Reviewer ’s report  
 
Title:  Association between serum IgG level and clinical course in primary sclerosing cholangitis  
 
Version: 0 Date: 23 Jun 2019 
 
Reviewer:  Marcial  Sebode  
 
Reviewer’s report:  
 
In their study entitled 'Association of serum IgG levels and clinical course in primary sclerosing 
cholangitis' Hippchen et al. retrospectively analyze a cohort of 148 PSC patients at a single 
tertiary centre in Germany with a median follow -up of about 9 y ears. As the main result of their 
study, the authors have found amongst others that elevation of IgG levels at the time of PSC 
diagnosis was associated with an impaired outcome, defined by reduced transplant -free survival. 
The results are of interest in th e field of PSC since elevation of IgG levels is a relatively frequent 
clinical observation in PSC patients but its relevance and prognostic impact is unclear.  
 
Some major and several minor concerns should be addressed in a revised version of the 
manuscrip t before publication.  
 
 
Major concerns  
 
1) Elevated IgG levels can be detected in patients as a result of liver cirrhosis of any liver 
disease, and presence of cirrhosis obviously impacts outcome. The authors address this 
important aspect in the discussion section, claiming that end -stage liver disease was not 
present at the time of PSC diagnosis in their cohort. Liver cirrhosis was, however, 
histologically excluded in only 44% of patients at the time of diagnosis. How did the 
authors exclude cirrhosis in th e remaining patients? How is 'advanced liver disease' 
defined in the manuscript? It would be of interest to know whether other signs of 
cirrhosis (ascites, varices, etc.) were absent in these patients in order to ensure cirrhosis at 
PSC diagnosis not biasi ng the authors´ findings. Besides, was transient elastography 
performed in any patients?  
 
2) The inclusion and diagnostic criteria should be clarified:  
 
a) Further explanation should be given in the 'Material & Methods' -section as to which PSC 
patients wer e included into the study: both large AND small duct PSC patients AND patients 
with AIH/PSC overlap? If so, how many small duct and how many large duct PSC patients were 
included into the study? Or were there only large duct PSC patients included? In that case, why 
was liver biopsy performed when MRCP or ERC showed typical signs of PSC?  
 
b) Diagnostic criteria for PSC are defined by the authors as follows: 'The diagnosis of PSC was 
established on the basis of typical endoscopic retrograde cholangiography ( ERC) findings, serum 
alkaline phosphatase (AP) activity of at least twice the reference range, negative 
antimitochondrial antibody and the results of liver biopsy consistent with the diagnosis of PSC.' 
According to this statement, diagnosis of PSC was not based on MRCP findings and thus 
deviates from proposed criteria by international guidelines. What is the reason for this? 
Moreover, what were the exact histopathological criteria for PSC?  
 
c) According to the authors, 'the diagnosis of AIH/PSC overlap was  established following the 
current EASL guidelines' citing the EASL guideline for AIH and referring to the simplified 
IAIHG score. However, in the EASL guideline for AIH, diagnostic criteria for AIH/PSC variant 
syndromes are not given and the simplified IA IHG score is not recommended as a means for the 
diagnosis of AIH/PSC variant syndrome (owing to the fact that it was not developed to make the 
diagnosis of an AIH/PSC variant syndrome). The authors should comment on this issue in the 
manuscript.  
 
3) The a uthors should provide more information on immunosuppressive treatment of their 
cohort as it can have impact on serum IgG levels and therefore be a major bias for the 
study's results. How many patients were already under immunosuppression before PSC 
diagnos is due to IBD? The kind of immunosuppression might also affect IgG levels, 
which is why information on that aspect should not be withheld from the reader.  
 
4) How many patients with elevated IgG levels or normal IgG levels received liver biopsy, 
respectiv ely? This information is relevant for ensuring that overseen AIH did not bias the 
authors' findings.   
 
5) English language with regard to application of technical terms and spelling deserves 
major improvement throughout the manuscript. The following missp ellings and misused 
words were identified on the first 8 pages - the rest of the manuscript should be corrected 
by the authors themselves!  
 
