Comparative Study of Azelaic Acid Peeling vs. Tranexamic Acid Microneedling for the Treatment of Melasma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents a prospective comparative study evaluating azelaic acid chemical peeling versus microneedling-assisted tranexamic acid delivery for the treatment of melasma. Topical tranexamic acid combined with microneedling or fractional CO2 laser have been described extensively (ref:Mamdouh Kamal S. et al. Efficacy and Safety of Topical Tranexamic Acid Alone or in Combination with Either Fractional Carbon Dioxide Laser or Microneedling for the Treatment of Melasma. Dermatol Pract Concept. 2023/7/31/ 2023:e2023195. doi:10.5826/dpc.1303a195. The study is also limited by its relatively small sample size (esp. while melasma is a very common disease),  and absence of long-term follow-up to assess recurrence or durability of response. Additionally, no histological or instrumental assessments like Dermalab, OCT, RCM were performed to corroborate clinical findings. 

Author Response

• Regarding the combination of tranexamic acid with microneedling or fractional CO₂ laser:

 

We acknowledge that previous studies have addressed the use of tranexamic acid in combination with microneedling or fractional laser. However, our study aimed to contribute additional data by directly comparing tranexamic acid delivered via microneedling with azelaic acid chemical peeling, a comparative approach that remains underexplored, particularly in specific populations.

 

• Regarding the sample size:

 

We agree that the relatively small sample size is a limitation. However, as this was an initial prospective, controlled study with practical application in a clinical setting, we opted for a smaller, yet methodologically rigorous sample. This aspect has been emphasized in the conclusions section of the manuscript, and we highlight our intention to conduct future studies with larger and multicentric samples to validate our findings (342 – 350 lines).

 

• Concerning the lack of long-term follow-up:

 

We appreciate this pertinent observation. Indeed, the follow-up period was limited to short and medium terms. This has already been acknowledged as a limitation in the manuscript, and we reiterate our commitment to conducting longitudinal studies to assess the durability of results and recurrence rates in melasma.

 

• Regarding the absence of complementary evaluation methods (histology, Dermalab, OCT, RCM):

 

We appreciate the reviewer’s suggestion. Due to technical and budgetary constraints, this study focused on clinical evaluation using validated scales. Nonetheless, we fully recognize the value of instrumental and histological analyses to support and expand clinical findings, and we intend to incorporate such methodologies in future research to deepen the understanding of the underlying mechanisms and to objectively validate outcomes. It is important to note, however, that the use of a split-face (hemiface) design added methodological strength to the study by controlling for interindividual variability and reducing heterogeneity between treatment groups, thereby enhancing the reliability of the comparative results.

 

Once again, we thank the reviewer for the thoughtful feedback, which has significantly contributed to improving the quality of our manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

The article addresses a relevant and timely topic – the treatment of melasma, a chronic condition with a significant psychosocial impact. The study attempts a direct comparison of two therapeutic methods: 30% azelaic acid peeling and microneedling with tranexamic acid. The use of a hemiface model allows for a reduction in inter-individual variability, making the study cognitively valuable.

Despite being a well-constructed manuscript, I noticed several issues or omissions in the text that should be corrected or clarified:

1. The Introduction does not specify which non-parametric statistical tests were used.
2. Line 25 – "centrofacial region” – it would be better to use a full, precise term such as: central facial area forehead, cheeks
3. Line 26 – The photographic evaluation and MASI showed a significant improvement on both sides of the face, with the final values higher than the initial ones.– Did the MASI scores really increase? This contradicts the study’s conclusions.
4. Line 67 – "cosmetics" – some cosmetics aggravate melasma, while others are therapeutic. This should be clarified.
5. Line 130 – There is no information provided on whether the microneedling needles were single-use.
6. Line 135 – Was the azelaic acid product a commercial preparation?
7. Line 165 – Why did one participant not complete the study? This should be explained.
8. Line 199 – "p-value" – typographical error.
9. The average MASI values for each session are not provided.
10. Lines 247–249 – There is no mention of potential adverse effects of tranexamic acid.

 

Author Response

We sincerely thank you for your positive feedback and for recognizing the relevance of the topic addressed, as well as the methodological value of our study. We fully agree that melasma represents a significant therapeutic challenge, not only due to its clinical aspects but also because of its lasting psychosocial impact.

