Intradermal injection of botulinum toxin for erythema in rosacea: A scoping review and meta-analysis

Data source and search strategy

Database (Pubmed, Cochrane Library and Embase) search was performed from inception to 30 January 2024. The search focused on clinical human studies in English. The keywords included the following: ‘botulinum toxin’ or ‘neurotoxin A’ combined with ‘rosacea’ or ‘erythematotelangietatic rosacea’ or ‘papulopustular rosacea’ and ‘rosacea erythema’. References of the screened articles were also included in the initial screening. The detailed search strategy is presented in Supplementary Table 1.

Eligibility criteria and study selection

The inclusion criteria for this study encompassed comparative investigations (randomised controlled trials/non-randomised controlled trials [RCTs/nRCTs]) that examined the treatment effects of intradermal BoNT-A in comparison to placebo. Additionally, studies that evaluated the combination of intradermal BoNT-A with another treatment for rosacea patients were considered eligible for inclusion. Furthermore, single-armed studies and case series focusing on intradermal BoNT-A monotherapy were also incorporated into the analysis. Review articles and conference reports were excluded.

In the existing literature, the terms ‘flushing’ and ‘erythema’ have been used interchangeably, leading to potential confusion. To ensure a comprehensive evaluation, we focused on studies that specifically addressed erythema and/or flushing in rosacea patients as well as reports involving patients with idiopathic persistent facial erythema, which is consistent with the phenotype of rosacea. Studies involving healthy populations – facial flushing caused by menopause, pregnancy, or other known medical conditions or using botulinum toxin other than type A – were excluded from our analysis.

Two independent investigators (MCHY and YCS) performed the initial screening of titles and abstracts to identify relevant articles, and subsequently, irrelevant publications were excluded from consideration.

Main outcomes

The principal objective of this research was to evaluate the efficacy of intradermal injection of BoNT-A in ameliorating erythema in rosacea. The timing of outcome assessment was up to three months after injection.

Quality assessment

The quality of the articles was evaluated independently using a methodological index for non-randomised studies (MINORS),⁹ which is a validated instrument to assess the methodological quality of non-randomised or non-comparative studies. It was originally designed for specialities in which randomised trials were difficult to conduct, such as surgical fields. It consists of 12 items, with the first eight tailored explicitly for non-comparative studies.

Data extraction

Two authors independently extracted the data and performed quality assessment (MCHY and YCS). Any disagreement between the two investigators was discussed and a consensus was reached. For each study, we extracted the study design, study country, sample size, patient population, treatment regimen, follow-up duration, and AEs. The extracted results are shown in Table 1, and the mean score and standard deviation of clinical erythema score for quantitative analysis are summarised in Supplementary Table 2. The assessment of erythema improvement was accomplished through a multifaceted approach, encompassing clinical evaluations conducted by qualified physicians, analysis of photographs or measurements obtained from specialised instruments such as a mexameter. If studies included both physician assessment and measurements from instruments, the results of physician assessment were used.

Statistical analysis

A random effects model was used for pooled estimates for all outcomes. To accommodate the different erythema scales from the studies, standardised mean difference (SMD) and 95% confidence interval were calculated. For heterogeneity across the studies, we used the I2 statistics. A threshold of > 50% was considered substantial. A p-value of < 0.05 was considered significant. Publication bias was not included as only less than ten RCTs were included in the study. The analysis was performed using the Comprehensive Meta-Analysis software version 3 (Biostat, Englewood, NK). Certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria.

Search results and trial characteristics

Initially, the literature search yielded 805 studies, from which 150 duplicates were removed. Seventeen studies were included in the systematic review and seven studies with 167 participants were found to meet the inclusion criteria for the meta-analysis. The PRISMA flow diagram is presented in Figure 1. It is worth noting that although four RCTs and 13 case series were included in the review, after stringent selection, only two RCTs and five case series entered quantitative analysis.

Close

Figure 1:

The screening, inclusion and exclusion flow chart of the systematic review.

