Title: A retrospective, observational study to examine the effect of early tumor necrosis factor
inhibitor use on rates of surgery for Crohn’s disease in Japan
Version: 2 Date: 04 Oct 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This retrospective study evaluated whether tumor necrosis factor
inhibitors (TNFi) reduce surgery rates in Japanese Crohn’s disease (CD) patients. The analysis
included 124 patients (TNFi-treated: 86; untreated: 38). Surgery was required in significantly
fewer TNFi-treated patients (3/86) than untreated (17/38), with higher surgery-free survival
rates in the TNFi group. Both infliximab and adalimumab showed significant reductions in
surgeries. Infliximab-treated patients had the highest surgery-free survival. TNFi therapy may
reduce surgery rates and delay the need for surgery in CD.
This retrospective two center study comes at a time when more robust data sets are available to
inform the field. As indicated by the authors national data have been published and meta analysis
have demonstrated the efficacy of TNFi therapy.
REQUESTED REVISIONS:
I like the hypothesis, (use of TNFis lead to a reduction in surgery rates) but I would like to point
out that a retrospective study is unable to distinguish association from causation regardless of
outcome.
An important issue is whether all patients had equally access to TNFis. The authors mention
that patients were treated according to the Japanese guidelines, but reimbursement issues and
availability kept a lid on widespread use , in particular during the first 10 years of market
access. Limited availability affects penetration of the drug into the market, and probably the
most severely affected patients were the first recipients. How did the authors balance this out?
(some authors would use propensity scored matching here)
Did the approach to surgery change in Japan over time or did guidelines change (laparotomic
to laparoscopic, indications? )
A key item is the decision to surgery. How was this taken, and on basis of what? There is a
tendency towards therapies of less invasive nature over time which introduces bias.
I would advise the authors to use  a formal system for classifying CD distribution such as the
Montreal Classification, which categorizes the disease into three main phenotypes based on the
location and behavior of the disease and age at diagnosis. In particular this would require a
change in the make up of table 1 .
It is impressive that “All patients provided written, informed consent. “ while I am in no position
to doubt this statement, this study is of retrospective nature and it is entirely possible that patients
are lost to follow-up in particular in view of the long reported follow-up. Please rethink this
statement.
ADDITIONAL REQUESTS/SUGGESTIONS:
The authors tout the long follow up. I have 2 remarks here. For some patients the follow-up
was very short (at least 2 had follow-up of 0.41 years and 0.08 years. These patients probably
have not been exposed long enough to the disease to tell us whether they will develop need for
surgery or whether INFi is able to prevent that.
On the flip side, the follow-up is very long for some patients and antedate that of the advent
of TNFi. I would like to see a separate analysis with entry of TNFi on the Japanese market as
stating point  (so exclude patients with a diagnosis before 2002) and with a reasonable minimum
follow-up of 5 years
Title: A retrospective, observational study to examine the effect of early tumor necrosis factor
inhibitor use on rates of surgery for Crohn’s disease in Japan
Version: 2 Date: 04 Oct 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This retrospective study evaluated whether tumor necrosis factor
inhibitors (TNFi) reduce surgery rates in Japanese Crohn’s disease (CD) patients. The analysis
included 124 patients (TNFi-treated: 86; untreated: 38). Surgery was required in significantly
fewer TNFi-treated patients (3/86) than untreated (17/38), with higher surgery-free survival
rates in the TNFi group. Both infliximab and adalimumab showed significant reductions in
surgeries. Infliximab-treated patients had the highest surgery-free survival. TNFi therapy may
reduce surgery rates and delay the need for surgery in CD.
This retrospective two center study comes at a time when more robust data sets are available to
inform the field. As indicated by the authors national data have been published and meta analysis
have demonstrated the efficacy of TNFi therapy.
REQUESTED REVISIONS:
I like the hypothesis, (use of TNFis lead to a reduction in surgery rates) but I would like to point
out that a retrospective study is unable to distinguish association from causation regardless of
outcome.
An important issue is whether all patients had equally access to TNFis. The authors mention
that patients were treated according to the Japanese guidelines, but reimbursement issues and
availability kept a lid on widespread use , in particular during the first 10 years of market
access. Limited availability affects penetration of the drug into the market, and probably the
most severely affected patients were the first recipients. How did the authors balance this out?
(some authors would use propensity scored matching here)
Did the approach to surgery change in Japan over time or did guidelines change (laparotomic
to laparoscopic, indications? )
A key item is the decision to surgery. How was this taken, and on basis of what? There is a
tendency towards therapies of less invasive nature over time which introduces bias.
I would advise the authors to use  a formal system for classifying CD distribution such as the
Montreal Classification, which categorizes the disease into three main phenotypes based on the
location and behavior of the disease and age at diagnosis. In particular this would require a
change in the make up of table 1 .
It is impressive that “All patients provided written, informed consent. “ while I am in no position
to doubt this statement, this study is of retrospective nature and it is entirely possible that patients
are lost to follow-up in particular in view of the long reported follow-up. Please rethink this
statement.
ADDITIONAL REQUESTS/SUGGESTIONS:
The authors tout the long follow up. I have 2 remarks here. For some patients the follow-up
was very short (at least 2 had follow-up of 0.41 years and 0.08 years. These patients probably
have not been exposed long enough to the disease to tell us whether they will develop need for
surgery or whether INFi is able to prevent that.
On the flip side, the follow-up is very long for some patients and antedate that of the advent
of TNFi. I would like to see a separate analysis with entry of TNFi on the Japanese market as
stating point  (so exclude patients with a diagnosis before 2002) and with a reasonable minimum
follow-up of 5 years
Please review this paper.
user
Title: A retrospective, observational study to examine the effect of early tumor necrosis factor
inhibitor use on rates of surgery for Crohn’s disease in Japan
Version: 2 Date: 04 Oct 2024
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (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?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically
sound? If not, can revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This retrospective study evaluated whether tumor necrosis factor
inhibitors (TNFi) reduce surgery rates in Japanese Crohn’s disease (CD) patients. The analysis
included 124 patients (TNFi-treated: 86; untreated: 38). Surgery was required in significantly
fewer TNFi-treated patients (3/86) than untreated (17/38), with higher surgery-free survival
rates in the TNFi group. Both infliximab and adalimumab showed significant reductions in
surgeries. Infliximab-treated patients had the highest surgery-free survival. TNFi therapy may
reduce surgery rates and delay the need for surgery in CD.
This retrospective two center study comes at a time when more robust data sets are available to
inform the field. As indicated by the authors national data have been published and meta analysis
have demonstrated the efficacy of TNFi therapy.
REQUESTED REVISIONS:
I like the hypothesis, (use of TNFis lead to a reduction in surgery rates) but I would like to point
out that a retrospective study is unable to distinguish association from causation regardless of
outcome.
An important issue is whether all patients had equally access to TNFis. The authors mention
that patients were treated according to the Japanese guidelines, but reimbursement issues and
availability kept a lid on widespread use , in particular during the first 10 years of market
access. Limited availability affects penetration of the drug into the market, and probably the
most severely affected patients were the first recipients. How did the authors balance this out?
(some authors would use propensity scored matching here)
Did the approach to surgery change in Japan over time or did guidelines change (laparotomic
to laparoscopic, indications? )
A key item is the decision to surgery. How was this taken, and on basis of what? There is a
tendency towards therapies of less invasive nature over time which introduces bias.
I would advise the authors to use  a formal system for classifying CD distribution such as the
Montreal Classification, which categorizes the disease into three main phenotypes based on the
location and behavior of the disease and age at diagnosis. In particular this would require a
change in the make up of table 1 .
It is impressive that “All patients provided written, informed consent. “ while I am in no position
to doubt this statement, this study is of retrospective nature and it is entirely possible that patients
are lost to follow-up in particular in view of the long reported follow-up. Please rethink this
statement.
ADDITIONAL REQUESTS/SUGGESTIONS:
The authors tout the long follow up. I have 2 remarks here. For some patients the follow-up
was very short (at least 2 had follow-up of 0.41 years and 0.08 years. These patients probably
have not been exposed long enough to the disease to tell us whether they will develop need for
surgery or whether INFi is able to prevent that.
On the flip side, the follow-up is very long for some patients and antedate that of the advent
of TNFi. I would like to see a separate analysis with entry of TNFi on the Japanese market as
stating point  (so exclude patients with a diagnosis before 2002) and with a reasonable minimum
follow-up of 5 years
assistant