Azelaic Acid Treatment For Rosacea and Melasma
Overview
This study evaluated the effectiveness and safety of topical azelaic acid (AA) for various dermatological conditions, including acne vulgaris, rosacea, hyperpigmentation/melasma, and skin aging. The researchers conducted a systematic review of randomized controlled trials (RCTs) with a minimum treatment duration of 6 weeks, searching databases like MEDLINE, Embase, CINAHL, and ClinicalTrials.gov up to December 2022. A total of 43 RCTs met the inclusion criteria.
In the context of rosacea, the meta-analyses from 20 studies demonstrated that azelaic acid significantly improved erythema severity, inflammatory lesion counts, overall improvement, and treatment success (achieving skin clarity) compared to a vehicle after 12 weeks of treatment. Furthermore, azelaic acid proved more effective than metronidazole 0.75% for improving erythema severity, overall improvement, and inflammatory lesion counts.
For acne, the analysis of 16 studies indicated that azelaic acid was more effective than a vehicle in enhancing global assessments and reducing acne severity. Notably, azelaic acid 20% also led to a significant reduction in lesions compared to erythromycin gel.
Within the realm of melasma, seven studies suggested that azelaic acid 20% was significantly superior to a vehicle in both severity and global improvement. Additionally, azelaic acid 20% yielded notably better results for global improvement compared to hydroquinone 2%.
Despite these promising findings, there were few significant differences in the occurrence of adverse events between AA and the comparison treatments. Notably, there were no eligible RCTs identified for evaluating the effects of azelaic acid on skin aging.
In conclusion, this study revealed that topical azelaic acid (AA) is more effective than a vehicle for treating rosacea, acne, and melasma. Moreover, comparisons between azelaic acid and other treatments often showed similar outcomes. In cases where these treatments are equivalent, azelaic acid may be considered a viable option for specific clinical situations. However, more RCT evidence is needed to assess the effectiveness of azelaic acid for addressing skin aging concerns.
Introduction
Azelaic acid (AA) is a natural dicarboxylic acid found in grains like barley, wheat, and rye. It is also produced by Malasezzia furfur, a yeast residing on the skin, known to cause pityriasis (Tinea) versicolor, which affects melanin production and may result in hypopigmented areas. Additionally, azelaic acid possesses antimicrobial and anti-comedonal properties, along with various anti-inflammatory attributes. It inhibits tyrosinase, a key enzyme in melanin production, and suppresses the production of reactive oxygen species and proinflammatory cytokines, including IL-1, IL-6, and TNF-a.
Studies have revealed that azelaic acid can counteract inflammatory reactions induced by UV radiation, making it a valuable agent for conditions like rosacea, triggered or aggravated by sunlight exposure. Specifically, azelaic acid has been found to reduce the effects of ultraviolet B light on nuclear factor κB p65 subunit and p38 mitogen and stress-activated protein kinase. Moreover, azelaic acid enhances the activity of peroxisome proliferator-activated receptor γ (PPARγ), a crucial player in controlling inflammation.
Currently, AA is widely licensed and recommended worldwide for managing rosacea and acne vulgaris. It has also been employed for treating melasma, hyperpigmentation, and post-inflammatory hyperpigmentation (PIH), particularly in cases associated with acne and individuals with darker skin.
The aim of this systematic review is to provide an updated, high-quality evidence base assessing the efficacy and safety of topical azelaic acid for a range of dermatological concerns, including acne, rosacea, melasma, hyperpigmentation, and skin aging. This review serves to inform best practices and serves as a valuable reference for both patients and healthcare professionals in their decision-making processes.
Method
This systematic review adhered to established principles outlined in the Cochrane handbook and the guidance provided by the Centre for Reviews and Dissemination. The review’s protocol was registered on PROSPERO (CRD42020220648).
The inclusion criteria encompassed randomized controlled trials (RCTs) with a treatment duration of at least 6 weeks. These trials compared topical azelaic acid (AA) in any dose or form with a vehicle, different azelaic acid doses, other medical treatments, or procedures. The study participants were healthy adolescents or adults aged 12 years or older. Outcomes of interest included the improvement in various dermatological conditions such as facial rosacea, acne, melasma, hyperpigmentation, and measures of anti-aging, including enhancements in photoaging, wrinkle reduction, and skin luminosity. Studies that assessed the combination of azelaic acid with other active medications in comparison to those medications alone were also included. Any treatment effectiveness scoring system was considered.
