Reviewer’s report
Title: 
High infliximab trough concentrations are associated with sustained
histologic remission in inflammatory bowel disease: a prospective cohort study
Version: 
0 
Date: 
06 Oct 2020
Reviewer's report:
Wilson et al report on a prospective study of IFX trough levels and associations
with histological healing in IBD. While the novel aspect of their work is
important there are a number of major limitations that mean this work should be
seen as a pilot rather than showing any definitive evidence. The statistics are
well done but don't reduce flaws due to the observational nature of the study
with many variations in care and assessments.
1. It is completely unclear when and for what reasons colonoscopies where
performed. This introduces strong bias as 1/3 of patients on IFX maintenance
were excluded as they did not have 2 procedures. A truly prospective study
would have had 2 defined colonoscopies as part of the study protocol and
reduced the chance of selecting a subset of patients who for clinical reasons
required 2 procedures.
2. The histopathology assessment is open to bias. A stronger approach with
blinding of pathologists, use of scores for UC (Nancy, Geboes or Robarts) and a
2nd histopathologist reviewing would have added much needed strength. There
is a risk of considerable variation. To overcome my concerns the researcher
could at least have a blinded re-assessment of a sub set of biopsies by a 2nd
pathologist and present a kappa value.
3. I' not clear how the IFX trough levels were used for analysis. Did you use the
trough level at the study inclusion or study end or did you use an average of all
trough levels from the patient?
4. The median time between the 2 colonoscopies is 3 months. This si extremely
short. In my view way too short to call this sustained remission. Given a 3 month
follow-up between procedures this part is too weak to give meaningful insight. I
would suggest a meaningful definition of sustained remission is >6 ideally ≥12
months.
5. As there was no clear protocol for clinical care individual clinicians could
have altered dosing of IFX dependent on many factors including the initial
histology results. This would introduce an amount of bias that makes sustained
results meaningless.
6. In principle the study of histological healing in UC is much easier as the
disease is less patchy and therefore easier to study. In Cd this is far more
difficult due to the patchy nature and the fact that colonoscopy does not reach
the proximal SB. This should be acknowledged.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons upon publication of the manuscript. If you have already registered at
Publons, they will notify you of the receipt of this review and update your profile
as per your settings and their policy. If you are not registered with Publons, you
will receive an email from them asking you to register in order for them to be
able to recognize your review on your new profile page. Publons may use the
Review Data to generate derivative metadata for the benefit of Publons and you
as a reviewer, carefully considering the sensitivity of such information. For
example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help
editors to identify candidate reviewers. Please find the details of processing in
Publons’ privacy policy 
https://publons.com/about/terms
Yes
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 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.
CPS has received unrestricted research grants from Warner Chilcott, Janssen and
AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda,
Fresenius Kabi and Janssen, and had speaker arrangements with Warner
Chilcott, Dr Falk, AbbVie, MSD, Pfizer and Takeda.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
High infliximab trough concentrations are associated with sustained
histologic remission in inflammatory bowel disease: a prospective cohort study
Version: 
0 
Date: 
06 Oct 2020
Reviewer's report:
Wilson et al report on a prospective study of IFX trough levels and associations
with histological healing in IBD. While the novel aspect of their work is
important there are a number of major limitations that mean this work should be
seen as a pilot rather than showing any definitive evidence. The statistics are
well done but don't reduce flaws due to the observational nature of the study
with many variations in care and assessments.
1. It is completely unclear when and for what reasons colonoscopies where
performed. This introduces strong bias as 1/3 of patients on IFX maintenance
were excluded as they did not have 2 procedures. A truly prospective study
would have had 2 defined colonoscopies as part of the study protocol and
reduced the chance of selecting a subset of patients who for clinical reasons
required 2 procedures.
2. The histopathology assessment is open to bias. A stronger approach with
blinding of pathologists, use of scores for UC (Nancy, Geboes or Robarts) and a
2nd histopathologist reviewing would have added much needed strength. There
is a risk of considerable variation. To overcome my concerns the researcher
could at least have a blinded re-assessment of a sub set of biopsies by a 2nd
pathologist and present a kappa value.
3. I' not clear how the IFX trough levels were used for analysis. Did you use the
trough level at the study inclusion or study end or did you use an average of all
trough levels from the patient?
