Reviewer ’s report  
 
Title: The IGF system in patients with inflammatory bowel disease treated with prednisolone or 
infliximab: potential role of the stanniocalcin -2 / PAPP -A / IGFBP -4 axis 
 
Version: 0 Date: 11 Nov 2018  
 
Reviewer: Dimitrios K. Christodoulou  
 
Reviewer's report:  
 
This is an interesting original article investigatin g the role of prednisolone and infliximab in the 
circulating IGF system and in particular in the STC2/PAPP -A/IGFBP -4 axis, of patients with 
active IBD.   However there are several important limitations preventing the article to reach its 
full potential tha t should be addressed:  
 
ABSTRACT: the phrase "but whereas" sounds incorrect, consider changing the paragraph syntax  
BACKGROUND:  
-line 66 -67 the Phrase "indeed treatment with….."  adds little to the discussion and perhaps it 
should be removed.  
- IGFBP -4 is believed to be the principal PAPP -A substrate. However there are more IGFBP's 
cleaved by PAPP -A, in particular 2,4,5.  
Another pappalysin, namely PAPP -A2 cleaves IGFBP - 3 and 5.In your study you describe 
results of  IGFBP -3, however PAPP -A. We recommend that these results should be removed, as 
they cannot be associated with PAPP -A. Claus Oxvig J Cell Commun Signal. 2015 Jun; 9(2): 
177-187. 
METHODS:  
- What was the treatment that patients were receiving prior INFx or prednisolone 
initiation? Where there any  naïve patients? What was the exact number of UC and CD patients 
receiving INFx or prednisolone in each group?  
- As clinical indexes are not the best markers to distinguish active from quiescent disease , 
where there any other objective measures of diseas e activity?  
- What was the rationale of measuring egfr and cortisol? Since clinical indexes were used 
to assess disease activity why CRP was chosen to assess response of treatment? Why did tou 
especially chose TNF -a and IL6 and not a universal marker of tr eatment response? (eg 
prednisolone does not affect TNF -a) 
- Why measuring IGFBP -3? Only PAPP -A2 cleaves IGFBP -3. 
RESULTS  
-The presentation of data confuses the reader. Please make it more concise presenting data that 
are absolutely relevant to the concept of your study.  
- Its very interesting that every patient responded to therapy when especially INFx treatment 
results in response in about 50 -60% of patients. Is there a bias? Please explain?  
- You state that "These data have been previously published (27)". Is your results part of another  
study. This can lead to significant bias . Please explain.  
- Again you state that IGF -I was higher in the INFx group. Could this be due to bias?  
- Page 10 l ine 215. Please indicate the correlation as it seems that something is missing.  
-Page 10 line 221. Please remove the  references and comment on the reults. The discusiion of 
results should be mad only in the discussion section.  Please remove the results r egarding kidney 
function and fragments or explain in the discussion, why a normal kidney function results in low 
serum fragments.  
-Page 10 line 223. How CRP IL6 etc are associated with the axis?  
DISCUSSION  
Page 11 line 237. The proposed rationale for inve stigation seems not well established.  
 
 
 
 
 
 
 
 
 
 
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 y ou 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 recommend additional statistical review  
 
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 relating to the content of the  
manuscript?  
 
4. Have you recei ved 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 o f 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 will 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: The IGF system in patients with inflammatory bowel disease treated with prednisolone or 
infliximab: potential role of the stanniocalcin -2 / PAPP -A / IGFBP -4 axis 
 
Version: 0 Date: 11 Nov 2018  
 
Reviewer: Dimitrios K. Christodoulou  
 
Reviewer's report:  
 
This is an interesting original article investigatin g the role of prednisolone and infliximab in the 
circulating IGF system and in particular in the STC2/PAPP -A/IGFBP -4 axis, of patients with 
active IBD.   However there are several important limitations preventing the article to reach its 
full potential tha t should be addressed:  
 