The review also examined adverse events data, encompassing local skin reactions like burning, pruritus, erythema, exfoliation, pain, dryness, discoloration, or irritation. Furthermore, serious adverse events, defined as reactions graded III or above by the study authors, were evaluated.
The search strategy for relevant trials involved searching various databases, including MEDLINE, PubMed, Embase, CINAHL, AMED, the TRIP database, Cochrane Library (CDSR and CENTRAL), NIHR Health Technology Assessment (NIHR HTA), and other NIHR journals, DARE, and the HTA database. Search terms encompassed keywords such as ‘azelaic acid,’ ‘Skinoren,’ ‘Finacea,’ ‘acne vulgaris,’ ‘hyperpigmentation,’ ‘melasma,’ ‘anti-aging,’ ‘photoaging,’ ‘wrinkles,’ and ‘rosacea.’
Two reviewers independently screened titles and abstracts from the search results, and full papers were retrieved for further assessment. The selected trials were critically appraised using the RoB 2 tool for RCTs, with disagreements resolved through discussion between the two reviewers.
Statistical Analysis
Data synthesis in this review involved the collection of means and standard deviations for continuous outcomes, allowing for the estimation of study-specific and pooled mean differences, each accompanied by 95% confidence intervals (CIs). For dichotomous outcomes, numerators and denominators were collected, enabling the use of Mantel–Haenszel (M-H) risk ratios (RRs) and 95% CIs to summarize effect sizes.
Statistical heterogeneity was assessed through various means, including the χ2 test, the I2 statistic, and examination of random effects between study variance (τ2). Sensitivity analyses were conducted, which involved the exclusion of studies deemed to have a high risk of bias to assess the robustness of the results. Whenever possible, the GRADE system was employed to provide an assessment of the quality of evidence for each outcome.
In total, 43 randomized controlled trials (RCTs) met the eligibility criteria. Among these, 38 RCTs reported inter-individual comparisons, while five were intra-individual RCTs where each side of the face was randomized to receive different treatments. Among the reported outcomes, 20 RCTs assessed rosacea, 16 reported outcomes on acne, and seven reported outcomes on melasma. No RCTs were identified that specifically evaluated hyperpigmentation or measures of anti-aging.
Regarding the concentration of Azelaic Acid (AA), 20 RCTs assessed AA 20% in gel or cream form, 19 assessed AA 15% in gel or foam form, one evaluated AA 5% in gel form, and two trials did not report the dose of azelaic acid used. The studies were conducted in various countries, with the USA, Iran, and the UK being the primary locations. Some studies were multinational in scope. Of the study populations, 29 trials were conducted in adults, 11 in both adolescents and adults, and three did not report the age range of the participants. Additionally, six studies provided details on the Fitzpatrick skin type.
Assessing the risk of bias, 37 out of the 43 RCTs were found to have ‘some concerns’ in at least one aspect, including the randomization process, deviations from intended interventions, missing outcome data, measurement of outcomes, or selection of reported results. Six RCTs were considered to have a high risk of bias due to factors such as inadequate allocation concealment, substantial participant withdrawals leading to per protocol analysis, or lack of blinding. Notably, no studies were classified as having a low risk of bias.
Result
The study included 20 randomized controlled trials (RCTs) focusing on rosacea, 16 RCTs related to acne, and 7 RCTs pertaining to melasma. These trials involved various treatment comparisons, including azelaic acid (AA) versus different control treatments, as well as comparisons of treatment frequencies.
For Rosacea:
- Study participants were mainly adults aged 18–83, with an average age of 49.7, predominantly female (75.4%), and primarily of white ethnicity (89.2%).
- The rosacea study outcomes were assessed using parameters like improved erythema (redness of the skin) severity, lesion counts, overall improvement, and treatment success.
Erythema Severity:
- A meta-analysis showed that azelaic acid, specifically azelaic acid 15%, was more effective than a vehicle in improving erythema severity. The analysis found a 51% mean improvement in patients using azelaic acid compared to a 36% improvement in the control group.
- There was some heterogeneity statistically in the studies.
- The quality of study findings was considered to be moderate.
Inflammatory Lesion Counts:
- There was consistent, moderate-quality evidence that both azelaic acid 15% and 20% were more effective than the vehicle in reducing inflammatory lesion counts (papules and pustules).
