Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors

Round 1

Reviewer 1 Report

The authors propose to review the diferent cutaneous side effects related to immune checkpoint inhibitor treament. Especially focusing on the most serious adverse events, this review intends to shed light to a global health issue. The amount of references cited seems to cover a relevant percentage of the published material in the field.

Unfortunately, the manuscript is not really easy to read, some paragraphs are redundant and often the text is an exact copy-pasting of the cited reference. The English is rather poor and altogether it makes the whole document rather unpalatable. 

Hereafter is a non-exhaustive list of the suggested changes in the English. 

In addition, the conclusion does not develop enough around the commonalities of the different irAEs which could help clinicians to better understand and eventually anticipate and treat those irAEs globally and not only individually. No doubt that genome profiling may provide important data and help elaborate new hypothesis, but other multi-omics data are more likely to be needed to get a clearer picture. 

The manuscript would need major improvement before being published. 

 

Comments for author File: Comments.pdf

Comments about the English are included in the attached .pdf file and the above review.

nothing to add. 

 

Author Response

• Comment 1:

The authors propose to review the diferent cutaneous side effects related to immune checkpoint inhibitor treament. Especially focusing on the most serious adverse events, this review intends to shed light to a global health issue. The amount of references cited seems to cover a relevant percentage of the published material in the field. Unfortunately, the manuscript is not really easy to read, some paragraphs are redundant and often the text is an exact copy-pasting of the cited reference. The English is rather poor and altogether it makes the whole document rather unpalatable. Hereafter is a non-exhaustive list of the suggested changes in the English.

Response:

Thank you for pointing this out. Therefore, we have corrected all spelling and grammatical errors that you pointed out in this article. Additionally, we have rephrase certain paragraphs and improve the overall readability of the article.

 

• Comment 2:

In addition, the conclusion does not develop enough around the commonalities of the different irAEs which could help clinicians to better understand and eventually anticipate and treat those irAEs globally and not only individually. No doubt that genome profiling may provide important data and help elaborate new hypothesis, but other multi-omics data are more likely to be needed to get a clearer picture. The manuscript would need major improvement before being published.

Response:

Thank you for this suggestion. We agree with this and we have, accordingly, modified the paragraph in the conclusion to emphasize this point. In the revised conclusion, we have added an additional paragraph to discuss the shared characteristics among various immune-related adverse events (irAEs).

Reviewer 2 Report

Please define, discuss and justify the search criteria to add certain references and choose relevant and important topics for this manuscript.

It is ok.

Author Response

• Comment 1:

Please define, discuss and justify the search criteria to add certain references and choose relevant and important topics for this manuscript.

• Comment 2:

Authors provided relevant references (ref: 8, 10, 11, 12, 13, 14) to support this topic but did not search criteria to include/exclude studies in this manuscript.

Response:

Thank you for your suggestion. As a narrative review, this article does not include the specific search criteria in the text. However, in response to reviewer 2's feedback, we have included an additional paragraph to provide a simplified explanation of our search strategy, including the criteria for inclusion and exclusion.

Reviewer 3 Report

This paper, entitled “Molecular mechanisms of cutaneous immune-related adverse events (irAEs) induced by immune checkpoint inhibitors”, provide an overview about on the ICIs induced skin manifestations and its possible mechanisms.

The topic is interesting, also in consideration of the ever-increasing indications for this type of drugs. However, some changes are necessary before this work can be considered for publication.

 

The main criticisms are as follows:

 

Some information on the management of skin reactions caused by ICIs should be included. Moreover, some explanatory clinical images of the main manifestations could help, also in consideration of the objectives set by the authors (early recognition and treatment). 

 

Often, the appearance of irAEs is related to the patient's prognosis, for example, the appearance of vitiligo during treatment has a favorable prognostic value. This aspect should be discussed.

 

In the literature there are numerous reports, even as small case reports or single case reports, relating to other immune-related cutaneous adverse events. these should at least be mentioned, in a separate paragraph.

 

I suggest also to include the percentages for each side effect in the Summary Table.

 

There are some typos and formatting errors, which need to be corrected.

This paper, entitled “Molecular mechanisms of cutaneous immune-related adverse events (irAEs) induced by immune checkpoint inhibitors”, provide an overview about on the ICIs induced skin manifestations and its possible mechanisms.

The topic is interesting, also in consideration of the ever-increasing indications for this type of drugs. However, some changes are necessary before this work can be considered for publication.

 

The main criticisms are as follows:

 

Some information on the management of skin reactions caused by ICIs should be included. Moreover, some explanatory clinical images of the main manifestations could help, also in consideration of the objectives set by the authors (early recognition and treatment). 