ABSTRACT: the phrase "but whereas" sounds incorrect, consider changing the paragraph syntax  
BACKGROUND:  
-line 66 -67 the Phrase "indeed treatment with….."  adds little to the discussion and perhaps it 
should be removed.  
- IGFBP -4 is believed to be the principal PAPP -A substrate. However there are more IGFBP's 
cleaved by PAPP -A, in particular 2,4,5.  
Another pappalysin, namely PAPP -A2 cleaves IGFBP - 3 and 5.In your study you describe 
results of  IGFBP -3, however PAPP -A. We recommend that these results should be removed, as 
they cannot be associated with PAPP -A. Claus Oxvig J Cell Commun Signal. 2015 Jun; 9(2): 
177-187. 
METHODS:  
- What was the treatment that patients were receiving prior INFx or prednisolone 
initiation? Where there any  naïve patients? What was the exact number of UC and CD patients 
receiving INFx or prednisolone in each group?  
- As clinical indexes are not the best markers to distinguish active from quiescent disease , 
where there any other objective measures of diseas e activity?  
- What was the rationale of measuring egfr and cortisol? Since clinical indexes were used 
to assess disease activity why CRP was chosen to assess response of treatment? Why did tou 
especially chose TNF -a and IL6 and not a universal marker of tr eatment response? (eg 
prednisolone does not affect TNF -a) 
- Why measuring IGFBP -3? Only PAPP -A2 cleaves IGFBP -3. 
RESULTS  
-The presentation of data confuses the reader. Please make it more concise presenting data that 
are absolutely relevant to the concept of your study.  
- Its very interesting that every patient responded to therapy when especially INFx treatment 
results in response in about 50 -60% of patients. Is there a bias? Please explain?  
- You state that "These data have been previously published (27)". Is your results part of another  
study. This can lead to significant bias . Please explain.  
- Again you state that IGF -I was higher in the INFx group. Could this be due to bias?  
- Page 10 l ine 215. Please indicate the correlation as it seems that something is missing.  
-Page 10 line 221. Please remove the  references and comment on the reults. The discusiion of 
results should be mad only in the discussion section.  Please remove the results r egarding kidney 
function and fragments or explain in the discussion, why a normal kidney function results in low 
serum fragments.  
-Page 10 line 223. How CRP IL6 etc are associated with the axis?  
DISCUSSION  
Page 11 line 237. The proposed rationale for inve stigation seems not well established.  
 
 
 
 
 
 
 
 
 
 
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 y ou 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 recommend additional statistical review  
 
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 relating to the content of the  
manuscript?  
 
4. Have you recei ved 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 o f 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 will 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: The IGF system in patients with inflammatory bowel disease treated with prednisolone or 
infliximab: potential role of the stanniocalcin -2 / PAPP -A / IGFBP -4 axis 
 
Version: 0 Date: 11 Nov 2018  
 
Reviewer: Dimitrios K. Christodoulou  
 
Reviewer's report:  
 
This is an interesting original article investigatin g the role of prednisolone and infliximab in the 
circulating IGF system and in particular in the STC2/PAPP -A/IGFBP -4 axis, of patients with 
active IBD.   However there are several important limitations preventing the article to reach its 
full potential tha t should be addressed:  
 
ABSTRACT: the phrase "but whereas" sounds incorrect, consider changing the paragraph syntax  
BACKGROUND:  
-line 66 -67 the Phrase "indeed treatment with….."  adds little to the discussion and perhaps it 
should be removed.  
- IGFBP -4 is believed to be the principal PAPP -A substrate. However there are more IGFBP's 
cleaved by PAPP -A, in particular 2,4,5.  
Another pappalysin, namely PAPP -A2 cleaves IGFBP - 3 and 5.In your study you describe 
results of  IGFBP -3, however PAPP -A. We recommend that these results should be removed, as 
they cannot be associated with PAPP -A. Claus Oxvig J Cell Commun Signal. 2015 Jun; 9(2): 
177-187. 
METHODS:  
- What was the treatment that patients were receiving prior INFx or prednisolone 
initiation? Where there any  naïve patients? What was the exact number of UC and CD patients 
receiving INFx or prednisolone in each group?  
- As clinical indexes are not the best markers to distinguish active from quiescent disease , 
where there any other objective measures of diseas e activity?  
- What was the rationale of measuring egfr and cortisol? Since clinical indexes were used 
to assess disease activity why CRP was chosen to assess response of treatment? Why did tou 
especially chose TNF -a and IL6 and not a universal marker of tr eatment response? (eg 
prednisolone does not affect TNF -a) 
- Why measuring IGFBP -3? Only PAPP -A2 cleaves IGFBP -3. 
RESULTS  
-The presentation of data confuses the reader. Please make it more concise presenting data that 
are absolutely relevant to the concept of your study.  
- Its very interesting that every patient responded to therapy when especially INFx treatment 
results in response in about 50 -60% of patients. Is there a bias? Please explain?  
- You state that "These data have been previously published (27)". Is your results part of another  
study. This can lead to significant bias . Please explain.  
- Again you state that IGF -I was higher in the INFx group. Could this be due to bias?  
- Page 10 l ine 215. Please indicate the correlation as it seems that something is missing.  
-Page 10 line 221. Please remove the  references and comment on the reults. The discusiion of 
results should be mad only in the discussion section.  Please remove the results r egarding kidney 
function and fragments or explain in the discussion, why a normal kidney function results in low 
serum fragments.  
-Page 10 line 223. How CRP IL6 etc are associated with the axis?  
DISCUSSION  
Page 11 line 237. The proposed rationale for inve stigation seems not well established.  
 
 
 
 
 
 
 
 
 
 
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 y ou 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 recommend additional statistical review  
 
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 relating to the content of the  
manuscript?  
 
4. Have you recei ved 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 o f 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 will 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