00777-5

50.

Shrestha

Fariba

Abdijadid

Paroxetine. In: StatPearls. StatPearls Publishing; 2024;1-4. Cited June 25, 2024. http://www.ncbi.nlm.nih.gov/books/NBK526022/

51.

Akhavan

Bershad

Topical acne drugs: review of clinical properties, systemic exposure, and safety. Am J Clin Dermatol. 2003;4(7):473-492. doi:10.2165/00128071-200304070-00004

52.

Gupta

Nicol

The use of sulfur in dermatology. J Drugs Dermatol. 2004;3(4):427-431.

53.

Wolf

Silapunt

The use of sodium sulfacetamide in dermatology. Cutis. 2015;96(2):128-130.

54.

Keri

Shiman

An update on the management of acne vulgaris. Clinical, Cosmetic and Investigational Dermatology. 2009;2:105-110. doi:10.2147/ccid.s3630

55.

Kong

Guo

Cui

MicroRNA-21 Mediates the inhibiting effect of praziquantel on NLRP3 inflammasome in Schistosoma japonicum infection. Frontiers in Veterinary Science. 2019;6:517. doi:10.3389/fvets.2019.00517

56.

Abokwidir

Feldman

SR.

Rosacea management. Skin Appendage Disord. 2016;2(1-2):26-34. doi:10.1159/000446215

57.

Hao

Mao

Park

Bae

Park

BH.

Repurposing the anthelmintic praziquantel to treat psoriasis. Br J Pharmacol. 2021;178(23):4726-4740. doi:10.1111/bph.15652

58.

Forton

Seys

Marchal

Song

AM.

Demodex folliculorum and topical treatment: acaricidal action evaluated by standardized skin surface biopsy. Br J Dermatol. 1998;138(3):461-466. doi:10.1046/j.1365-2133.1998.02125.x

59.

Narayanan

Hünerbein

Getie

Jäckel

Neubert

RHH

. Scavenging properties of metronidazole on free oxygen radicals in a skin lipid model system. J Pharm Pharmacol. 2007;59(8):1125-1130. doi:10.1211/jpp.59.8.0010

60.

Lacey

Delaney

Kavanagh

Powell

FC.

Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007;157(3):474-481. doi:10.1111/j.1365-2133.2007.08028.x

61.

Ávila

Martínez-Pulgarín

Rizo Madrid

Topical ivermectin-metronidazole gel therapy in the treatment of blepharitis caused by Demodex spp.: a randomized clinical trial. Cont Lens Anterior Eye. 2021;44(3):101326. doi:10.1016/j.clae.2020.04.011

62.

Van Zuuren

Arents

BWM

van der Linden

MMD

Vermeulen

Fedorowicz

Tan

Rosacea: new concepts in classification and treatment. Am J Clin Dermatol. 2021;22(4):457-465. doi:10.1007/s40257-021-00595-7

63.

Freeman

Klutman

Lamp

KC.

Metronidazole. Drugs. 1997;54(5):679-708. doi:10.2165/00003495-199754050-00003

64.

Silverberg

Lio

Simpson

, et al Efficacy and safety of topically applied therapeutic ammonia oxidising bacteria in adults with mild-to-moderate atopic dermatitis and moderate-to-severe pruritus: a randomised, double-blind, placebo-controlled, dose-ranging, phase 2b trial. eClinicalMedicine. 2023;60:102002. doi:10.1016/j.eclinm.2023.102002

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.05 MB