Topical Management of Cellulite (Edematous-Fibro-Sclerotic Panniculopathy, EFSP): Current Insights and Emerging Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The current article entitled "Topical Management of Cellulite (Edematous-Fibro-Sclerotic Panniculopathy, EFSP): Current Insights and Emerging Approaches " provide a comprhehnsive overview of current approches for the topical management of cellulite. The article is very well structured and written with clear language and I only recommend some changes to improve it as follows:

1. In the methods part, providing a simple flowchart to illustrate the number of articles identified, screened and included would give the reader a clear idea how the selection was done.
2. The discussion would benefit from more direct comparative analysis of the efficacy of the different topical treatment categories, they were well categorized and described in the results section but the discussion part would go deeper in to the mechanisms of the different approaches to conclude the most promising one or even propose the best combinations.
3. A clear clinical key takeaways or recommendations for practitioners would be helpful
4. Any safety concerns or side effects of the treatements should also be discussed.

Author Response

Reviewer comment: “In the methods part, providing a simple flowchart to illustrate the number of articles identified, screened and included would give the reader a clear idea how the selection was done.”
Response: We agree and have added a flowchart to the Materials and Methods section (Figure 2), summarizing records identified, screened, assessed for eligibility, and included.

Reviewer comment: “The discussion would benefit from more direct comparative analysis of the efficacy of the different topical treatment categories… to conclude the most promising one or even propose the best combinations.”
Response: We have revised the Discussion to include a concise comparative appraisal of the main topical categories (methylxanthines, retinoids, polyphenol/venotonic agents).

Reviewer comment: “A clear clinical key takeaways or recommendations for practitioners would be helpful.”
Response: We inserted a brief set of practice-oriented recommendations in the Discussion section.

Reviewer comment: “Any safety concerns or side effects of the treatments should also be discussed.”
Response: We added a short Safety and tolerability paragraph in the Discussion. As noted, adverse events are sparsely reported in the topical cellulite literature, and studies frequently state no adverse events or good tolerability. Nonetheless, we explicitly acknowledge the well-known local reactions to topical retinoids  and include practical mitigation.

Reviewer 2 Report

Comments and Suggestions for Authors

Well written, well organized, comprehensive. Methodology is sound and reproducible. The article is fine without the mention of AI and its role in standardizing outcomes. "AI-based image analytics can standardize outcome measurement, predictive models can optimize formulation design, and algorithm-driven personalization may guide patient-specific protocols." is all conjecture. There is no substantial evidence that I am aware of that proves that. The article needs to be made much more concise and emphasis should be placed on clinical outcomes and critical review of the literature, rather than in vitro studies. Readers should easily takeaway, after reading the article, what topical options are there for cellulite, specifically which categories of therapies, and which ones, if any, of them actually work -- it doesn't seem like most readers will arrive at those conclusions in its current form

Author Response

Reviewer comment: “The article is fine without the mention of AI and its role in standardizing outcomes. "AI-based image analytics can standardize outcome measurement, predictive models can optimize formulation design, and algorithm-driven personalization may guide patient-specific protocols." is all conjecture. There is no substantial evidence that I am aware of that proves that.”

Response: We appreciate the reviewer’s perspective and have revised accordingly. The sentence on AI has been reformulated to align strictly with the cited reference, avoiding any overstatement: we now limit claims to the feasibility of AI-assisted infrared thermography for objective identification/monitoring and its potential role in assessment and stratification within PPPM frameworks, as reported in Bauer et al. In parallel, and because another reviewer considered this a strength of the manuscript, we have modestly expanded and clarified this section while keeping claims strictly aligned with the cited evidence.

 

Reviewer comment: “The article needs to be made much more concise and emphasis should be placed on clinical outcomes and critical review of the literature, rather than in vitro studies. Readers should easily takeaway, after reading the article, what topical options are there for cellulite, specifically which categories of therapies, and which ones, if any, of them actually work -- it doesn't seem like most readers will arrive at those conclusions in its current form.”

Response: To address conciseness, we streamlined the manuscript, especially the Results, by removing redundancies and tightening descriptions. We also shifted the emphasis to clinical outcomes and critical appraisal: the Discussion now includes a short comparative synthesis of topical categories and clear practical takeaways so readers can discern which options show the most consistent signals. Regarding preclinical work, we reduced its extent and now use it primarily to supply mechanistic context where clinical or RCT evidence is limited for widely used actives.

Reviewer 3 Report

Comments and Suggestions for Authors

1. Standardize Cellulite Terminology: While the title correctly defines cellulite as Edematous-Fibro-Sclerotic Panniculopathy (EFSP), the abstract and introduction use the terms interchangeably with "cellulite." For maximum scientific rigor, consider using EFSP predominantly, or consistently use the combination (e.g., "cellulite/EFSP") when discussing its pathophysiology, as this aligns with the mechanism-first view of the review.

2. Refine "Oxinflammation": The term "oxinflammation" is used frequently and is effective. Please ensure the manuscript explicitly defines this term early on (perhaps in the introduction or at the start of Section 3.4) as the combined process of oxidative stress and chronic low-grade inflammation.

3. Differentiate Retinoids: In the abstract and results sections, please clarify which specific retinoid was used (e.g., retinol, retinyl palmitate, tretinoin, etc.) when discussing their effects, especially since the mechanism and potency can vary greatly. For instance, Piérard-Franchimont et al. used topical retinol, and this specificity should be maintained.

4. Massage-Related Effects: The discussion correctly flags the confounding effect of massage and application technique. Please make a stronger recommendation in the conclusion for future studies to incorporate a rigorous "vehicle-plus-massage-only" control arm to truly isolate the ingredient's effect from the mechanical one. This would significantly address one of the major limitations of the current evidence base.