 

We are pleased that the comparative approach between 30% azelaic acid peeling and microneedling with tranexamic acid was considered pertinent, and we appreciate your acknowledgment of the split-face model. This design indeed proved effective in minimizing inter-individual variability, thereby increasing the robustness and reliability of our analyses.

 

Our aim with this work was to provide clinical evidence that can contribute to more personalized and data-driven therapeutic decisions. Your encouraging comments reinforce our motivation to continue investigating this topic with scientific rigor and dedication.

 

Question 1: The Introduction does not specify which non-parametric statistical tests were used.

Answer: The required specification has been added to the introduction (lines 104 and        105).

Question 2: Line 25 – "centrofacial region” – it would be better to use a full, precise term such as: central facial area forehead, cheeks

Answer: The term was adjusted as required (line 25 and 26).

 

Question 3: Line 26 – The photographic evaluation and MASI showed a significant improvement on both sides of the face, with the final values higher than the initial ones.– Did the MASI scores really increase? This contradicts the study’s conclusions.

Answer: The sentence was written incorrectly. The intended idea was that the MASI scores were better at the end of the treatment compared to the beginning, indicating an improvement in melasma. The sentence has been corrected in the text (line: 27).

 

Question 4: Line 67 – "cosmetics" – some cosmetics aggravate melasma, while others are therapeutic. This should be clarified.

Answer: "Cosmetics" was added together with photosensitizing medications (line 67).

 

Question 5: Line 130 – There is no information provided on whether the microneedling needles were single-use.

Answer: Each microneedling needles was used individually and only once, being discarded immediately after the session. The information was added to the manuscript (line 135 and 136).

 

Question 6: Line 135 – Was the azelaic acid product a commercial preparation?

Answer: No, the azelaic acid product used in this study was not a commercial preparation. It was compounded in a licensed compounding pharmacy, specifically formulated for the research according to the required concentration and excipients.

 

Question 7: Line 165 – Why did one participant not complete the study? This should be explained.

Answer: The participant was unable to complete the study due to multiple missed treatment sessions. Consequently, it was not possible to continue with the study protocol, leading to their withdrawal from the trial. The explanation has been added to the text (line 177 and 178).

 

Question 8: Line 199 – "p-value" – typographical error.

Answer: It has been fixed. Thanks for noticing (line 229).

 

Question 9: The average MASI values for each session are not provided.

Answer: The mean MASI values ​​for sessions 1, 4 and 5 were added to Table 4 in the manuscript. Values ​​correspond to the graph in Figure 5.

 

Question 10: Lines 247–249 – There is no mention of potential adverse effects of tranexamic acid.

Answer: Mention of adverse effects has been added to the text (line 279-281).

Reviewer 3 Report

Comments and Suggestions for Authors

The authors presenet a comparative trial evaluating the efficacy of AA 30% peeling and tranexamic acid applied with microneedling in the melasma treatment.

Te idea is of some interest considering the difficulties to teat melasma and maintenance of the obtained results a

The authors present a comparative trial evaluating the efficacy of AA 30% peeling and tranexamic acid applied with micro needling in the melasma treatment.

The idea is of some interest considering the difficulties to teat melasma and maintenance of the obtained results. However, several aspects need to be clarified or better explained

1. The reason why AA peeling and tranexamic acid were selected among the possible melasma treatment
2. Explaining the mechanism of action of AA inhibition of tyrosinase has been reported, that is true. However, is there any evidence that applied as peeling it penetrate or the effect is just exfoliative?
3. A follow-up after treatment stop would be useful to define the efficacy of both therapies

 

Author Response

We sincerely thank the reviewer for the thoughtful and constructive comments. We appreciate your recognition of the relevance of our study, particularly in addressing the challenges associated with the treatment and maintenance of results in melasma.

 

We carefully considered all the points raised, and the manuscript has been revised accordingly to clarify and expand on the aspects that required further explanation. Below, we provide detailed responses to each of your comments and describe the changes made to the manuscript.

 

Question 1: The reason why AA peeling and tranexamic acid were selected among the possible melasma treatment

Answer: The choice of 30% azelaic acid (AA) peeling and tranexamic acid (TA) delivered via microneedling was based on their widespread use in clinical practice for the treatment of melasma. Both treatments are supported by empirical evidence and are frequently recommended by dermatologists due to their depigmenting and anti-inflammatory properties. However, despite their popularity, there is a lack of high-quality, comparative clinical studies directly evaluating their efficacy against each other. Therefore, our study aimed to address this gap by providing prospective data to guide treatment selection and optimize clinical outcomes in melasma management.

