Reviewer’s report
Title: 
Systematic Review and Meta-analysis:Real-world Data Rates of Deep
Remission With Anti-TNFα in Inflammatory Bowel Disease
Version: 
1 
Date: 
07 Jun 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: * Have the authors responded adequately to each of
the questions or concerns you raised in your comments?
YES
* Have they also made changes to reflect their responses in the manuscript
itself?
YES
* What is your overall impression of the revised manuscript?
The revisions have greatly improved the systematic review, however there are a
few outstanding issues which I describe in my comments which follow.
REQUESTED REVISIONS: 
The authors have made significant changes to the manuscript including a
discussion of uncertainty in the findings and use of the PRISMA checklist. I
have a few minor issues which I detail below.
Abstract 
- the authors state that 'RCTs may not be generalizable to clinical
practice'. I disagree with this statement in that the aim of RCTs is to provide data
that are generalizable and applicable to clinical practice. 
it might be better to
state that real world data can provide information which is complementary to
RCTs particularly in terms of treatment duration. 
Background 
- line 94 ' Recent meta-*analyses* have 
examined' (plural)
Searches - it would be preferable if a further search were done up to the present
date to determine if any new studies have been published. 
Even if such newly
found studies are not integrated into the review text and analysis, they could be
summarised in the flow chart of studies and the number of studies found in an
updated search reported in the Results section. 
This would provide readers with
an indication of the current state of evidence and would give the authors the
opportunity to say that this review may be updated at a later stage. 
The clinical
applicability of the review is dependent on the age of the evidence included.
Interpretation - The interpretation has also been improved, particularly the
discussion around uncertainty and risk of bias. 
However, due to the cut off date
for including publications, I was disappointed to see that there is no comparison
with, and discussion of, the recent guidelines on inflammatory bowel disease
produced by the British Society of Gastroenterology, which use both RCT and
non RCT data in their guidelines. 
(Lamb CA, 
et al IBD guidelines eDelphi
consensus group, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen
R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on
the management of inflammatory bowel disease in adults. Gut. 2019
Dec;68(Suppl 3):s1-s106. doi: 10.1136/gutjnl-2019-318484. Epub 2019 Sep 27.
Erratum in: Gut. 2021 Apr;70(4):1. PMID: 31562236; PMCID: PMC6872448.).
The authors may wish to cite this publication in their discussion and compare
their findings with those of this large guideline and highlight any discrepancies
and potential reasons for these. Also see (First United Arab Emirates consensus
on diagnosis and management of inflammatory bowel diseases: A 2020 Delphi
consensus. Alkhatry M et a.l). 
While the authors state that "Our assessment is that the certainty of our findings
are consistent with a low GRADE certainty", I could not find any detailed
GRADE assessments referred to in the paper. I accept that the authors were not
making recommendations using GRADE criteria, however GRADE can be used
to assess the quality of the body of evidence without going on to make
recommendations. While the authors are probably correct in stating that the
evidence they found would be GRADE-ed as low or very low by GRADE, for
reasons of transparency, it is preferable to use the GRADE assessment tool
which is available online and provides the rationale for the decisions made,
rather than a subjective assessment that the evidence is very low to low quality.
In practical terms, for this paper, what the authors have done is acceptable 
- they
have provided an assessment of the quality of evidence for the outcome of deep
remission and no further work needs to be done.
Adverse events - I agree that adverse events are generally poorly reported in any
field of medicine. However they are important in terms of the acceptability of
therapy both for clinicians and patients. 
A short statement in the results or
discussion section would be enough to address the point that adverse effects were
poorly reported in the included studies.
Discussion - is good and greatly improved by the modifications made in this
draft. I thank the authors for following my suggestions to use the EPICOT tool to
restructure the discussion and I am pleased to see that the PRISMA checklist has
been employed and reported in a transparent way. 
This is an interesting paper which should provide additional evidence to support
clinical decision making, thank you for the opportunity to review it.
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.
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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
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No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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?
Yes
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: 
Systematic Review and Meta-analysis:Real-world Data Rates of Deep
Remission With Anti-TNFα in Inflammatory Bowel Disease
Version: 
1 
Date: 
07 Jun 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: * Have the authors responded adequately to each of
the questions or concerns you raised in your comments?
YES
* Have they also made changes to reflect their responses in the manuscript
itself?
YES
* What is your overall impression of the revised manuscript?
The revisions have greatly improved the systematic review, however there are a
few outstanding issues which I describe in my comments which follow.
REQUESTED REVISIONS: 
The authors have made significant changes to the manuscript including a
discussion of uncertainty in the findings and use of the PRISMA checklist. I
have a few minor issues which I detail below.
Abstract 
- the authors state that 'RCTs may not be generalizable to clinical
practice'. I disagree with this statement in that the aim of RCTs is to provide data
that are generalizable and applicable to clinical practice. 
it might be better to
state that real world data can provide information which is complementary to
RCTs particularly in terms of treatment duration. 
Background 
- line 94 ' Recent meta-*analyses* have 
examined' (plural)
Searches - it would be preferable if a further search were done up to the present
date to determine if any new studies have been published. 
Even if such newly
found studies are not integrated into the review text and analysis, they could be
summarised in the flow chart of studies and the number of studies found in an
updated search reported in the Results section. 
This would provide readers with
an indication of the current state of evidence and would give the authors the
opportunity to say that this review may be updated at a later stage. 
The clinical
applicability of the review is dependent on the age of the evidence included.
Interpretation - The interpretation has also been improved, particularly the
discussion around uncertainty and risk of bias. 
However, due to the cut off date
for including publications, I was disappointed to see that there is no comparison
with, and discussion of, the recent guidelines on inflammatory bowel disease
produced by the British Society of Gastroenterology, which use both RCT and
non RCT data in their guidelines. 
(Lamb CA, 
et al IBD guidelines eDelphi
consensus group, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen
R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on
the management of inflammatory bowel disease in adults. Gut. 2019
Dec;68(Suppl 3):s1-s106. doi: 10.1136/gutjnl-2019-318484. Epub 2019 Sep 27.
Erratum in: Gut. 2021 Apr;70(4):1. PMID: 31562236; PMCID: PMC6872448.).
The authors may wish to cite this publication in their discussion and compare
their findings with those of this large guideline and highlight any discrepancies
and potential reasons for these. Also see (First United Arab Emirates consensus
on diagnosis and management of inflammatory bowel diseases: A 2020 Delphi
consensus. Alkhatry M et a.l). 
While the authors state that "Our assessment is that the certainty of our findings
are consistent with a low GRADE certainty", I could not find any detailed
GRADE assessments referred to in the paper. I accept that the authors were not
making recommendations using GRADE criteria, however GRADE can be used
to assess the quality of the body of evidence without going on to make
recommendations. While the authors are probably correct in stating that the
evidence they found would be GRADE-ed as low or very low by GRADE, for
reasons of transparency, it is preferable to use the GRADE assessment tool
which is available online and provides the rationale for the decisions made,
rather than a subjective assessment that the evidence is very low to low quality.
In practical terms, for this paper, what the authors have done is acceptable 
- they
have provided an assessment of the quality of evidence for the outcome of deep
remission and no further work needs to be done.
Adverse events - I agree that adverse events are generally poorly reported in any
field of medicine. However they are important in terms of the acceptability of
therapy both for clinicians and patients. 
A short statement in the results or
discussion section would be enough to address the point that adverse effects were
poorly reported in the included studies.
Discussion - is good and greatly improved by the modifications made in this
draft. I thank the authors for following my suggestions to use the EPICOT tool to
restructure the discussion and I am pleased to see that the PRISMA checklist has
been employed and reported in a transparent way. 
This is an interesting paper which should provide additional evidence to support
clinical decision making, thank you for the opportunity to review it.
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 after the final decision on the manuscript has been made. 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
No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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?