4. The median time between the 2 colonoscopies is 3 months. This si extremely
short. In my view way too short to call this sustained remission. Given a 3 month
follow-up between procedures this part is too weak to give meaningful insight. I
would suggest a meaningful definition of sustained remission is >6 ideally ≥12
months.
5. As there was no clear protocol for clinical care individual clinicians could
have altered dosing of IFX dependent on many factors including the initial
histology results. This would introduce an amount of bias that makes sustained
results meaningless.
6. In principle the study of histological healing in UC is much easier as the
disease is less patchy and therefore easier to study. In Cd this is far more
difficult due to the patchy nature and the fact that colonoscopy does not reach
the proximal SB. This should be acknowledged.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons upon publication of the manuscript. If you have already registered at
Publons, they will notify you of the receipt of this review and update your profile
as per your settings and their policy. If you are not registered with Publons, you
will receive an email from them asking you to register in order for them to be
able to recognize your review on your new profile page. Publons may use the
Review Data to generate derivative metadata for the benefit of Publons and you
as a reviewer, carefully considering the sensitivity of such information. For
example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help
editors to identify candidate reviewers. Please find the details of processing in
Publons’ privacy policy 
https://publons.com/about/terms
Yes
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 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.
CPS has received unrestricted research grants from Warner Chilcott, Janssen and
AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda,
Fresenius Kabi and Janssen, and had speaker arrangements with Warner
Chilcott, Dr Falk, AbbVie, MSD, Pfizer and Takeda.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
High infliximab trough concentrations are associated with sustained
histologic remission in inflammatory bowel disease: a prospective cohort study
Version: 
0 
Date: 
06 Oct 2020
Reviewer's report:
Wilson et al report on a prospective study of IFX trough levels and associations
with histological healing in IBD. While the novel aspect of their work is
important there are a number of major limitations that mean this work should be
seen as a pilot rather than showing any definitive evidence. The statistics are
well done but don't reduce flaws due to the observational nature of the study
with many variations in care and assessments.
1. It is completely unclear when and for what reasons colonoscopies where
performed. This introduces strong bias as 1/3 of patients on IFX maintenance
were excluded as they did not have 2 procedures. A truly prospective study
would have had 2 defined colonoscopies as part of the study protocol and
reduced the chance of selecting a subset of patients who for clinical reasons
required 2 procedures.
2. The histopathology assessment is open to bias. A stronger approach with
blinding of pathologists, use of scores for UC (Nancy, Geboes or Robarts) and a
2nd histopathologist reviewing would have added much needed strength. There
is a risk of considerable variation. To overcome my concerns the researcher
could at least have a blinded re-assessment of a sub set of biopsies by a 2nd
pathologist and present a kappa value.
3. I' not clear how the IFX trough levels were used for analysis. Did you use the
trough level at the study inclusion or study end or did you use an average of all
trough levels from the patient?
4. The median time between the 2 colonoscopies is 3 months. This si extremely
short. In my view way too short to call this sustained remission. Given a 3 month
follow-up between procedures this part is too weak to give meaningful insight. I
would suggest a meaningful definition of sustained remission is >6 ideally ≥12
months.
5. As there was no clear protocol for clinical care individual clinicians could
have altered dosing of IFX dependent on many factors including the initial
histology results. This would introduce an amount of bias that makes sustained
results meaningless.
6. In principle the study of histological healing in UC is much easier as the
disease is less patchy and therefore easier to study. In Cd this is far more
difficult due to the patchy nature and the fact that colonoscopy does not reach
the proximal SB. This should be acknowledged.
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons upon publication of the manuscript. If you have already registered at
Publons, they will notify you of the receipt of this review and update your profile
as per your settings and their policy. If you are not registered with Publons, you
will receive an email from them asking you to register in order for them to be
able to recognize your review on your new profile page. Publons may use the
Review Data to generate derivative metadata for the benefit of Publons and you
as a reviewer, carefully considering the sensitivity of such information. For
example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help
editors to identify candidate reviewers. Please find the details of processing in
Publons’ privacy policy 
https://publons.com/about/terms
Yes
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 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.
CPS has received unrestricted research grants from Warner Chilcott, Janssen and
AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda,
Fresenius Kabi and Janssen, and had speaker arrangements with Warner
Chilcott, Dr Falk, AbbVie, MSD, Pfizer and Takeda.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the editorial
office before completing the review.
If you wish, you can include your name in your published report. Please note
you must decide whether to include your name at the start of the process and
confirm this decision whenever prompted. If you change your decision later, we
will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant