Title: Early assessment of treatment response in primary biliary cholangitis: key to timely
management
Version: 2 Date: 29 May 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
No - there are major issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Not sure - I am not able to assess the statistics in this study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This study examined predictive factors for complete biochemical
response (CBR) in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic
acid (UDCA). It included 155 patients from two Slovak hepatology centers between 1999–
2024. CBR was defined as normal bilirubin and ALP levels. At 12 months, 41.3% achieved
CBR; by the end of follow-up, 32.9% did. Achieving Toronto response at 6 months strongly
predicted later CBR (OR 46.36, p<0.001), especially in patients without cirrhosis. No hepatic
decompensation or liver-related mortality occurred in patients with sustained CBR. Early
response to UDCA predicts long-term outcomes and helps guide treatment escalation
Pro
This is a multicenter study, that has dug deep into the files in order to collect a large number of
data points. The effort must have been enormous.
Con
The relevance of meeting CBR and getting beyond the Toronto rules is well known and a plethora
of studies have shown that. At best this is a replication effort at worst it produces data that cannot
be compared as the authors have used incomparable timing (last check-up)
The authors use multiple  endpoints : normal bilirubin and ALP levels at 12 months & last check
up ALP # 1.67 × ULN and total bilirubin # 2 × ULN  after 6 months.
Please provide adequate references and background for the choice and timing of your endpoints
and align them with the literature. For example A reduction in serum alkaline phosphatase (ALP)
to less than 1.67 times the upper limit of normal (ULN) and a normal total bilirubin level at
12 months (but not 6 months) is considered an acceptable primary surrogate endpoint for PBC
by the FDA.
They select the primary outcome as the proportion of patients that achieved CBR, defined
as normal bilirubine and normal ALP levels, at last check-up. Please provide a thorough
argumentation and reference for the timing , specifically for the timing of last check.
Structure and style
Personally I am not a fan of ample use of bullet points in a scientific article, in particular the
methods results and discussion. I would like to see these points integrated in the text.
The authors use 9(!) tables and 9 figures to make their point. This manuscript deals with the
analysis of only 155 patients with PBC. I urge the authors to stick to their main message and
illustrate that. The overwhelming set of tables and figures is unattractive, will put readers off
and suggest that the authors were unable to choose. My suggestion is to limit to 2 tables and
1 figure (w/o panels)
REQUESTED REVISIONS:
I was unable to see how the authors dealt with use of first line and second line therapy. It appears
that these 43 patients were included in the analysis, is that correct? Why was that, it is reasonable
to surmise that these patients will follow a different trajectory? For example during the first  6
months they might have received only UDCA and received add second line therapy later so this
will affect the outcomes at last check up
How was the decision for second line treatment taken, according to local guidelines? Please cite.
Where the patients on OCA derived from a clinical trial?
ADDITIONAL REQUESTS/SUGGESTIONS:
There are a number of major / minor adjustments that the authors may want consider that are
listed below
I was unable to check which patients went into which table as the number of patients is lacking
from the tables. Please correct
Why was fenofibrate taken as a second line drug and not bezafibrate of ciprofibrate? A
multicenter exploratory study from Brazil evaluated the long-term biochemical responses of
different fibrates, including ciprofibrate, in patients with UDCA-unresponsive PBC. The study
found that combination therapy with either ciprofibrate or bezafibrate resulted in significant
decreases in ALP after two years. PMID 35126149
The first lines in the discussion usually summarize the main findings from the study. Here the
authors choose to provide a textbook piece rather than to put their findings first.
Title: Early assessment of treatment response in primary biliary cholangitis: key to timely
management
Version: 2 Date: 29 May 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
No - there are major issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Not sure - I am not able to assess the statistics in this study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This study examined predictive factors for complete biochemical
response (CBR) in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic
acid (UDCA). It included 155 patients from two Slovak hepatology centers between 1999–
2024. CBR was defined as normal bilirubin and ALP levels. At 12 months, 41.3% achieved
CBR; by the end of follow-up, 32.9% did. Achieving Toronto response at 6 months strongly
predicted later CBR (OR 46.36, p<0.001), especially in patients without cirrhosis. No hepatic
decompensation or liver-related mortality occurred in patients with sustained CBR. Early
response to UDCA predicts long-term outcomes and helps guide treatment escalation
Pro
This is a multicenter study, that has dug deep into the files in order to collect a large number of
data points. The effort must have been enormous.
Con
The relevance of meeting CBR and getting beyond the Toronto rules is well known and a plethora
of studies have shown that. At best this is a replication effort at worst it produces data that cannot
be compared as the authors have used incomparable timing (last check-up)
The authors use multiple  endpoints : normal bilirubin and ALP levels at 12 months & last check
up ALP # 1.67 × ULN and total bilirubin # 2 × ULN  after 6 months.
Please provide adequate references and background for the choice and timing of your endpoints
and align them with the literature. For example A reduction in serum alkaline phosphatase (ALP)
to less than 1.67 times the upper limit of normal (ULN) and a normal total bilirubin level at
12 months (but not 6 months) is considered an acceptable primary surrogate endpoint for PBC
by the FDA.
They select the primary outcome as the proportion of patients that achieved CBR, defined
as normal bilirubine and normal ALP levels, at last check-up. Please provide a thorough
argumentation and reference for the timing , specifically for the timing of last check.
Structure and style
Personally I am not a fan of ample use of bullet points in a scientific article, in particular the
methods results and discussion. I would like to see these points integrated in the text.
The authors use 9(!) tables and 9 figures to make their point. This manuscript deals with the
analysis of only 155 patients with PBC. I urge the authors to stick to their main message and
illustrate that. The overwhelming set of tables and figures is unattractive, will put readers off
and suggest that the authors were unable to choose. My suggestion is to limit to 2 tables and
1 figure (w/o panels)
REQUESTED REVISIONS:
I was unable to see how the authors dealt with use of first line and second line therapy. It appears
that these 43 patients were included in the analysis, is that correct? Why was that, it is reasonable
to surmise that these patients will follow a different trajectory? For example during the first  6
months they might have received only UDCA and received add second line therapy later so this
will affect the outcomes at last check up
How was the decision for second line treatment taken, according to local guidelines? Please cite.
Where the patients on OCA derived from a clinical trial?
ADDITIONAL REQUESTS/SUGGESTIONS:
There are a number of major / minor adjustments that the authors may want consider that are
listed below
I was unable to check which patients went into which table as the number of patients is lacking
from the tables. Please correct
Why was fenofibrate taken as a second line drug and not bezafibrate of ciprofibrate? A
multicenter exploratory study from Brazil evaluated the long-term biochemical responses of
different fibrates, including ciprofibrate, in patients with UDCA-unresponsive PBC. The study
found that combination therapy with either ciprofibrate or bezafibrate resulted in significant
decreases in ALP after two years. PMID 35126149
The first lines in the discussion usually summarize the main findings from the study. Here the
authors choose to provide a textbook piece rather than to put their findings first.
Please review this paper.
user
Title: Early assessment of treatment response in primary biliary cholangitis: key to timely
management
Version: 2 Date: 29 May 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?
No - there are major issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Not sure - key details are missing from the manuscript
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Not sure - I am not able to assess the statistics in this study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This study examined predictive factors for complete biochemical
response (CBR) in primary biliary cholangitis (PBC) patients treated with ursodeoxycholic
acid (UDCA). It included 155 patients from two Slovak hepatology centers between 1999–
2024. CBR was defined as normal bilirubin and ALP levels. At 12 months, 41.3% achieved
CBR; by the end of follow-up, 32.9% did. Achieving Toronto response at 6 months strongly
predicted later CBR (OR 46.36, p<0.001), especially in patients without cirrhosis. No hepatic
decompensation or liver-related mortality occurred in patients with sustained CBR. Early
response to UDCA predicts long-term outcomes and helps guide treatment escalation
Pro
This is a multicenter study, that has dug deep into the files in order to collect a large number of
data points. The effort must have been enormous.
Con
The relevance of meeting CBR and getting beyond the Toronto rules is well known and a plethora
of studies have shown that. At best this is a replication effort at worst it produces data that cannot
be compared as the authors have used incomparable timing (last check-up)
The authors use multiple  endpoints : normal bilirubin and ALP levels at 12 months & last check
up ALP # 1.67 × ULN and total bilirubin # 2 × ULN  after 6 months.
Please provide adequate references and background for the choice and timing of your endpoints
and align them with the literature. For example A reduction in serum alkaline phosphatase (ALP)
to less than 1.67 times the upper limit of normal (ULN) and a normal total bilirubin level at
12 months (but not 6 months) is considered an acceptable primary surrogate endpoint for PBC
by the FDA.
They select the primary outcome as the proportion of patients that achieved CBR, defined
as normal bilirubine and normal ALP levels, at last check-up. Please provide a thorough
argumentation and reference for the timing , specifically for the timing of last check.
Structure and style
Personally I am not a fan of ample use of bullet points in a scientific article, in particular the
methods results and discussion. I would like to see these points integrated in the text.
The authors use 9(!) tables and 9 figures to make their point. This manuscript deals with the
analysis of only 155 patients with PBC. I urge the authors to stick to their main message and
illustrate that. The overwhelming set of tables and figures is unattractive, will put readers off
and suggest that the authors were unable to choose. My suggestion is to limit to 2 tables and
1 figure (w/o panels)
REQUESTED REVISIONS:
I was unable to see how the authors dealt with use of first line and second line therapy. It appears
that these 43 patients were included in the analysis, is that correct? Why was that, it is reasonable
to surmise that these patients will follow a different trajectory? For example during the first  6
months they might have received only UDCA and received add second line therapy later so this
will affect the outcomes at last check up
How was the decision for second line treatment taken, according to local guidelines? Please cite.
Where the patients on OCA derived from a clinical trial?
ADDITIONAL REQUESTS/SUGGESTIONS:
There are a number of major / minor adjustments that the authors may want consider that are
listed below
I was unable to check which patients went into which table as the number of patients is lacking
from the tables. Please correct
Why was fenofibrate taken as a second line drug and not bezafibrate of ciprofibrate? A
multicenter exploratory study from Brazil evaluated the long-term biochemical responses of
different fibrates, including ciprofibrate, in patients with UDCA-unresponsive PBC. The study
found that combination therapy with either ciprofibrate or bezafibrate resulted in significant
decreases in ALP after two years. PMID 35126149
The first lines in the discussion usually summarize the main findings from the study. Here the
authors choose to provide a textbook piece rather than to put their findings first.
assistant