Yes
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: 
Systematic Review and Meta-analysis:Real-world Data Rates of Deep
Remission With Anti-TNFα in Inflammatory Bowel Disease
Version: 
1 
Date: 
07 Jun 2021
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
Yes - experiments and analyses were performed appropriately
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: * Have the authors responded adequately to each of
the questions or concerns you raised in your comments?
YES
* Have they also made changes to reflect their responses in the manuscript
itself?
YES
* What is your overall impression of the revised manuscript?
The revisions have greatly improved the systematic review, however there are a
few outstanding issues which I describe in my comments which follow.
REQUESTED REVISIONS: 
The authors have made significant changes to the manuscript including a
discussion of uncertainty in the findings and use of the PRISMA checklist. I
have a few minor issues which I detail below.
Abstract 
- the authors state that 'RCTs may not be generalizable to clinical
practice'. I disagree with this statement in that the aim of RCTs is to provide data
that are generalizable and applicable to clinical practice. 
it might be better to
state that real world data can provide information which is complementary to
RCTs particularly in terms of treatment duration. 
Background 
- line 94 ' Recent meta-*analyses* have 
examined' (plural)
Searches - it would be preferable if a further search were done up to the present
date to determine if any new studies have been published. 
Even if such newly
found studies are not integrated into the review text and analysis, they could be
summarised in the flow chart of studies and the number of studies found in an
updated search reported in the Results section. 
This would provide readers with
an indication of the current state of evidence and would give the authors the
opportunity to say that this review may be updated at a later stage. 
The clinical
applicability of the review is dependent on the age of the evidence included.
Interpretation - The interpretation has also been improved, particularly the
discussion around uncertainty and risk of bias. 
However, due to the cut off date
for including publications, I was disappointed to see that there is no comparison
with, and discussion of, the recent guidelines on inflammatory bowel disease
produced by the British Society of Gastroenterology, which use both RCT and
non RCT data in their guidelines. 
(Lamb CA, 
et al IBD guidelines eDelphi
consensus group, Gaya DR, Iqbal TH, Taylor SA, Smith M, Brookes M, Hansen
R, Hawthorne AB. British Society of Gastroenterology consensus guidelines on
the management of inflammatory bowel disease in adults. Gut. 2019
Dec;68(Suppl 3):s1-s106. doi: 10.1136/gutjnl-2019-318484. Epub 2019 Sep 27.
Erratum in: Gut. 2021 Apr;70(4):1. PMID: 31562236; PMCID: PMC6872448.).
The authors may wish to cite this publication in their discussion and compare
their findings with those of this large guideline and highlight any discrepancies
and potential reasons for these. Also see (First United Arab Emirates consensus
on diagnosis and management of inflammatory bowel diseases: A 2020 Delphi
consensus. Alkhatry M et a.l). 
While the authors state that "Our assessment is that the certainty of our findings
are consistent with a low GRADE certainty", I could not find any detailed
GRADE assessments referred to in the paper. I accept that the authors were not
making recommendations using GRADE criteria, however GRADE can be used
to assess the quality of the body of evidence without going on to make
recommendations. While the authors are probably correct in stating that the
evidence they found would be GRADE-ed as low or very low by GRADE, for
reasons of transparency, it is preferable to use the GRADE assessment tool
which is available online and provides the rationale for the decisions made,
rather than a subjective assessment that the evidence is very low to low quality.
In practical terms, for this paper, what the authors have done is acceptable 
- they
have provided an assessment of the quality of evidence for the outcome of deep
remission and no further work needs to be done.
Adverse events - I agree that adverse events are generally poorly reported in any
field of medicine. However they are important in terms of the acceptability of
therapy both for clinicians and patients. 
A short statement in the results or
discussion section would be enough to address the point that adverse effects were
poorly reported in the included studies.
Discussion - is good and greatly improved by the modifications made in this
draft. I thank the authors for following my suggestions to use the EPICOT tool to
restructure the discussion and I am pleased to see that the PRISMA checklist has
been employed and reported in a transparent way. 
This is an interesting paper which should provide additional evidence to support
clinical decision making, thank you for the opportunity to review it.
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 after the final decision on the manuscript has been made. 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
No
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
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?
Yes
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