Reviewer ’s report  
 
Title:  Association between serum IgG level and clinical course in primary sclerosing cholangitis  
 
Version: 0 Date: 30 Jun 2019 
 
Reviewer:  Karim  Hamesch  
 
Reviewer’s report:  
 
Hippchen and colleagues submitted a manuscript of a retrospective, longitudinal, monocentric 
cohort study  assessing whether serum IgG may predict the clinical course in PSC. Interestingly, 
serum IgG appears to be an independent risk factor for reduced transplant -free survival with 
potential implications for risk stratification of patients at the time of initi al diagnosis.  
 
The advantages are that the proposed marker is easy to implement (widely available and quite 
cheap) and that not many attractive predictive markers for PSC exist. Moreover, the cohort of 
decent size has a quite long follow -up. The manuscript is quite clear and the main message is of 
potential clinical relevance. Moreover, the authors have a track record in PSC and openly discuss 
the various weaknesses of this manuscript.  
 
However, among the disadvantages, are the retrospective design with incom plete data and that 
the cohort is monocentric.  
 
Overall, the conclusions made appear to be supported by the provided data. While the 
retrospective design has some drawbacks (which were acknowledged by the authors) the 
longitudinal follow -up offers interest ing insights, especially should IgG be able to predict other 
complications of PSC such as development of stenoses or cholangitis. The results of this 
interesting dataset might have an impact for GI specialists/hepatologists but several aspects need 
clarifi cation.  
 
I congratulate the authors on this manuscript as the findings add knowledge to the field and some 
of the results could directly translate into clinical management.  
 
 
Major aspects  
 
1) Please add the following parameters to table 2: MELD and fulfill ment of excMELD 
criteria (current SE for PSC according to Eurotransplant) at diagnosis (i.e. same time as 
IgG measurement). Please compare IgG to MELD in Fig. 1 - does IgG outperform 
MELD or perform comparably? Please also show ROC curves with AUROC. Which  cut-
off for IgG has a reasonable sensitivity and specificity?  
 
2) Did increased serum IgG levels predict the occurrence of dominant stenoses and/or 
recurrent cholangitis during follow -up? 
 
3) Please add the following parameters to table 1 and 3, if availab le: MELD (at 
inclusion/measurement of IgG), fulfillment of excMELD criteria (at 
inclusion/measurement of IgG), BMI (at inclusion/measurement of IgG), presence of 
diabetes, concomitant mean alcohol consumption, histological confirmation of diagnosis. 
Please  also add (at inclusion/measurement of IgG), also if only partly available: ANA, 
aSMA, SLA, LKM1, pANCA, AMA -M2, gp210, sp100, IgG4  
 
4) Please add Mayo risk score as well as LTX, Re -LTX, death, combined end point, and 
CCC (during follow -up) to Table 1.  
 
5) Please adjust the Cox regression analysis should any of the above mentioned parameters 
be a relevant confounder.  
 
6) Due to the described weaknesses of the study and the not so large effect size/significance 
level, a replication cohort would be ideal. At lea st this should be discussed.  
 
7) Please clearly state the a priori hypotheses. Were the criteria defined before statistical 
analysis?  
 
8) As some patients needed Re -LTX: Was this due to recurrent PSC? If yes, did high IgG 
levels point to recurrent PSC (albei t the low sample size)?  
 
9) Which ethnicity did the studied patients have? If the majority was not of the same 
ethnicity: Did it affect the results?  
 
10) Regarding the modeling: Did the authors account for cross correlation of variables for 
modeling of the c ox regression? Was prevention of over -fitting of the model attempted?  
 
 
Minor aspects  
 
11) Please clarify when exactly serum IgG was measured. I assume it is at time of 
diagnosis/inclusion, i.e. no serum samples were thawed in order to determine IgG 
afterwa rds. 
 
12) Did all patients receive ERC or were some diagnoses based on MRCP findings?  
 
13) Several language and typography errors as well as formal mistakes should be corrected.  
 