5. Isolation of Actives: The paper highlights that most regimens use multiple active ingredients, making it hard to pinpoint efficacy drivers. A concluding comment or a strong statement in the future directions should emphasize the need for factorial or head-to-head trials of single-active formulations versus combinations.

6. Dose and Concentration: The review mentions the concentration of caffeine in some formulations (e.g., ≈3% or 7% ) and specific botanical extracts (e.g., Centella pentacyclic triterpenes ), but for maximal utility, encourage the authors to include dosing/concentration details (or explain why they are unavailable) in the text or the tables whenever possible for better comparison of RCTs.

7. AI Applications: The section on Artificial Intelligence (AI) is a strong point. To enhance its impact, consider providing a more concrete example of how AI-assisted image analytics specifically improves on traditional methods, perhaps by detailing how it quantifies macro-relief or echogenicity more accurately than human graders.

8. Tolerability and Side Effects: The results consistently report "Well tolerated" or "No AEs". Given that many effective topicals (e.g., Retinoids or high-concentration caffeine) can cause irritation, a brief, generalized statement in the Discussion summarizing the excellent safety profile of the reviewed agents while acknowledging the potential for irritation in more aggressive formulations (or at higher concentrations) would provide a more balanced perspective.

Author Response

Thank you for your careful reading of our manuscript and for the constructive, highly useful suggestions. We have revised the paper accordingly, as detailed below.

1. Reviewer comment: Standardize Cellulite Terminology: While the title correctly defines cellulite as Edematous-Fibro-Sclerotic Panniculopathy (EFSP), the abstract and introduction use the terms interchangeably with "cellulite." For maximum scientific rigor, consider using EFSP predominantly, or consistently use the combination (e.g., "cellulite/EFSP") when discussing its pathophysiology, as this aligns with the mechanism-first view of the review. Response: We adopted the term “edematous fibrosclerotic panniculopathy (EFSP)” throughout the manuscript for greater scientific rigor, replacing less precise wording where appropriate.
2. Reviewer comment: Refine "Oxinflammation": The term "oxinflammation" is used frequently and is effective. Please ensure the manuscript explicitly defines this term early on (perhaps in the introduction or at the start of Section 3.4) as the combined process of oxidative stress and chronic low-grade inflammation. Response: We added an explicit definition in the Introduction clarifying oxinflammation as the coupled process in which persistent oxidative stress and chronic low-grade inflammation mutually reinforce one another.
3. Reviewer comment: Differentiate Retinoids: In the abstract and results sections, please clarify which specific retinoid was used (e.g., retinol, retinyl palmitate, tretinoin, etc.) when discussing their effects, especially since the mechanism and potency can vary greatly. For instance, Piérard-Franchimont et al. used topical retinol, and this specificity should be maintained. Response: In the section on retinoids, we now distinguish between different retinoid types used across studies and indicate when concentrations are available.
4. Reviewer comment: Massage-Related Effects: The discussion correctly flags the confounding effect of massage and application technique. Please make a stronger recommendation in the conclusion for future studies to incorporate a rigorous "vehicle-plus-massage-only" control arm to truly isolate the ingredient's effect from the mechanical one. This would significantly address one of the major limitations of the current evidence base.
5. Reviewer comment: Isolation of Actives: The paper highlights that most regimens use multiple active ingredients, making it hard to pinpoint efficacy drivers. A concluding comment or a strong statement in the future directions should emphasize the need for factorial or head-to-head trials of single-active formulations versus combinations.

Response to 4 and 5 comments: In the Discussion and Conclusions, we strengthened recommendations for future trials to include a rigorously standardized vehicle-plus-massage–only control arm to isolate mechanical/placebo effects, and use factorial or head-to-head designs comparing single-active formulations versus combinations to identify true efficacy drivers.

6. Reviewer comment: Dose and Concentration: The review mentions the concentration of caffeine in some formulations (e.g., ≈3% or 7% ) and specific botanical extracts (e.g., Centella pentacyclic triterpenes ), but for maximal utility, encourage the authors to include dosing/concentration details (or explain why they are unavailable) in the text or the tables whenever possible for better comparison of RCTs. Response: We have added active-ingredient percentages wherever available in the primary sources. We also note transparently when concentrations are not reported, which is frequent, particularly in studies using botanical derivatives or proprietary blends.

7. Reviewer comment: AI Applications: The section on Artificial Intelligence (AI) is a strong point. To enhance its impact, consider providing a more concrete example of how AI-assisted image analytics specifically improves on traditional methods, perhaps by detailing how it quantifies macro-relief or echogenicity more accurately than human graders. Response: We expanded the AI section with a concrete example: AI-assisted image analytics can reconstruct 3D skin macro-relief to quantify dimple count, depth, and area, and can auto-segment high-frequency ultrasound to compute dermal-hypodermal echogenicity ratios and septal thickness, thereby reducing inter-rater variability and improving sensitivity to change relative to human graders.

8. Reviewer comment: Tolerability and Side Effects: The results consistently report "Well tolerated" or "No AEs". Given that many effective topicals (e.g., Retinoids or high-concentration caffeine) can cause irritation, a brief, generalized statement in the Discussion summarizing the excellent safety profile of the reviewed agents while acknowledging the potential for irritation in more aggressive formulations (or at higher concentrations) would provide a more balanced perspective. Response: We added a subparagraph in the Discussion summarizing tolerability and adverse events. Most studies report good tolerability or provide limited safety detail.

We appreciate your insightful feedback, which has materially improved the clarity, rigor, and clinical relevance of our work.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Responses and revisions to my comments are satisfactory