Reviewer’s report
Title: 
Combined therapy with early initiation of infliximab following drainage of
perianal fistulising Crohn’s disease  a retrospective cohort study
Version: 
0 
Date: 
19 Sep 2021
Reviewer's report:
Abstract: 
fine and well written. Only minor comment is re: conlusion…
Authors state… "Combined therapy with early initiation of infliximab after
surgery could achieve promising results for PFCD patients"…
comment: 
I wonder whether the 
statement on early initiation of infliximab needs
to be tempered. Afterall the results have not demonstrated any significant
benefit, which was what the study set out to determine. 
Hence the natural
statement here, for the sake of clarity I wonder whether the authors would
consider highlighting this instead i.e. no benefit shown in this series.
Background - Page 3/4: 
Authors state "The traditional algorithm includes initial drainage with loose
seton for 2-3mths followed by infliximab infusion or definitive repair based on
the status of anorectal and intestinal inflammation" 
is this delay in medical treatment traditional? perhaps consensus statement or
guideline evidence may be helpful in adding weight to this sentence. I note
references used was a prospective study and a preliminary report. 
Authors state "With the number of clinicians chooses early combination therapy
increased[25], a direct comparison of long-term outcomes between early and
conventional combined treatment is urgently required."
comment: consider rewording this sentence to improve readership assimilation
Methods
Authors state.. "Based on a previous study in which a time interval of 6 weeks
between surgery and infliximab initiation was correlated with fistula closure, we
defined time interval shorter than 6 weeks as early combination therapy and
longer than 6 weeks as conventional combination therapy [24]."
comment/qns: did the authors attempt to review / find 'consensus' in recent
studies, on the question of timing of anti-TNF following definitive surgery? or
following abscess drainage? Just a thought that It might be helpful to the
readership to have a broader view on why "6weeks" was chosen as the
distinguishing timepoint between early and 'conventional' therapy; as opposed to
the 1 study referenced? 
Authors state: "Clinical fistula closure was defined as complete closure of the
fistula's external opening without discharge or discomfort. … A telephone
interview was conducted to inquire about the symptoms and maintenance"
comment/qns: was clinical fistula closure assessed via telephone? was this on
one occasion or on multiple occasions? was there any radiological confirmation
of healing?
Authors may consider acknowledging significant limitation (in their discussion)
of using 'external opening closure' as marker of healing / outcome measure in
fistula studies as highlighted by a recent core outcome set on the condition,
furthermore highlighting the work being done to build other outcome measures
including a PROM for Crohn's perianal fistula 
comment: Presumably the patients had their setons removed prior to assessing
closure in the patients who had drainages? At what point was this done? 
Results:
* Did the authors consider excluding those fistulas invading adjacent organs, as
this complexity may affect the healing rates? 
* Table 1 suggests Most patients had 
seton drainage procedures (96% of early vs
75%late) with very few comparative definitive treatment. I wonder if the title of
this manuscript is better suited to addressing timing of anti-TNF following
drainage of perianal sepsis in PFCD? as opposed to 'surgery' - especially in view
of the 
comparatively few definitive surgical interventions actually assessed…
Authors state "Seventy-four (63.2%) patients have achieved fistula closure at the
end of follow-up. Among them, 57 (48.7%) patients have achieved fistula
closure without any re-intervention free fistula closure)".
comment: Considering that majority had seton drainages (103/117, 88%), was
seton removal done manually or did they have another anaesthetic for removal?
and was this not considered a reintervention? just trying to help the reader easily
understand how a significant proportion of the 48.7% would have had seton
drainages and no further intervention prior to fistula closure
Discussion
Authors state: Heterogeneity in outcome definition hampers effective data
analysis and comparison between different studies about PFCD treatments. In
solutions try to address this issue, we used the need for fistula
‐
related re-
intervention as the primary endpoint. 
comment: In the abstract and methods authors state that "primary outcome was
to compare fistula closure and surgical re-intervention between early and
conventional combination groups." Probably worth deciding which one of
closure OR reintervention was the primary outcome for consistency. 
Authors state: Maintenance infliximab therapy more than 3 times is another risk
factor for surgical re-intervention in early combination group. Unlike previous
studies, which showed that maintenance therapy with infliximab could reduce
the risk of surgery and improve fistula closure in patients with PFCD [4,24].
This difference, however, may due to patients who need infliximab maintenance
therapy more than 3 times in our study usually have more refractory fistulas,
which required intermittent surgical intervention for local optimization. 
comment: I wonder if this is difficult to speculate on, particularly as the reasons
could 
be markedly different if characterising the 'surgery' according to drainage
vs. definitive surgical techniques. 