- 'histological proof' - up to date there is no 'proof' for AIH/PSC overlap since no 100% 
specific histological crite ria have been defined yet  
 
- 'transaminaseS might be elevated'  
 
- What do the authors mean by 'additional various pronounced features'?  
 
- 'Immune -mediated processed': processes!  
 
- 'who were followed for up to 28 years in (at!) our tertiary medical centre.'  
 
- 'we aimed to analyse (aimed at analysing!) risk factors'  
 
- 'The baseline characteristics including age, gender, history of IBD or MRS however did 
not defer in the screened and enrolled group': differ instead of defer!  
 
 
 
Minor concerns:  
 
6) The abbreviation 'DS' should be given immediately after dominant stenosis in the abstract  
 
7) I would prefer the term 'dominant stricture' instead of 'dominant stenosis' seeing as 
'dominant stricture' is the term used in the EASL as well the AASLD guidel ines for PSC  
 
8) Abbreviations: I would prefer the more common abbreviations 'ALP' and 'CCA'. 
Dominant strictures / DS are not mentioned in the abbreviations section.  
 
9) The prevalence of CCA and liver transplantation in PSC patients should be specified in  
the introduction instead of using the term 'in many cases'  
 
10) How did the authors define dominant stenosis?  
 
11) In the discussion, a citation would be desirable in the section where the authors discuss 
IgG serum levels can be elevated in patients with li ver cirrhosis due to any liver disease  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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: 23 Jun 2019 
 
Reviewer:  Marcial  Sebode  
 
Reviewer’s report:  
 
In their study entitled 'Association of serum IgG levels and clinical course in primary sclerosing 
cholangitis' Hippchen et al. retrospectively analyze a cohort of 148 PSC patients at a single 
tertiary centre in Germany with a median follow -up of about 9 y ears. As the main result of their 
study, the authors have found amongst others that elevation of IgG levels at the time of PSC 
diagnosis was associated with an impaired outcome, defined by reduced transplant -free survival. 
The results are of interest in th e field of PSC since elevation of IgG levels is a relatively frequent 
clinical observation in PSC patients but its relevance and prognostic impact is unclear.  
 
Some major and several minor concerns should be addressed in a revised version of the 
manuscrip t before publication.  
 
 
Major concerns  
 
1) Elevated IgG levels can be detected in patients as a result of liver cirrhosis of any liver 
disease, and presence of cirrhosis obviously impacts outcome. The authors address this 
important aspect in the discussion section, claiming that end -stage liver disease was not 
present at the time of PSC diagnosis in their cohort. Liver cirrhosis was, however, 
histologically excluded in only 44% of patients at the time of diagnosis. How did the 
authors exclude cirrhosis in th e remaining patients? How is 'advanced liver disease' 
defined in the manuscript? It would be of interest to know whether other signs of 
cirrhosis (ascites, varices, etc.) were absent in these patients in order to ensure cirrhosis at 
PSC diagnosis not biasi ng the authors´ findings. Besides, was transient elastography 
performed in any patients?  
 
2) The inclusion and diagnostic criteria should be clarified:  
 
a) Further explanation should be given in the 'Material & Methods' -section as to which PSC 
patients wer e included into the study: both large AND small duct PSC patients AND patients 
with AIH/PSC overlap? If so, how many small duct and how many large duct PSC patients were 
included into the study? Or were there only large duct PSC patients included? In that case, why 
was liver biopsy performed when MRCP or ERC showed typical signs of PSC?  
 
b) Diagnostic criteria for PSC are defined by the authors as follows: 'The diagnosis of PSC was 
established on the basis of typical endoscopic retrograde cholangiography ( ERC) findings, serum 
alkaline phosphatase (AP) activity of at least twice the reference range, negative 
antimitochondrial antibody and the results of liver biopsy consistent with the diagnosis of PSC.' 
According to this statement, diagnosis of PSC was not based on MRCP findings and thus 
deviates from proposed criteria by international guidelines. What is the reason for this? 
Moreover, what were the exact histopathological criteria for PSC?  
 
c) According to the authors, 'the diagnosis of AIH/PSC overlap was  established following the 
current EASL guidelines' citing the EASL guideline for AIH and referring to the simplified 
IAIHG score. However, in the EASL guideline for AIH, diagnostic criteria for AIH/PSC variant 
syndromes are not given and the simplified IA IHG score is not recommended as a means for the 
diagnosis of AIH/PSC variant syndrome (owing to the fact that it was not developed to make the 
diagnosis of an AIH/PSC variant syndrome). The authors should comment on this issue in the 
manuscript.  
 