14) Please provide a diagram showing the inclusion and exclusion criteria. This should point 
out how other causes of (autoimmune) liver disease were ruled out (see also aspect 3) and 
how many patients were biopsied. For example, refer to the CONSORT statem ent. 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not,  please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relatin g to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload wil l be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4 .0/). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  Association between serum IgG level and clinical course in primary sclerosing cholangitis  
 
Version: 0 Date: 30 Jun 2019 
 
Reviewer:  Karim  Hamesch  
 
Reviewer’s report:  
 
Hippchen and colleagues submitted a manuscript of a retrospective, longitudinal, monocentric 
cohort study  assessing whether serum IgG may predict the clinical course in PSC. Interestingly, 
serum IgG appears to be an independent risk factor for reduced transplant -free survival with 
potential implications for risk stratification of patients at the time of initi al diagnosis.  
 
The advantages are that the proposed marker is easy to implement (widely available and quite 
cheap) and that not many attractive predictive markers for PSC exist. Moreover, the cohort of 
decent size has a quite long follow -up. The manuscript is quite clear and the main message is of 
potential clinical relevance. Moreover, the authors have a track record in PSC and openly discuss 
the various weaknesses of this manuscript.  
 
However, among the disadvantages, are the retrospective design with incom plete data and that 
the cohort is monocentric.  
 
Overall, the conclusions made appear to be supported by the provided data. While the 
retrospective design has some drawbacks (which were acknowledged by the authors) the 
longitudinal follow -up offers interest ing insights, especially should IgG be able to predict other 
complications of PSC such as development of stenoses or cholangitis. The results of this 
interesting dataset might have an impact for GI specialists/hepatologists but several aspects need 
clarifi cation.  
 
I congratulate the authors on this manuscript as the findings add knowledge to the field and some 
of the results could directly translate into clinical management.  
 
 
Major aspects  
 
1) Please add the following parameters to table 2: MELD and fulfill ment of excMELD 
criteria (current SE for PSC according to Eurotransplant) at diagnosis (i.e. same time as 
IgG measurement). Please compare IgG to MELD in Fig. 1 - does IgG outperform 
MELD or perform comparably? Please also show ROC curves with AUROC. Which  cut-
off for IgG has a reasonable sensitivity and specificity?  
 
2) Did increased serum IgG levels predict the occurrence of dominant stenoses and/or 
recurrent cholangitis during follow -up? 
 
3) Please add the following parameters to table 1 and 3, if availab le: MELD (at 
inclusion/measurement of IgG), fulfillment of excMELD criteria (at 
inclusion/measurement of IgG), BMI (at inclusion/measurement of IgG), presence of 
diabetes, concomitant mean alcohol consumption, histological confirmation of diagnosis. 
Please  also add (at inclusion/measurement of IgG), also if only partly available: ANA, 
aSMA, SLA, LKM1, pANCA, AMA -M2, gp210, sp100, IgG4  
 
4) Please add Mayo risk score as well as LTX, Re -LTX, death, combined end point, and 
CCC (during follow -up) to Table 1.  
 
5) Please adjust the Cox regression analysis should any of the above mentioned parameters 
be a relevant confounder.  
 
6) Due to the described weaknesses of the study and the not so large effect size/significance 
level, a replication cohort would be ideal. At lea st this should be discussed.  
 
7) Please clearly state the a priori hypotheses. Were the criteria defined before statistical 
analysis?  
 
8) As some patients needed Re -LTX: Was this due to recurrent PSC? If yes, did high IgG 
levels point to recurrent PSC (albei t the low sample size)?  
 
9) Which ethnicity did the studied patients have? If the majority was not of the same 
ethnicity: Did it affect the results?  
 
10) Regarding the modeling: Did the authors account for cross correlation of variables for 
modeling of the c ox regression? Was prevention of over -fitting of the model attempted?  
 
 
Minor aspects  
 
11) Please clarify when exactly serum IgG was measured. I assume it is at time of 
diagnosis/inclusion, i.e. no serum samples were thawed in order to determine IgG 
afterwa rds. 
 
12) Did all patients receive ERC or were some diagnoses based on MRCP findings?  
 
13) Several language and typography errors as well as formal mistakes should be corrected.  
 
