Chronic Hand Eczema: From Nosological Ambiguity to Therapeutic Identity in the Era of Targeted Topical JAK Inhibition

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This narrative review addresses a timely and clinically relevant topic —  chronic hand eczema (CHE) as a distinct therapeutic entity following the regulatory approval of topical delgocitinib. The manuscript is well-written, with a clear conceptual arc from nosological ambiguity to targeted therapy. The barrier-immune axis framework reppresents a valuable intellectual contribution.

Suggested revisons:

Title and author name typos. "Nosologocal"  there is a typo. Change in  "nosological" in the title; 

-In the Abbreviations section, TSLP is expanded as "Thymic Stromal Lynphopoietin" — the correct spelling is "Lymphopoietin."

-Formatting of references must be harmonized throughout.

- The statement that "approximately 48% of patients achieved clear or almost clear status after 24 weeks" (Section 6) should specify that this refers to the alitretinoin 30 mg arm specifically, not the overall trial population (placebo response was 17%).

- Delgocitinib is never mentioned by name in the abstract text, despite being the central subject of the review. Clarify the choice

- The section about cosmetic intervention is too short considering that the manuscript has been submitted to a cosmetic journal. The authors should expand this section with more specific discussion of emollient formulation strategies (ceramide ratios, cholesterol, fatty acid composition), translational cosmetic science approaches, and practical guidance for clinicians.

- Some references supporting epidemiological claims are dated (e.g., Meding & Swanbeck, 2001; Tupker et al., 1990). More recent systematic reviews and meta-analyses on CHE prevalence and TEWL measurement should be considered.

- The citation attributed to "Worm, M. et al., Lancet 2024, 403, 123–134" does not correspond to any identifiable publication. No article exists in Lancet volume 403 at those pages with those authors on this topic. The actual DELTA 1/DELTA 2 pivotal trial was published by Bissonnette et al. (Lancet 2024;404:461–473), already correctly listed as ref 31. Consider that ref 7 is cited at least five times throughout the manuscript (Introduction, Diagnostic Framing, Registrative Evidence, Discussion).

-ref 30, 33, and 39 are bibliographically incomplete, lacking volume numbers, page ranges, or DOIs. 

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Dear Editor and Reviewers,

We would like to thank the Editor and the Reviewers for their careful evaluation of our manuscript and for their constructive comments. We have revised the manuscript accordingly and have addressed all points raised. The changes have improved the clarity, accuracy, and overall quality of the manuscript. Below, we provide a point-by-point response.

Reviewer 1

Comment 1: Title typo (“nosologocal”).
Response: Corrected. The title now reads: “Chronic Hand Eczema: from nosological ambiguity to therapeutic identity in the era of targeted topical JAK inhibition.”

Comment 2: Typo in Abbreviations (TSLP).
Response: Corrected to “Thymic Stromal Lymphopoietin.”

Comment 3: Reference formatting inconsistent.
Response: The reference list has been fully revised and harmonized according to journal guidelines.

Comment 4: Clarify alitretinoin efficacy statement.
Response: Revised to specify that the 48% response rate refers to the alitretinoin 30 mg arm, with inclusion of the placebo response for clarity.

Comment 5: Delgocitinib not mentioned in abstract.
Response: The abstract has been revised to explicitly include delgocitinib.

Comment 6: Cosmetic section too short.
Response: Section 10 has been substantially expanded. We added detailed discussion on lipid-based barrier repair (ceramides, cholesterol, fatty acids), formulation strategies (lamellar systems, biomimetic approaches), and practical clinical guidance.

Comment 7: Outdated epidemiological references.
Response: The section has been updated with more recent literature, while retaining selected older references where historically relevant.

Comment 8: Incorrect Lancet reference (Worm et al.).
Response: The incorrect reference has been removed. All citations have been corrected and replaced with Bissonnette et al. (Lancet 2024;404:461–473).

Comment 9: Overuse of incorrect reference.
Response: All instances have been corrected accordingly.

Comment 10: Incomplete references (30, 33, 39).
Response: These references have been completed with full bibliographic details.

We thank the Reviewers for their helpful suggestions, which have significantly improved the manuscript. We hope that the revised version is suitable for publication in Cosmetics.

Sincerely,
The Authors

Reviewer 2 Report

Comments and Suggestions for Authors

The following should be emphasized: diagnostic challenges for CHE- clinical heterogenity and lack of biomarkers as well mentioned classification for CHE and their limitations. The advantages of the investigated medication should be highlighted more clearly and precisely in comparison with conventional therapy. Additionally, the conclusions could be more compelling by clearly emphasizing that CHE,  previously a poorly defined condition, is becoming a more precisely treatable entity and targeted therapies- JAK inhibitors are transforming the treatment paradigm or principle.

 

   

 

       

 

Author Response

Dear Reviewer,

We thank you for your insightful comments and for the opportunity to improve our manuscript.

Comment 1: Diagnostic challenges for CHE, including clinical heterogeneity, lack of biomarkers, and classification limitations, should be emphasized.

Response:
We have revised the manuscript to explicitly highlight the marked clinical heterogeneity of CHE and the current absence of validated biomarkers. In addition, we expanded the discussion on existing classification systems, underlining their descriptive nature and limited capacity to reflect underlying molecular mechanisms or guide therapeutic stratification.

Comment 2: The advantages of the investigated medication should be more clearly and precisely highlighted compared to conventional therapy.

Response:
The manuscript has been revised to provide a clearer comparison between topical delgocitinib and conventional therapies. We now emphasize its upstream mechanism of action (JAK-STAT inhibition), lack of corticosteroid-related skin atrophy, absence of systemic exposure and monitoring requirements compared to systemic treatments, and its efficacy across heterogeneous clinical phenotypes.

Comment 3: The conclusions should more clearly emphasize the evolving treatability of CHE and the impact of targeted therapies.

Response:
The conclusion has been strengthened to underscore the transition of CHE from a poorly defined condition to a more precisely treatable disease entity. We now explicitly highlight the paradigm shift toward targeted therapies, particularly JAK inhibitors, as a key advancement in CHE management.

We believe these revisions have improved the clarity and impact of the manuscript.

Sincerely,

Martina

Reviewer 3 Report

Comments and Suggestions for Authors

1- The term "nosologocal" in the manuscript title appears to be a typo. Please correct it to "nosological".

2- Certain parts of the Discussion, particularly the comparisons between JAK inhibitors and other treatment modalities, could be streamlined to avoid redundancy and improve the overall flow.

3- To enhance the reproducibility and rigor of this review, please detail the literature search methodology. This should include the specific databases searched, keywords used, timeframes, and explicit inclusion/exclusion criteria.

4- Consider adding a dedicated subsection in the literature review to discuss the recent advances in the diagnosis and treatment of different CHE phenotypes.

5- To improve the readability of Section 7, please introduce a summary table comparing the DELTA 1, DELTA 2, DELTA 3, and DELTA FORCE trials. Key columns should include study design, sample size, baseline characteristics, primary endpoints (e.g., IGA-CHE success at week 16), and key safety data.

6- To visually convey the core concepts and greatly enhance readability, I strongly recommend adding two schematic diagrams: one illustrating the "Barrier-Immune Axis Mechanism of CHE," and another detailing the "Mechanism of Action of Delgocitinib."

7- Given the scope of Cosmetics, please incorporate recent literature discussing the current research status of cosmetic skincare as an adjuvant therapy in CHE management.

8- To better align with the journal's focus, the Discussion section should more strongly emphasize the synergistic effects of cosmetic skincare (specifically barrier repair products) and pharmacological treatments. Please provide specific skincare intervention recommendations, such as the selection of appropriate barrier repair products tailored to different CHE phenotypes.

9- Beyond mentioning short follow-up periods and selection bias in Section 8, please expand the discussion on how future observational cohort studies could be better designed despite the lack of standardized outcome measures. Additionally, address how to optimize patient adherence to both targeted therapies and basic emollients in real-world settings.

10- To ensure a balanced and objective perspective, please add a paragraph in the Discussion addressing the limitations of this review itself (e.g., limitations of the included literature or research areas not covered).

11- Please provide more specific recommendations for "Future Research Directions" that align with the journal's theme. Examples could include clinical intervention studies integrating cosmetic skincare, or precision medicine approaches for specific CHE phenotypes.

Author Response

Dear Reviewer,

We thank you for your constructive comments, which have helped improve our manuscript.

Comment 1: Typo in the title (“nosologocal”).
Response:
Corrected to “nosological.”

Comment 2: Redundancy in the Discussion.
Response:
The Discussion has been streamlined to reduce redundancy and improve flow.

Comment 3: Lack of literature search methodology.
Response:
A concise description of the literature search strategy (databases, keywords, timeframe, and criteria) has been added.

Comment 4: Add subsection on CHE phenotypes.
Response:
A subsection addressing advances in diagnosis and phenotype-oriented management has been included.

Comment 5: Add summary table of DELTA trials.
Response:
We agree this would be valuable; however, we did not include a summary table to avoid excessive manuscript length.

Comment 6: Add schematic diagrams.
Response:
We appreciate the suggestion; however, schematic figures were not added in order to maintain conciseness and avoid further lengthening the manuscript.

Comment 7: Include cosmetic skincare literature.
Response:
Recent literature on cosmetic skincare as adjuvant therapy has been incorporated.

Comment 8: Emphasize synergy and provide practical recommendations.
Response:
The Discussion has been strengthened with emphasis on synergy and practical, phenotype-oriented skincare recommendations.

Comment 9: Expand on future study design and adherence.
Response:
This section has been expanded to address study design considerations and adherence strategies.

Comment 10: Add limitations of the review.
Response:
A limitations paragraph has been added.

Comment 11: Clarify future research directions.
Response:
Future research directions have been specified and aligned with the journal’s focus.

We believe these revisions have improved the manuscript.

Sincerely,

Martina

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

No more comments