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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.
previously received honorarium for Takeda advisory / consultancy work.
otherwise no competing interests
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: 
Combined therapy with early initiation of infliximab following drainage of
perianal fistulising Crohn’s disease  a retrospective cohort study
Version: 
0 
Date: 
19 Sep 2021
Reviewer's report:
Abstract: 
fine and well written. Only minor comment is re: conlusion…
Authors state… "Combined therapy with early initiation of infliximab after
surgery could achieve promising results for PFCD patients"…
comment: 
I wonder whether the 
statement on early initiation of infliximab needs
to be tempered. Afterall the results have not demonstrated any significant
benefit, which was what the study set out to determine. 
Hence the natural
statement here, for the sake of clarity I wonder whether the authors would
consider highlighting this instead i.e. no benefit shown in this series.
Background - Page 3/4: 
Authors state "The traditional algorithm includes initial drainage with loose
seton for 2-3mths followed by infliximab infusion or definitive repair based on
the status of anorectal and intestinal inflammation" 
is this delay in medical treatment traditional? perhaps consensus statement or
guideline evidence may be helpful in adding weight to this sentence. I note
references used was a prospective study and a preliminary report. 
Authors state "With the number of clinicians chooses early combination therapy
increased[25], a direct comparison of long-term outcomes between early and
conventional combined treatment is urgently required."
comment: consider rewording this sentence to improve readership assimilation
Methods
Authors state.. "Based on a previous study in which a time interval of 6 weeks
between surgery and infliximab initiation was correlated with fistula closure, we
defined time interval shorter than 6 weeks as early combination therapy and
longer than 6 weeks as conventional combination therapy [24]."
comment/qns: did the authors attempt to review / find 'consensus' in recent
studies, on the question of timing of anti-TNF following definitive surgery? or
following abscess drainage? Just a thought that It might be helpful to the
readership to have a broader view on why "6weeks" was chosen as the
distinguishing timepoint between early and 'conventional' therapy; as opposed to
the 1 study referenced? 
Authors state: "Clinical fistula closure was defined as complete closure of the
fistula's external opening without discharge or discomfort. … A telephone
interview was conducted to inquire about the symptoms and maintenance"
comment/qns: was clinical fistula closure assessed via telephone? was this on
one occasion or on multiple occasions? was there any radiological confirmation
of healing?
Authors may consider acknowledging significant limitation (in their discussion)
of using 'external opening closure' as marker of healing / outcome measure in
fistula studies as highlighted by a recent core outcome set on the condition,
furthermore highlighting the work being done to build other outcome measures
including a PROM for Crohn's perianal fistula 
comment: Presumably the patients had their setons removed prior to assessing
closure in the patients who had drainages? At what point was this done? 
Results:
* Did the authors consider excluding those fistulas invading adjacent organs, as
this complexity may affect the healing rates? 
* Table 1 suggests Most patients had 
seton drainage procedures (96% of early vs
75%late) with very few comparative definitive treatment. I wonder if the title of
this manuscript is better suited to addressing timing of anti-TNF following
drainage of perianal sepsis in PFCD? as opposed to 'surgery' - especially in view
of the 
comparatively few definitive surgical interventions actually assessed…
Authors state "Seventy-four (63.2%) patients have achieved fistula closure at the
end of follow-up. Among them, 57 (48.7%) patients have achieved fistula
closure without any re-intervention free fistula closure)".
comment: Considering that majority had seton drainages (103/117, 88%), was
seton removal done manually or did they have another anaesthetic for removal?
and was this not considered a reintervention? just trying to help the reader easily
understand how a significant proportion of the 48.7% would have had seton
drainages and no further intervention prior to fistula closure
Discussion
Authors state: Heterogeneity in outcome definition hampers effective data
analysis and comparison between different studies about PFCD treatments. In
solutions try to address this issue, we used the need for fistula
‐
related re-
intervention as the primary endpoint. 
comment: In the abstract and methods authors state that "primary outcome was
to compare fistula closure and surgical re-intervention between early and
conventional combination groups." Probably worth deciding which one of
closure OR reintervention was the primary outcome for consistency. 
Authors state: Maintenance infliximab therapy more than 3 times is another risk
factor for surgical re-intervention in early combination group. Unlike previous
studies, which showed that maintenance therapy with infliximab could reduce
the risk of surgery and improve fistula closure in patients with PFCD [4,24].
This difference, however, may due to patients who need infliximab maintenance
therapy more than 3 times in our study usually have more refractory fistulas,
which required intermittent surgical intervention for local optimization. 
comment: I wonder if this is difficult to speculate on, particularly as the reasons
could 
be markedly different if characterising the 'surgery' according to drainage
vs. definitive surgical techniques. 
