Efficacy and safety of oxymetazoline for the treatment of rosacea: A meta‐analysis

Since there is currently no conclusion on the efficacy and adverse effects of oxymetazoline, this meta‐analysis attempts to explore its efficacy and adverse events, so as to provide guidance for clinical medication.


| INTRODUC TI ON
Rosacea is a chronic skin disease characterized by persistent facial erythema, flushing, telangiectasia, and inflammatory papules or pustules, and it is estimated to affect 16 million adults in the United State. 1 Rosacea has four main subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular rosacea. [2][3][4] The most common sign of rosacea is persistent erythema, which is usually related to social embarrassment and psychological distress. [5][6][7] The pathophysiology of rosacea is not yet fully understood, but it is believed to be due to an inflammatory process caused by multiple etiologies. 8 Although most topical pharmacological agents can reduce the inflammatory lesions of rosacea and erythema around the lesion, they are less effective for persistent erythema, which makes the treatment options for rosacea persistent facial erythema limited. 9,10 It is reported that activating the α1-and α2-adrenergic receptors on vascular smooth muscle can promote vasoconstriction, which may help to improve the persistent erythema associated with rosacea. 11 Oxymetazoline hydrochloride cream 1.0% (oxymetazoline; Rhofade, Allergan plc) is an α1-adrenergic receptor agonist that has been approved for the treatment of persistent facial erythema associated with rosacea in adults. 12 The pharmacokinetic data of oxymetazoline is limited, however, ocular absorption studies in rabbits have shown that oxymetazoline is malabsorption, indicating low systemic exposure. 13 However, there is currently no conclusion on the efficacy and adverse effects of the drug in the treatment of rosacea, and no clear guidance is given in the guidelines. This study attempts to use evidence-based medicine to conduct meta-analysis by including the currently reported studies on the use of oxymetazoline in the treatment of rosacea, to explore its efficacy and adverse events, so as to provide guidance for clinical medication.

| Literature inclusion and exclusion criteria
The inclusion criteria were as follows: the study type is randomized controlled trial (RCT); eligible patients were randomly assigned to receive oxymetazoline or vehicle; the language is limited to English.
Exclusion criteria: duplicate publication; research without full text, incomplete information or inability to conduct data extraction; animal experiments; reviews and systematic reviews.

| Literature screening and data extraction
The literature search, screening, and information extraction were all independently completed by two researchers. When there were doubts or disagreements, the decision was made after discussion or consultation with a third person. The data extraction included the author, year, study area, research type, number of cases and the indicators for evaluating outcome, including Clinician Erythema Assessment (CEA) success rate, Subject Self-Assessment for rosacea facial redness (SSA) success rate, satisfaction rate, treatmentemergent adverse events (TEAEs) rate (Tables S1-S7).

| Literature quality assessment
Two researchers independently conducted literature quality evaluation, using Review manager 5.3 software risk assessment tool, according to Cochrane risk assessment scale, according to random sequence generation, allocation concealment, blind method, whether the research results were blindly evaluated, and the completeness of the result data Evaluation of the included literature. When the opinions are inconsistent, it is decided through discussion or consultation with the third person. The meta-analysis was performed based on the related items of Preferred Reporting Items for Systematic Reviews and Meta-analysis statement (PRISMA statement). 14 2.6 | Data synthesis and statistical analysis STATA

| The results of literature search
In this study, a total of 136 studies were retrieved from the database including Pubmed, Embase, Cochrane Library. After the removal of duplicate studies, 72 were obtained. After browsing titles and abstracts, 31 studies were obtained. Finally, seven articles were included in this meta-analysis ( Figure 1).  (Table 1).

| Quality assessment of the included studies
As shown in the Figures 2 and 3, the seven studies included in this study all described the formation of random sequences and all conducted double blinding. In summary, the quality of the literature in this study is relatively high ( Table 2).

| Efficacy
Three studies involving 1770 patients reported CEA success of 3, for rosacea is significantly higher than that of vehicle ( Figure 5).
In addition, we also pay attention to patients' satisfaction after 1.14-1.89, p = 0.000) -hours SSA success rate after oxymetazoline treatment for rosacea is significantly higher than that of vehicle ( Figure 6).

F I G U R E 4
Comparison of CEA success rate between Oxymetazoline group and vehicle group.

| Subgroup analysis
In order to have a clearer understanding of the incidence of multiple adverse reactions, we conducted a subgroup analysis for different diseases. The results showed that the oxymetazoline group was only significantly higher than the vehicle group in the incidence of  Table 2).

| Sensitivity analysis
Sensitivity analysis eliminates each included study one by one, and performs a summary analysis on the remaining studies to assess whether a single included study has an excessive impact on the results of the entire meta-analysis. The result of the sensitivity analysis is shown in Figure 9. The results showed that none of the studies had an excessive impact on the results of the meta-analysis, indicating that the results of the remaining studies are stable and reliable.

F I G U R E 5
Comparison of SSA success rate between Oxymetazoline group and vehicle group.

| Publication bias
The funnel plot of this study is shown in Figure 10. It can be seen that the funnel plot is basically symmetrical, and the p value of Egger's test is 0.951, indicating that there is no obvious publication bias in this study.

| DISCUSS ION
Facial erythema is a sign of rosacea and a mandatory standard for diagnosis. The facial erythema of rosacea usually consists of persistent congestion and macular congestion, as well as focal congestion surrounding individual papules and pustules. 17 The FDA-approved drugs for the treatment of rosacea are mainly antimicrobial drugs, such as metronidazole, azelaic acid, sulfenamide/sodium sulfur, doxycycline and ivermectin. Although these therapies have a beneficial effect on papules and pustules associated with rosacea, they have no effect on persistent erythema remaining after the lesion has been cleared. 10  F I G U R E 9 Sensitivity analysis for searching the heterogeneity of this metaanalysis.
F I G U R E 1 0 Funnel plot for evaluating the publication bias of this meta-analysis. study are not completely objective, and more randomized controlled trials are still needed to further confirm. Secondly, the lack of included studies makes the results of the investigation of bias low credibility, and there may still be potential publication biases in the results of this study.

| CON CLUS ION
Oxymetazoline is effective and can be selected for the treatment of persistent facial erythema of rosacea. Additionally, application-site dermatitis was the most important one. Additionally, that most of the TEAEs of oxymetazoline were considered mild or moderate in severity, of which application-site dermatitis was the most important one.

AUTH O R CO NTR I B UTI O N S
HYF and HBL performed the research. QJZ, YC, HBL, and FL de-

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors declare that they have no competing interests.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

E TH I C S S TATEM ENT
Authors declare human ethics approval was not needed for this study..