 

Often, the appearance of irAEs is related to the patient's prognosis, for example, the appearance of vitiligo during treatment has a favorable prognostic value. This aspect should be discussed.

 

In the literature there are numerous reports, even as small case reports or single case reports, relating to other immune-related cutaneous adverse events. these should at least be mentioned, in a separate paragraph.

 

I suggest also to include the percentages for each side effect in the Summary Table.

 

There are some typos and formatting errors, which need to be corrected.

Author Response

• Comment 1:

Some information on the management of skin reactions caused by ICIs should be included. Moreover, some explanatory clinical images of the main manifestations could help, also in consideration of the objectives set by the authors (early recognition and treatment).

Response:

Thank you for your opinions. However, in this review, our primary focus is to explore the underlying mechanisms of cutaneous immune-related adverse events (irAEs), rather than discussing their management. Therefore, we have not extensively covered the treatment options associated with cutaneous irAEs.

 

• Comment 2:

Often, the appearance of irAEs is related to the patient's prognosis, for example, the appearance of vitiligo during treatment has a favorable prognostic value. This aspect should be discussed.

Response:

Thank you for pointing this out. In this article, we have already discussed the favorable prognosis associated with VLD in the previous paragraph (line 363-367 in revised version). However, in response to the feedback from Reviewer 3, we have incorporated an additional paragraph in the final section to address the prognosis of cutaneous irAEs.

 

• Comment 3:

In the literature there are numerous reports, even as small case reports or single case reports, relating to other immune-related cutaneous adverse events. these should at least be mentioned, in a separate paragraph.

Response:

Thank you for your suggestion. We agree with this and have revised the paragraph accordingly.

 

• Comment 4:

I suggest also to include the percentages for each side effect in the Summary Table.

Response:

Thank you for your comment. We have included the frequency of each cutaneous immune-related adverse event (irAE) in the summary table.

 

• Comment 5:

There are some typos and formatting errors, which need to be corrected.

Response:

Thank you for pointing this out. We have addressed and corrected all spelling and formatting errors present in the manuscript.

Reviewer 4 Report

This review has the main objective of giving an overview of the cutaneous immune-related adverse events induced by immune checkpoint inhibitors (ICIs), with particular attention to the molecular mechanisms.

The topic of the MS is interesting and up-to-date, since the use of ICIs in the management of the different types of cancer represents, at present, an important immunotherapeutic option although frequently associated with the onset of irAEs that need to be better investigated.

In my opinion, the MS needs to be revised before being accepted for publication.

Why the AAs decided to indicate only the FDA-approved ICIs for cutaneous malignancies? Is there any association between cutaneous malignancies and improved frequency of manifesting cutaneous irAEs? If so, this information must be clearly stated, otherwise, it is necessary to explain why not all the FDA-approved ICIs have been listed. 

In my opinion, a table summarizing the frequency of the different types of irAEs in the different malignancies could be added. 

Author Response

• Comment 1:

In my opinion, the MS needs to be revised before being accepted for publication. Why the AAs decided to indicate only the FDA-approved ICIs for cutaneous malignancies? Is there any association between cutaneous malignancies and improved frequency of manifesting cutaneous irAEs? If so, this information must be clearly stated, otherwise, it is necessary to explain why not all the FDA-approved ICIs have been listed.  Response:

Thank you for your suggestion. However, this review specifically focuses on cutaneous irAEs, which led us to exclusively list the FDA-approved immune checkpoint inhibitors (ICIs) for the treatment of cutaneous malignancies.

 

• Comment 2:

In my opinion, a table summarizing the frequency of the different types of irAEs in the different malignancies could be added.

Response:

We have included the frequency of each cutaneous immune-related adverse event (irAE) in the summary table.

Round 2

Reviewer 1 Report

The manuscript has been decently improved by the authors. There paragraphs that were unclear are much better now. There are still some typos but nothing dramatic. 

The part 6 is very interesting per se, but is not fitting with the purpose of the review. If you're willing to keep it in, you may want to adjust abstract and conclusion to include this. Especially for the conclusion, more outlook about the way to include the irAEs in the patient stratification and treatment strategy would be of real value. 

The quality of the English has been significantly improved. The manuscript now reads well. 

 

Author Response

We appreciate your suggestion, and we concur with it. Consequently, we have made the necessary modifications to the abstract and included an additional paragraph in the conclusion to highlight this particular point.

Reviewer 3 Report

The paper can be accepted in the present form

The paper can be accepted in the present form

Author Response

Thank you for your comments.