Export to PPT

Quality assessment

Table 1 summarises the findings and the quality assessment of the included studies. For the four included RCTs, three RCTs were between 15 and 21, indicating a medium risk of bias. One RCT was scored 14, indicating a high risk of bias. Most randomised trials failed to report the inclusion of consecutive patients; only one study¹⁰ had a loss of follow-up rate less than 5% and none of the studies included a prospective calculation of the study size. The case series and case reports exhibited scores ranging from 7 to 13 out of 16, implying a medium to high risk of bias.

Characterisation of rosacea patients and botox use

The extracted clinical erythema scores ranging from ‒1.1 to 1.5 (negative denotes improvement of erythema) for meta-analysis are summarised in Supplementary Table 2. The utilisation of diverse BoNT-A products is from various companies. To enable an appropriate comparison between the different products, the units were standardised by converting them to the unit level of BOTOX. The studies also employed differing concentrations of BoNT-A, specifically 1U, 1.25U, 1.4U, 1.6U, 2U, 4U per 0.1 mL for the intradermal injections. Due to the requirement for multiple injections, the reported injection volumes varied, with quantities of 0.01, 0.02, 0.05, and 0.1 mL being documented.

Results of meta-analysis

The results of treatment from two RCTs, involving a total of 55 patients in split-faced trials, were subjected to quantitative analysis. The treatment’s effects did not show significance against the control during the initial and subsequent months (SMD for the first month: 3.386, 95% CI: 7.825–1.054, I2: 97.34%; SMD for the second month: 2.354, 95% CI: 5.492–0.784, I2: 96.51%). However, the treatment effect of BoNT-A became significant in the third month (SMD: 1.676, 95% CI: 2.278–1.074, I2: 35.76%) [Figure 2]. The GRADE evaluation rated the quality as moderate for the analysis of the first and second months and high for the third-month analysis [see Supplementary Table 3]. Other RCTs were reviewed, some of which utilised different result formats or presented incomplete findings. Khoury et al.¹⁵ assessed the potential adjunctive effect of intradermal BoNT-A combined with intense pulsed light therapy (IPL). While there appeared to be a tendency of greater improvement in erythema among patients who received both IPL and BoNT-A injection, the results did not show statistical significance. Dayan et al.¹⁶ conducted a trial against placebo saline injection; however, they only reported the reduction of the erythema score in the treatment arm. They observed a significant reduction in erythema starting from the first week, reaching its peak at the fourth week post-injection (‒1.4 ± 0.63, with the negative sign denoting a decrease in erythema compared to baseline). Scarcity of the RCTs was noted in this analysis, and future studies warrant more robust results.

Close

Figure 2:

Forest plot for adjunct intradermal botulinum toxin A against placebo (a) one month after treatment, (b) two months after treatment, (c) three months after treatment. (CI: confidence interval)

Export to PPT

To gain a more comprehensive understanding of the pre-post treatment effect, seven studies with single-armed treatment of intradermal injection of BoNT-A for a total 93 patients were analysed. The treatment effect was significant in the first (SMD: 2.712, 95 % CI: 4.1182–1.243, I²: 89.529%), second (SMD: 2.213, 95% CI: 3.702–0.725, I²: 89.529%) and third month (SMD: 1.912, 95% CI: 2.882–0.941, I²: 78.219%) [Figure 3]. Although the treatment seemed effective, it is important to note that due to the high heterogeneity of the study, the GRADE evaluation for the quality of evidence was very low [Supplementary Table 3].

Close

Figure 3:

Forest plot for single-armed intradermal botulinum toxin A for erythema in rosacea (a) one month after treatment, (b) two months after treatment, (c) three months after treatment. (CI: confidence interval)

Export to PPT

Adverse events

Major AEs, including mild facial paralysis, asymmetric facial expression, mouth corner paralysis and cheek drop, and minor AEs, including injectional purpura and pain, were reported. It was worth noticing that facial muscle complication was reported in different toxin concentrations, including 4U, 2U, 1.6U, 1.4U, 1.25U and 1U per 0.1 mL (equivalent dose to onabotulinum toxin). In addition, facial muscle complications can occur in studies with single injection volume of 0.05 mL, but were not observed in studies with 0.02 or 0.01 mL [Table 1].