3) The a uthors should provide more information on immunosuppressive treatment of their 
cohort as it can have impact on serum IgG levels and therefore be a major bias for the 
study's results. How many patients were already under immunosuppression before PSC 
diagnos is due to IBD? The kind of immunosuppression might also affect IgG levels, 
which is why information on that aspect should not be withheld from the reader.  
 
4) How many patients with elevated IgG levels or normal IgG levels received liver biopsy, 
respectiv ely? This information is relevant for ensuring that overseen AIH did not bias the 
authors' findings.   
 
5) English language with regard to application of technical terms and spelling deserves 
major improvement throughout the manuscript. The following missp ellings and misused 
words were identified on the first 8 pages - the rest of the manuscript should be corrected 
by the authors themselves!  
 
- 'histological proof' - up to date there is no 'proof' for AIH/PSC overlap since no 100% 
specific histological crite ria have been defined yet  
 
- 'transaminaseS might be elevated'  
 
- What do the authors mean by 'additional various pronounced features'?  
 
- 'Immune -mediated processed': processes!  
 
- 'who were followed for up to 28 years in (at!) our tertiary medical centre.'  
 
- 'we aimed to analyse (aimed at analysing!) risk factors'  
 
- 'The baseline characteristics including age, gender, history of IBD or MRS however did 
not defer in the screened and enrolled group': differ instead of defer!  
 
 
 
Minor concerns:  
 
6) The abbreviation 'DS' should be given immediately after dominant stenosis in the abstract  
 
7) I would prefer the term 'dominant stricture' instead of 'dominant stenosis' seeing as 
'dominant stricture' is the term used in the EASL as well the AASLD guidel ines for PSC  
 
8) Abbreviations: I would prefer the more common abbreviations 'ALP' and 'CCA'. 
Dominant strictures / DS are not mentioned in the abbreviations section.  
 
9) The prevalence of CCA and liver transplantation in PSC patients should be specified in  
the introduction instead of using the term 'in many cases'  
 
10) How did the authors define dominant stenosis?  
 
11) In the discussion, a citation would be desirable in the section where the authors discuss 
IgG serum levels can be elevated in patients with li ver cirrhosis due to any liver disease  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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: 23 Jun 2019 
 
Reviewer:  Marcial  Sebode  
 
Reviewer’s report:  
 
In their study entitled 'Association of serum IgG levels and clinical course in primary sclerosing 
cholangitis' Hippchen et al. retrospectively analyze a cohort of 148 PSC patients at a single 
tertiary centre in Germany with a median follow -up of about 9 y ears. As the main result of their 
study, the authors have found amongst others that elevation of IgG levels at the time of PSC 
diagnosis was associated with an impaired outcome, defined by reduced transplant -free survival. 
The results are of interest in th e field of PSC since elevation of IgG levels is a relatively frequent 
clinical observation in PSC patients but its relevance and prognostic impact is unclear.  
 
Some major and several minor concerns should be addressed in a revised version of the 
manuscrip t before publication.  
 
 
Major concerns  
 
1) Elevated IgG levels can be detected in patients as a result of liver cirrhosis of any liver 
disease, and presence of cirrhosis obviously impacts outcome. The authors address this 
important aspect in the discussion section, claiming that end -stage liver disease was not 
present at the time of PSC diagnosis in their cohort. Liver cirrhosis was, however, 
histologically excluded in only 44% of patients at the time of diagnosis. How did the 
authors exclude cirrhosis in th e remaining patients? How is 'advanced liver disease' 
defined in the manuscript? It would be of interest to know whether other signs of 
cirrhosis (ascites, varices, etc.) were absent in these patients in order to ensure cirrhosis at 
PSC diagnosis not biasi ng the authors´ findings. Besides, was transient elastography 
performed in any patients?  
 