 

Question 2: Explaining the mechanism of action of AA inhibition of tyrosinase has been reported, that is true. However, is there any evidence that applied as peeling it penetrate or the effect is just exfoliative?

Answer: We appreciate the reviewer’s thoughtful question regarding the mechanism of action of azelaic acid (AA) when used as a chemical peel. While AA is widely recognized as a tyrosinase inhibitor with anti-inflammatory properties, we understand the concern about whether its effect in peel form results primarily from superficial exfoliation or actual epidermal penetration.

Recent clinical studies have shown that azelaic acid peels—particularly at concentrations of 20–30%—are capable of penetrating the stratum corneum and exerting biological effects beyond keratolysis. For instance, a study by Wong et al. (2025) evaluated a peeling system containing azelaic acid and tranexamic acid and reported significant improvement in hyperpigmented lesions, pigmentation area, and skin homogeneity, suggesting effective transcutaneous delivery and pharmacological action beyond surface exfoliation [https://doi.org/10.1007/s13555-025-01399-x]. Another study involving a 20% AA combined with resorcinol and phytic acid demonstrated significant MASI score reduction and sustained clinical improvement at 3-month follow-up, further supporting epidermal activity of the formulation [https://doi.org/10.4103/2277-9175.200784].

Moreover, given AA’s relatively low molecular weight (~188 Da), its epidermal penetration is pharmacologically plausible, especially when formulated in peel vehicles designed to enhance absorption. While exfoliation undoubtedly contributes to clinical improvement, these findings support the conclusion that azelaic acid peels also act through direct modulation of melanogenesis and inflammation at the epidermal level. We have clarified this point in the revised version of the manuscript.

 

Question 3: A follow-up after treatment stop would be useful to define the efficacy of both therapies

Answer: We agree with the reviewer that a post-treatment follow-up period would be valuable to assess the long-term efficacy and durability of both therapeutic approaches. Due to the limitations of this initial prospective study, follow-up was restricted to the treatment phase. However, we acknowledge this as a limitation in the manuscript and intend to address this point in future studies through extended follow-up periods to evaluate recurrence rates and the sustained effects of both interventions. This note was added at the conclusion of the manuscript (line 336-339).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The abstract addresses an important clinical question comparing two common modalities for melasma treatment. The split-face design is appropriate, and the authors report preliminary efficacy data for both azelaic acid peeling and tranexamic acid microneedling. 

The study includes only 10 patients, with 9 completing treatment. While this is acceptable for a pilot study, it should be clearly acknowledged as a limitation in the conclusions. No mention is made of power calculations or whether the sample size is adequate to detect meaningful differences.

Author Response

We would like to express our sincere gratitude to the reviewers for their careful reassessment of our manuscript and for the additional constructive feedback provided. We greatly appreciate the opportunity to revise our work and further clarify and improve specific aspects of the study. In this revised version, we have addressed all comments thoroughly and made the corresponding changes to the manuscript, which we believe have strengthened its clarity, methodological transparency, and scientific value. Below, we provide detailed responses to each point raised, along with the modifications implemented.

 

Reviewer #1: The abstract addresses an important clinical question comparing two common modalities for melasma treatment. The split-face design is appropriate, and the authors report preliminary efficacy data for both azelaic acid peeling and tranexamic acid microneedling.

 

The study includes only 10 patients, with 9 completing treatment. While this is acceptable for a pilot study, it should be clearly acknowledged as a limitation in the conclusions. No mention is made of power calculations or whether the sample size is adequate to detect meaningful differences

 

Answers

Thank you for this thoughtful comment. We have included a paragraph in the Discussion section addressing this important methodological limitation (lines 334 – 347), as in the abstract (lines 18 and 33,34), and materials and methods (lines 112,113). We clarify that the study was conducted using a convenience sample, which is typical in pilot studies with an exploratory nature. In such cases, power calculations are not expected, as the goal is not to make population-level inferences but rather to generate hypotheses and explore preliminary treatment efficacy. Nevertheless, we acknowledge that the small sample size limits the generalizability of the findings, and we have emphasized this point more clearly in the revised version of the manuscript. We believe that the observed results support the continuation of research with larger samples and more robust designs.