- The mean reduction in inflammatory lesion count was 63% with azelaic acid and 48% with the vehicle.
- Low-dose azelaic acid (5%) combined with clindamycin was also more effective than clindamycin alone.
- No significant differences were observed in comparisons between azelaic acid and other treatments in most cases.
Overall Improvement:
- Azelaic acid (15% or 20%) was found to be better than a vehicle in terms of overall improvement in rosacea. Those using azelaic acid were 1.5 times more likely to experience complete remission, marked improvement, or ‘good to excellent’ ratings compared to those receiving a vehicle.
- Some heterogeneity was noted statistically.
- No significant differences were observed in some comparisons, such as treatment frequency or between azelaic acid and specific treatments.
Treatment Success:
- High-quality evidence indicated that azelaic acid 15% was more effective than the vehicle in achieving ‘skin clear or nearly clear’ results.
- No studies were considered to have a high risk of bias.
Maintenance Therapy in Rosacea:
- A study assessed the efficacy of azelaic acid 15% as a maintenance therapy in rosacea. Initially, a significant proportion of participants experienced improvement, and this was maintained during the second phase of the study, with azelaic acid 15% gel outperforming the vehicle.
For Acne:
- Sixteen RCTs examined ten different treatment comparisons for acne vulgaris. Participants were aged 11–50, predominantly female (53%), and had mild to moderate acne.
- Common outcomes included reduction in lesion counts, global improvement, and reduction in severity.
Reduction in Lesion Counts:
- Some evidence suggested that azelaic acid 20% was more effective than the vehicle in reducing lesions.
- Low-dose azelaic acid (5%) combined with clindamycin outperformed clindamycin alone.
- Azelaic acid 20% was better than erythromycin gel 2%, but combined benzoyl peroxide 3% and clindamycin 1% gel performed better than AA 20%.
- In some comparisons, no significant differences were observed.
Global Improvement:
- AA 20% was more effective than a vehicle and benzoyl peroxide 5% in terms of overall improvement.
- No significant differences were observed between azelaic acid and other treatments in most cases.
Reduction in Severity:
- Some evidence showed that azelaic acid 20% was better than the vehicle, with a 3.06 times more effective result in terms of the Acne Severity Index (ASI) scores.
- Low-dose AA (5%) combined with clindamycin gel 2% outperformed clindamycin alone.
For Melasma:
- Seven RCTs examined four different treatment comparisons for melasma. Participants had Fitzpatrick skin types II–V and were mainly of Asian/Middle Eastern, Hispanic, or Black ethnicity.
- The reported outcomes included melasma severity, global improvement, and lesion size reduction.
Melasma Severity:
- Results varied depending on the assessment method.
- AA 20% was more effective than the vehicle, and AA 20% was better than hydroquinone 2% in terms of reducing melasma severity.
- Topical tranexamic acid 3% was more effective than AA 20%.
- No significant differences were observed in some comparisons.
Global Improvement:
- AA 20% was more effective than the vehicle.
- AA 20% was more effective than hydroquinone 2%, but not hydroquinone 4%.
- No significant differences were observed in one comparison.
Lesion Size Reduction:
- No significant differences were observed in this regard.
Skin Aging Studies:
- No studies on the use of azelaic acid in skin aging were included in the review.
Adverse Events:
- Serious adverse events were rare, with most studies reporting no serious adverse events.
- Commonly reported adverse events included itching, pain, dryness, and irritation. These side effects were more pronounced in the AA groups compared to the control groups in some cases. However, very few significant differences were observed between azelaic acid and the comparison treatments in terms of adverse events.
Conclusion
This systematic review highlights the effectiveness of azelaic acid (AA) in the treatment of rosacea, acne, and melasma. When compared to vehicles (placebo), Azelaic acid consistently showed superior results in managing these skin conditions. In cases where azelaic acid demonstrated similar efficacy to other active treatments, it can still be a valuable option, especially for patients who cannot tolerate equivalent treatments or where the safety of other treatments during pregnancy is a concern.
It’s worth noting that, while there were few notable differences in commonly reported adverse events between azelaic acid and comparators, potential side effects, such as itching and pain, should be considered by clinicians.
However, the review also underscores the need for further research to explore the role of azelaic acid in anti-aging. Additional studies in this area could provide valuable insights into the potential benefits of azelaic acid in addressing age-related skin concerns.
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