2) The inclusion and diagnostic criteria should be clarified:  
 
a) Further explanation should be given in the 'Material & Methods' -section as to which PSC 
patients wer e included into the study: both large AND small duct PSC patients AND patients 
with AIH/PSC overlap? If so, how many small duct and how many large duct PSC patients were 
included into the study? Or were there only large duct PSC patients included? In that case, why 
was liver biopsy performed when MRCP or ERC showed typical signs of PSC?  
 
b) Diagnostic criteria for PSC are defined by the authors as follows: 'The diagnosis of PSC was 
established on the basis of typical endoscopic retrograde cholangiography ( ERC) findings, serum 
alkaline phosphatase (AP) activity of at least twice the reference range, negative 
antimitochondrial antibody and the results of liver biopsy consistent with the diagnosis of PSC.' 
According to this statement, diagnosis of PSC was not based on MRCP findings and thus 
deviates from proposed criteria by international guidelines. What is the reason for this? 
Moreover, what were the exact histopathological criteria for PSC?  
 
c) According to the authors, 'the diagnosis of AIH/PSC overlap was  established following the 
current EASL guidelines' citing the EASL guideline for AIH and referring to the simplified 
IAIHG score. However, in the EASL guideline for AIH, diagnostic criteria for AIH/PSC variant 
syndromes are not given and the simplified IA IHG score is not recommended as a means for the 
diagnosis of AIH/PSC variant syndrome (owing to the fact that it was not developed to make the 
diagnosis of an AIH/PSC variant syndrome). The authors should comment on this issue in the 
manuscript.  
 
3) The a uthors should provide more information on immunosuppressive treatment of their 
cohort as it can have impact on serum IgG levels and therefore be a major bias for the 
study's results. How many patients were already under immunosuppression before PSC 
diagnos is due to IBD? The kind of immunosuppression might also affect IgG levels, 
which is why information on that aspect should not be withheld from the reader.  
 
4) How many patients with elevated IgG levels or normal IgG levels received liver biopsy, 
respectiv ely? This information is relevant for ensuring that overseen AIH did not bias the 
authors' findings.   
 
5) English language with regard to application of technical terms and spelling deserves 
major improvement throughout the manuscript. The following missp ellings and misused 
words were identified on the first 8 pages - the rest of the manuscript should be corrected 
by the authors themselves!  
 
- 'histological proof' - up to date there is no 'proof' for AIH/PSC overlap since no 100% 
specific histological crite ria have been defined yet  
 
- 'transaminaseS might be elevated'  
 
- What do the authors mean by 'additional various pronounced features'?  
 
- 'Immune -mediated processed': processes!  
 
- 'who were followed for up to 28 years in (at!) our tertiary medical centre.'  
 
- 'we aimed to analyse (aimed at analysing!) risk factors'  
 
- 'The baseline characteristics including age, gender, history of IBD or MRS however did 
not defer in the screened and enrolled group': differ instead of defer!  
 
 
 
Minor concerns:  
 
6) The abbreviation 'DS' should be given immediately after dominant stenosis in the abstract  
 
7) I would prefer the term 'dominant stricture' instead of 'dominant stenosis' seeing as 
'dominant stricture' is the term used in the EASL as well the AASLD guidel ines for PSC  
 
8) Abbreviations: I would prefer the more common abbreviations 'ALP' and 'CCA'. 
Dominant strictures / DS are not mentioned in the abbreviations section.  
 
9) The prevalence of CCA and liver transplantation in PSC patients should be specified in  
the introduction instead of using the term 'in many cases'  
 
10) How did the authors define dominant stenosis?  
 
11) In the discussion, a citation would be desirable in the section where the authors discuss 
IgG serum levels can be elevated in patients with li ver cirrhosis due to any liver disease  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
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