Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by the RUCAM: A New Evidence-Based Classification

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The primary aim of this paper is to classify and characterize four types of immune-associated idiosyncratic drug-induced liver injury (iDILI). The goal of the paper is clear, but the introduction could better outline the scope of the study, explain why these particular subtypes were chosen, and how they fit into the broader context of iDILI research.

The introduction mentions traditional idiosyncratic and intrinsic drug-induced liver injury and provides background on immune features in iDILI. However, the distinction between idiosyncratic and intrinsic liver injury could be clarified further.

The introduction could briefly mention the global impact and clinical relevance of DILI to highlight the significance of the review.

The RUCAM section is detailed and informative, but it is suggested to add a critical evaluation of the limitations of RUCAM, particularly in its application for classifying immune-related iDILI. How might new immunological markers or the evolving causal assessment methods impact the future application of RUCAM?

Clinical Features: While the clinical features of each subtype are summarized, it would be valuable to include a discussion of the prognosis and management strategies for each subtype, particularly treatment options for immune-related iDILI patients.

Immune Mechanisms: The immune mechanisms of each subtype could be explored in greater depth. In addition to autoimmune or immune responses, it would be beneficial to discuss the roles of specific immune cells (such as T cells, B cells, and dendritic cells) in each subtype.

Proposing Novel Approaches: Given that the focus of the review is on immune-related iDILI, discussing new diagnostic tools (such as genetic testing or advanced immunological analyses) could improve the classification and diagnosis of these subtypes, making the review more forward-looking and relevant.

Spelling/Grammar: There are some minor spelling issues (e.g., “iDILI” should be consistently written). Terminology: Ensure consistent and accurate use of terms such as “autoimmune hepatitis” and “autoimmune iDILI.”

Overall, the paper provides a valuable review of the immunological features of iDILI and offers an updated classification of the four subtypes. By further strengthening the depth of the immunological discussion and emphasizing clinical relevance, the article would be more complete.

Author Response

Comments and Suggestions for Authors

The primary aim of this paper is to classify and characterize four types of immune-associated idiosyncratic drug-induced liver injury (iDILI). The goal of the paper is clear, but the introduction could better outline the scope of the study, explain why these particular subtypes were chosen, and how they fit into the broader context of iDILI research.

The introduction mentions traditional idiosyncratic and intrinsic drug-induced liver injury and provides background on immune features in iDILI. However, the distinction between idiosyncratic and intrinsic liver injury could be clarified further.

The introduction could briefly mention the global impact and clinical relevance of DILI to highlight the significance of the review.

The RUCAM section is detailed and informative, but it is suggested to add a critical evaluation of the limitations of RUCAM, particularly in its application for classifying immune-related iDILI. How might new immunological markers or the evolving causal assessment methods impact the future application of RUCAM?

Clinical Features: While the clinical features of each subtype are summarized, it would be valuable to include a discussion of the prognosis and management strategies for each subtype, particularly treatment options for immune-related iDILI patients.

Immune Mechanisms: The immune mechanisms of each subtype could be explored in greater depth. In addition to autoimmune or immune responses, it would be beneficial to discuss the roles of specific immune cells (such as T cells, B cells, and dendritic cells) in each subtype.

Proposing Novel Approaches: Given that the focus of the review is on immune-related iDILI, discussing new diagnostic tools (such as genetic testing or advanced immunological analyses) could improve the classification and diagnosis of these subtypes, making the review more forward-looking and relevant.

Spelling/Grammar: There are some minor spelling issues (e.g., “iDILI” should be consistently written). Terminology: Ensure consistent and accurate use of terms such as “autoimmune hepatitis” and “autoimmune iDILI.”

Overall, the paper provides a valuable review of the immunological features of iDILI and offers an updated classification of the four subtypes. By further strengthening the depth of the immunological discussion and emphasizing clinical relevance, the article would be more complete.

Dear Reviewer 1:

 

Thank you for your constructive proposals. Here are my comments:

1. The primary aim was amplified in the abstract and at the end of the introduction.
2. The introduction now clarified the distinction L59-61.
3. The introduction expands now the global impact and clinical relevance L98-101.
4. The RUCAM issues were pointed out later in the text, L130-146.
5. Prognosis and management, now covered on L368-377.
6. Immune mechanisms details were expanded, L362-367.
7. Proposing novel approaches were considered L398-402.
8. Spelling/Grammer was rectified.
9. Overall, thank you for your encouragement.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by RUCAM: A New Evidence Based Classification”. However, it needs major revisions, and I strongly recommend professional English editing.

Please prepare the “References” section following the requirements for authors. 

No blank line spacing between individual references.

For page ranges use the long dash (−) from the symbol function, instead of a short (-) from the keyboard

Please check if the abbreviated name journal is correct according to the ISO4 system

Some other comments include;

I suggested improving the background of the introduction.

Liver injury first which kind of effect need to write introduction.

Line 78 need to write hypothesis.

Line 117 to 121 need to clarify sentence.

Line 128-130 need to rewrite sentence.

Line 213 ALT and ALP

Line 236 add which kind gender and age which affects add specifically.

Line 301-306 need to rewrite sentence

Conclusions not clear need to rewrite.

 

 

 

Author Response

Reviewer 2:

 

Comments and Suggestions for Authors

The manuscript entitled “Immunology Highlights of Four Major Idiosyncratic DILI Subtypes Verified by RUCAM: A New Evidence Based Classification”. However, it needs major revisions, and I strongly recommend professional English editing.

Please prepare the “References” section following the requirements for authors. 

No blank line spacing between individual references.

For page ranges use the long dash (−) from the symbol function, instead of a short (-) from the keyboard

Please check if the abbreviated name journal is correct according to the ISO4 system

Some other comments include;

I suggested improving the background of the introduction.

Liver injury first which kind of effect need to write introduction.

Line 78 need to write hypothesis.

Old L117 to 121 need to clarify sentence.

Line 128-130 need to rewrite sentence.

Line 213 ALT and ALP

Line 236 add which kind gender and age which affects add specifically.

Line 301-306 need to rewrite sentence

Conclusions not clear need to rewrite.

Dear Reviewer 2:

 

Thank you for your valuable suggestions. Here are my answers:

1. Major revision and English editing were done.
2. References, there are now no blank lines any more. Long dashes could not be included (my PC does not provide this symbol), this hopefully can be done by the production section.
3. Abbreviations were checked and are correct: ref 36 and 121.
4. Background was improved, L10-15 and last para of introduction.
5. Liver injury was clarified on L299
6. Old L78, hypothesis does not fit here. Instead, I included the term ”proposal” on new L99, which reads now on L96-99: The aim was to characterize these four different types and formulate the results of the analysis as a practical proposal for clinical use, because patients with iDILI and an immune or autoimmune background could well benefit from a steroid therapy.
7. Old L117-121, now: L149-153 has been clarified.
8. Old L128-130, has been deleted: new L 160-162.
9. Old L 213 but likely L230, ALT and ALP remained and “as well” was deleted, new L246.
10. Old L236, not found here but included on new L269.
11. Conclusion, clarification was made.

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript comprehensively classifies drugs based on the immunological concept of four types of iDILI based on RUCAM, and provides important evidence for the future application of iDILI.

It will be a good reference for the safety evaluation of clinical fields and new drug development by utilizing immunological profiles according to the classification of drug-related iDILI.

The following supplements are required.

1. Additional introduction of drugs that are not clearly classified into four types and additional discussion on future medical measures are required.

2. Discussion on the addition or consideration of related parameters other than the four types is required, as the influence of prior drug administration should be considered in many patients even if included in DIAIH.

3. The differences between RUCAM and other cohort analysis methods and the prospects for linking data should be included in the discussion.

 

 

Author Response

Reviewer 3:

 

Comments and Suggestions for Authors

This manuscript comprehensively classifies drugs based on the immunological concept of four types of iDILI based on RUCAM, and provides important evidence for the future application of iDILI.

It will be a good reference for the safety evaluation of clinical fields and new drug development by utilizing immunological profiles according to the classification of drug-related iDILI.

The following supplements are required.

1. Additional introduction of drugs that are not clearly classified into four types and additional discussion on future medical measures are required.
2. Discussion on the addition or consideration of related parameters other than the four types is required, as the influence of prior drug administration should be considered in many patients even if included in DIAIH.
3. The differences between RUCAM and other cohort analysis methods and the prospects for linking data should be included in the discussion.

Dear Reviewer 3:

 

Thank you for your recommendations, here are my comments:

1. Introduction, comment was added that many cases were without classification, and future measures were discussed on L96-101 and more specifically at the end of the conclusions.
2. Other parameters were discussed on L142-146, and prior drug use on L121-123.
3. Differences between RUCAM and other tools are now discussed on L130-140.

 

 

 

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Accepted