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
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.
previously received honorarium for Takeda advisory / consultancy work.
otherwise no competing interests
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: 
Combined therapy with early initiation of infliximab following drainage of
perianal fistulising Crohn’s disease  a retrospective cohort study
Version: 
0 
Date: 
19 Sep 2021
Reviewer's report:
Abstract: 
fine and well written. Only minor comment is re: conlusion…
Authors state… "Combined therapy with early initiation of infliximab after
surgery could achieve promising results for PFCD patients"…
comment: 
I wonder whether the 
statement on early initiation of infliximab needs
to be tempered. Afterall the results have not demonstrated any significant
benefit, which was what the study set out to determine. 
Hence the natural
statement here, for the sake of clarity I wonder whether the authors would
consider highlighting this instead i.e. no benefit shown in this series.
Background - Page 3/4: 
Authors state "The traditional algorithm includes initial drainage with loose
seton for 2-3mths followed by infliximab infusion or definitive repair based on
the status of anorectal and intestinal inflammation" 
is this delay in medical treatment traditional? perhaps consensus statement or
guideline evidence may be helpful in adding weight to this sentence. I note
references used was a prospective study and a preliminary report. 
Authors state "With the number of clinicians chooses early combination therapy
increased[25], a direct comparison of long-term outcomes between early and
conventional combined treatment is urgently required."
comment: consider rewording this sentence to improve readership assimilation
Methods
Authors state.. "Based on a previous study in which a time interval of 6 weeks
between surgery and infliximab initiation was correlated with fistula closure, we
defined time interval shorter than 6 weeks as early combination therapy and
longer than 6 weeks as conventional combination therapy [24]."
comment/qns: did the authors attempt to review / find 'consensus' in recent
studies, on the question of timing of anti-TNF following definitive surgery? or
following abscess drainage? Just a thought that It might be helpful to the
readership to have a broader view on why "6weeks" was chosen as the
distinguishing timepoint between early and 'conventional' therapy; as opposed to
the 1 study referenced? 
Authors state: "Clinical fistula closure was defined as complete closure of the
fistula's external opening without discharge or discomfort. … A telephone
interview was conducted to inquire about the symptoms and maintenance"
comment/qns: was clinical fistula closure assessed via telephone? was this on
one occasion or on multiple occasions? was there any radiological confirmation
of healing?
Authors may consider acknowledging significant limitation (in their discussion)
of using 'external opening closure' as marker of healing / outcome measure in
fistula studies as highlighted by a recent core outcome set on the condition,
furthermore highlighting the work being done to build other outcome measures
including a PROM for Crohn's perianal fistula 
comment: Presumably the patients had their setons removed prior to assessing
closure in the patients who had drainages? At what point was this done? 
Results:
* Did the authors consider excluding those fistulas invading adjacent organs, as
this complexity may affect the healing rates? 
* Table 1 suggests Most patients had 
seton drainage procedures (96% of early vs
75%late) with very few comparative definitive treatment. I wonder if the title of
this manuscript is better suited to addressing timing of anti-TNF following
drainage of perianal sepsis in PFCD? as opposed to 'surgery' - especially in view
of the 
comparatively few definitive surgical interventions actually assessed…
Authors state "Seventy-four (63.2%) patients have achieved fistula closure at the
end of follow-up. Among them, 57 (48.7%) patients have achieved fistula
closure without any re-intervention free fistula closure)".
comment: Considering that majority had seton drainages (103/117, 88%), was
seton removal done manually or did they have another anaesthetic for removal?
and was this not considered a reintervention? just trying to help the reader easily
understand how a significant proportion of the 48.7% would have had seton
drainages and no further intervention prior to fistula closure
Discussion
Authors state: Heterogeneity in outcome definition hampers effective data
analysis and comparison between different studies about PFCD treatments. In
solutions try to address this issue, we used the need for fistula
‐
related re-
intervention as the primary endpoint. 
comment: In the abstract and methods authors state that "primary outcome was
to compare fistula closure and surgical re-intervention between early and
conventional combination groups." Probably worth deciding which one of
closure OR reintervention was the primary outcome for consistency. 
Authors state: Maintenance infliximab therapy more than 3 times is another risk
factor for surgical re-intervention in early combination group. Unlike previous
studies, which showed that maintenance therapy with infliximab could reduce
the risk of surgery and improve fistula closure in patients with PFCD [4,24].
This difference, however, may due to patients who need infliximab maintenance
therapy more than 3 times in our study usually have more refractory fistulas,
which required intermittent surgical intervention for local optimization. 
comment: I wonder if this is difficult to speculate on, particularly as the reasons
could 
be markedly different if characterising the 'surgery' according to drainage
vs. definitive surgical techniques. 
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
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.
previously received honorarium for Takeda advisory / consultancy work.
otherwise no competing interests
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