14) Please provide a diagram showing the inclusion and exclusion criteria. This should point 
out how other causes of (autoimmune) liver disease were ruled out (see also aspect 3) and 
how many patients were biopsied. For example, refer to the CONSORT statem ent. 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not,  please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relatin g to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload wil l be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4 .0/). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  Association between serum IgG level and clinical course in primary sclerosing cholangitis  
 
Version: 0 Date: 30 Jun 2019 
 
Reviewer:  Karim  Hamesch  
 
Reviewer’s report:  
 
Hippchen and colleagues submitted a manuscript of a retrospective, longitudinal, monocentric 
cohort study  assessing whether serum IgG may predict the clinical course in PSC. Interestingly, 
serum IgG appears to be an independent risk factor for reduced transplant -free survival with 
potential implications for risk stratification of patients at the time of initi al diagnosis.  
 
The advantages are that the proposed marker is easy to implement (widely available and quite 
cheap) and that not many attractive predictive markers for PSC exist. Moreover, the cohort of 
decent size has a quite long follow -up. The manuscript is quite clear and the main message is of 
potential clinical relevance. Moreover, the authors have a track record in PSC and openly discuss 
the various weaknesses of this manuscript.  
 
However, among the disadvantages, are the retrospective design with incom plete data and that 
the cohort is monocentric.  
 
Overall, the conclusions made appear to be supported by the provided data. While the 
retrospective design has some drawbacks (which were acknowledged by the authors) the 
longitudinal follow -up offers interest ing insights, especially should IgG be able to predict other 
complications of PSC such as development of stenoses or cholangitis. The results of this 
interesting dataset might have an impact for GI specialists/hepatologists but several aspects need 
clarifi cation.  
 
I congratulate the authors on this manuscript as the findings add knowledge to the field and some 
of the results could directly translate into clinical management.  
 
 
Major aspects  
 
1) Please add the following parameters to table 2: MELD and fulfill ment of excMELD 
criteria (current SE for PSC according to Eurotransplant) at diagnosis (i.e. same time as 
IgG measurement). Please compare IgG to MELD in Fig. 1 - does IgG outperform 
MELD or perform comparably? Please also show ROC curves with AUROC. Which  cut-
off for IgG has a reasonable sensitivity and specificity?  
 
2) Did increased serum IgG levels predict the occurrence of dominant stenoses and/or 
recurrent cholangitis during follow -up? 
 
3) Please add the following parameters to table 1 and 3, if availab le: MELD (at 
inclusion/measurement of IgG), fulfillment of excMELD criteria (at 
inclusion/measurement of IgG), BMI (at inclusion/measurement of IgG), presence of 
diabetes, concomitant mean alcohol consumption, histological confirmation of diagnosis. 
Please  also add (at inclusion/measurement of IgG), also if only partly available: ANA, 
aSMA, SLA, LKM1, pANCA, AMA -M2, gp210, sp100, IgG4  
 
4) Please add Mayo risk score as well as LTX, Re -LTX, death, combined end point, and 
CCC (during follow -up) to Table 1.  
 
5) Please adjust the Cox regression analysis should any of the above mentioned parameters 
be a relevant confounder.  
 
6) Due to the described weaknesses of the study and the not so large effect size/significance 
level, a replication cohort would be ideal. At lea st this should be discussed.  
 
7) Please clearly state the a priori hypotheses. Were the criteria defined before statistical 
analysis?  
 
8) As some patients needed Re -LTX: Was this due to recurrent PSC? If yes, did high IgG 
levels point to recurrent PSC (albei t the low sample size)?  
 
9) Which ethnicity did the studied patients have? If the majority was not of the same 
ethnicity: Did it affect the results?  
 
10) Regarding the modeling: Did the authors account for cross correlation of variables for 
modeling of the c ox regression? Was prevention of over -fitting of the model attempted?  
 
 
Minor aspects  
 
11) Please clarify when exactly serum IgG was measured. I assume it is at time of 
diagnosis/inclusion, i.e. no serum samples were thawed in order to determine IgG 
afterwa rds. 
 
12) Did all patients receive ERC or were some diagnoses based on MRCP findings?  
 
13) Several language and typography errors as well as formal mistakes should be corrected.  
 
14) Please provide a diagram showing the inclusion and exclusion criteria. This should point 
out how other causes of (autoimmune) liver disease were ruled out (see also aspect 3) and 
how many patients were biopsied. For example, refer to the CONSORT statem ent. 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not,  please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain or lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relatin g to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload wil l be posted on the website along with the authors' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4 .0/). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant