The Personalized Management of Primary Biliary Cholangitis in the Era of Precision Medicine: Current Challenges and Future Perspectives

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a comprehensive review on the personalized management of PBC. The article is well-structured and accurately presents current trends in PBC treatment. The synthesis of modern therapeutics, non-invasive prognostic tools and future perspectives including -omics is of high quality. 

I have the following comments:

1. In Future Perspectives the discussion on new markers is strong. Please consider adding a brief section explaining how these promising signatures can affect clinical decisions.

2. Figure 2 is a great diagram, but the "TAILORED APPROACH" part should be revised to be clearer and easier to read.
3. Prognosis and Predicting treatment response sections are a bit mixed. You could integrate them into a single section.

Author Response

Reviewer 1

This is a comprehensive review on the personalized management of PBC. The article is well-structured and accurately presents current trends in PBC treatment. The synthesis of modern therapeutics, non-invasive prognostic tools and future perspectives including -omics is of high quality.

I have the following comments:

• In Future Perspectives the discussion on new markers is strong. Please consider adding a brief section explaining how these promising signatures can affect clinical decisions.

Reply:  We sincerely thank the Reviewer for this valuable suggestion. In line with the request, we have expanded the Future Perspectives section by adding a dedicated subsection that explicitly addresses how emerging biomarker signatures may influence clinical decision-making in PBC. This new section highlights their potential role in early risk stratification, dynamic monitoring of therapeutic response, individualized treatment allocation, and prognostic refinement, thereby bridging mechanistic insights with actionable strategies in precision medicine. We believe this addition strengthens the translational relevance of our discussion and clarifies the impact of novel markers on patient management.

 

• Figure 2 is a great diagram, but the "TAILORED APPROACH" part should be revised to be clearer and easier to read.

Reply: We thank the Reviewer for the positive feedback on Figure 2 and for the helpful suggestion. In response, we have revised the “TAILORED APPROACH” section of the diagram to improve clarity and readability. Specifically, we simplified the wording, reorganized the layout to highlight the key steps in patient stratification and therapeutic decision-making, and ensured that the visual flow is more intuitive. We believe these modifications enhance the figure’s accessibility and strengthen its role in illustrating the transition from conventional to personalized management strategies in PBC.

 

• Prognosis and Predicting treatment response sections are a bit mixed. You could integrate them into a single section.

Reply: We sincerely thank the Reviewer for this precious suggestion. In the revised version of our manuscript, prognosis and predicting treatment response have been integrated into a single section.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a comprehensive and well-structured review of the personalized management of Primary Biliary Cholangitis (PBC), offering an in-depth synthesis of pathogenesis, diagnostic evolution, prognostic tools, and emerging therapeutic options within the framework of precision medicine.

The scientific quality is overall high, with extensive referencing, clear explanations of mechanistic pathways, and a coherent narrative connecting clinical heterogeneity to the need for individualized care.

Methodologically, the review is rigorous in its literature appraisal, although at times overly descriptive, leading to sections that feel disproportionately long and potentially overwhelming for readers.

The results and discussions are relevant, particularly the critical analysis of UDCA non-responsiveness, the nuanced examination of OCA’s regulatory setbacks, and the balanced presentation of new PPAR agonists.

The conclusions are well aligned with the evidence, highlighting unmet needs and future directions. However, the manuscript would benefit from improved conciseness, clearer synthesis tables, and a more explicit critical appraisal rather than primarily descriptive reporting. 

The authors are invited to take the following items into consideration during the revision of manuscript:

-Could the authors provide a more explicit critical comparison of PPAR agonists (elafibranor vs. seladelpar) beyond biochemical response, especially regarding long-term benefit uncertainty?

-The discussion of OCA would benefit from a more balanced view, including whether any subgroups could still theoretically benefit despite regulatory withdrawal. Can the authors comment?

-The review is extremely long; can the authors condense sections on epidemiology and diagnosis to enhance readability?

Several mechanistic descriptions (e.g., bile acid transporters, IL-31 pathways) could be summarized with more targeted focus. Would the authors consider adding a graphical overview?

-Can the authors clarify how precision-medicine tools (biomarkers, scores, AI-based prediction models) may realistically be integrated into routine care in the next decade?

Author Response

The authors are invited to take the following items into consideration during the revision of manuscript:

• Could the authors provide a more explicit critical comparison of PPAR agonists (elafibranor vs. seladelpar) beyond biochemical response, especially regarding long-term benefit uncertainty?

Reply: We sincerely thank the Reviewer for this insightful comment. In accordance with the suggestion, in the revised version of our manuscript, we have expanded the discussion to provide a more explicit critical comparison between elafibranor and seladelpar beyond their biochemical efficacy, remarking on both the strengths and the residual uncertainties regarding their long-term clinical benefit.

 

• The discussion of OCA would benefit from a more balanced view, including whether any subgroups could still theoretically benefit despite regulatory withdrawal. Can the authors comment?

Reply: We sincerely thank the Reviewer for this constructive comment. In response, we have revised the discussion on OCA to provide a more balanced perspective by incorporating this view into the revised version of our manuscript, emphasizing both the limitations of current evidence and the residual theoretical benefit in specific subgroups, as suggested.

 

• The review is extremely long; can the authors condense sections on epidemiology and diagnosis to enhance readability?

Reply: We sincerely appreciate the Reviewer’s observation regarding the length of the manuscript. In response, we have carefully condensed the sections on epidemiology and diagnosis by streamlining descriptive details, removing redundancies, and focusing on the most clinically relevant information. This revision enhances readability while preserving the essential context and scientific rigor of the discussion.

 

• Several mechanistic descriptions (e.g., bile acid transporters, IL-31 pathways) could be summarized with more targeted focus. Would the authors consider adding a graphical overview?

Reply: We thank the Reviewer for this constructive suggestion. In line with the request, we have prepared a graphical overview that summarizes the key mechanistic pathways discussed in the manuscript.

 

• Can the authors clarify how precision-medicine tools (biomarkers, scores, AI-based prediction models) may realistically be integrated into routine care in the next decade?

Reply: We are grateful to the Reviewer for this insightful recommendation. In accordance with the request, we have revised the Future Perspectives section by introducing a dedicated subsection that specifically discusses the potential impact of emerging (bio)marker signatures on clinical decision-making in PBC. This addition underscores their relevance for early patient stratification, real-time monitoring of therapeutic efficacy, individualized treatment selection, and refinement of prognostic assessment, thereby linking mechanistic discoveries with practical applications in precision medicine. We believe that this expansion enhances the translational dimension of our discussion and provides a clearer perspective on how novel tools may shape patient management strategies.

Author Response File: Author Response.pdf