Title: Prediction of long-term remission in patients following discontinuation of anti-TNF
therapy in ulcerative colitis - a 10 year follow up study
Version: 3 Date: 21 Jul 2022
Reviewer's report:
This study is a detailed and retrospective investigation of the relationship between the profiles of
various cytokine mRNAs in lesional mucosal tissues at the time of TNF inhibitor discontinuation
and the long-term course after its discontinuation in UC patients in whom remission was induced
by TNF inhibitors. As a result, the authors found that a decrease in TNFmRNA(Mucosal TNF
copies/µg mRNA < 10 000) and normalization of IL1RL1 in lesional mucosal biopsies taken at
the time of TNF inhibitor discontinuation were closely associated with the clinical course after
discontinuation. These results are clinically important for more optimal TNF inhibitor therapy,
and this report is considered suitable for publication in this journal.
However, the following points require modification or comment.
Major
(1) Was there any correlation between the time required from the start of TNF inhibitor treatment
to the induction of remission, or the duration of TNF inhibitor treatment from the start of
treatment to its discontinuation, and the low TNFmRNA levels in lesional mucosal tissues at
the time of discontinuation?.  In other words, was there a tendency for TNFmRNA levels in
lesional tissues to decrease with shorter time to induction of remission and longer duration of
TNF inhibitor therapy?
(2) Details regarding the site and number of biopsy tissues, which are the samples from which
cytokine mRNA is measured, need to be added.
(iii) In this new study, in which the observation period was extended, the criteria after
discontinuation of TNF inhibitors are more stringent than in the previous study. This may result
in differences in relapse rates after discontinuation of TNF inhibitors. It would be clinically
useful to clarify whether the clinical course after discontinuation differs between the earlier and
later periods, when the criteria for discontinuation are different.
The present study only included patients once remission was induced by TNF inhibitors, which
potently inhibit the nuclear transcription factor NF-kB, resulting in suppression of the production
and secretion of proinflammatory cytokines, including TNF-alpha. It is unclear whether similar
results would be demonstrated when treated with vedolizumab or JAK inhibitors, which have
different mechanisms of action. Therefore, additional comments regarding limitation are needed.
Title: Prediction of long-term remission in patients following discontinuation of anti-TNF
therapy in ulcerative colitis - a 10 year follow up study
Version: 3 Date: 21 Jul 2022
Reviewer's report:
This study is a detailed and retrospective investigation of the relationship between the profiles of
various cytokine mRNAs in lesional mucosal tissues at the time of TNF inhibitor discontinuation
and the long-term course after its discontinuation in UC patients in whom remission was induced
by TNF inhibitors. As a result, the authors found that a decrease in TNFmRNA(Mucosal TNF
copies/µg mRNA < 10 000) and normalization of IL1RL1 in lesional mucosal biopsies taken at
the time of TNF inhibitor discontinuation were closely associated with the clinical course after
discontinuation. These results are clinically important for more optimal TNF inhibitor therapy,
and this report is considered suitable for publication in this journal.
However, the following points require modification or comment.
Major
(1) Was there any correlation between the time required from the start of TNF inhibitor treatment
to the induction of remission, or the duration of TNF inhibitor treatment from the start of
treatment to its discontinuation, and the low TNFmRNA levels in lesional mucosal tissues at
the time of discontinuation?.  In other words, was there a tendency for TNFmRNA levels in
lesional tissues to decrease with shorter time to induction of remission and longer duration of
TNF inhibitor therapy?
(2) Details regarding the site and number of biopsy tissues, which are the samples from which
cytokine mRNA is measured, need to be added.
(iii) In this new study, in which the observation period was extended, the criteria after
discontinuation of TNF inhibitors are more stringent than in the previous study. This may result
in differences in relapse rates after discontinuation of TNF inhibitors. It would be clinically
useful to clarify whether the clinical course after discontinuation differs between the earlier and
later periods, when the criteria for discontinuation are different.
The present study only included patients once remission was induced by TNF inhibitors, which
potently inhibit the nuclear transcription factor NF-kB, resulting in suppression of the production
and secretion of proinflammatory cytokines, including TNF-alpha. It is unclear whether similar
results would be demonstrated when treated with vedolizumab or JAK inhibitors, which have
different mechanisms of action. Therefore, additional comments regarding limitation are needed.
Please review this paper.
user
Title: Prediction of long-term remission in patients following discontinuation of anti-TNF
therapy in ulcerative colitis - a 10 year follow up study
Version: 3 Date: 21 Jul 2022
Reviewer's report:
This study is a detailed and retrospective investigation of the relationship between the profiles of
various cytokine mRNAs in lesional mucosal tissues at the time of TNF inhibitor discontinuation
and the long-term course after its discontinuation in UC patients in whom remission was induced
by TNF inhibitors. As a result, the authors found that a decrease in TNFmRNA(Mucosal TNF
copies/µg mRNA < 10 000) and normalization of IL1RL1 in lesional mucosal biopsies taken at
the time of TNF inhibitor discontinuation were closely associated with the clinical course after
discontinuation. These results are clinically important for more optimal TNF inhibitor therapy,
and this report is considered suitable for publication in this journal.
However, the following points require modification or comment.
Major
(1) Was there any correlation between the time required from the start of TNF inhibitor treatment
to the induction of remission, or the duration of TNF inhibitor treatment from the start of
treatment to its discontinuation, and the low TNFmRNA levels in lesional mucosal tissues at
the time of discontinuation?.  In other words, was there a tendency for TNFmRNA levels in
lesional tissues to decrease with shorter time to induction of remission and longer duration of
TNF inhibitor therapy?
(2) Details regarding the site and number of biopsy tissues, which are the samples from which
cytokine mRNA is measured, need to be added.
(iii) In this new study, in which the observation period was extended, the criteria after
discontinuation of TNF inhibitors are more stringent than in the previous study. This may result
in differences in relapse rates after discontinuation of TNF inhibitors. It would be clinically
useful to clarify whether the clinical course after discontinuation differs between the earlier and
later periods, when the criteria for discontinuation are different.
The present study only included patients once remission was induced by TNF inhibitors, which
potently inhibit the nuclear transcription factor NF-kB, resulting in suppression of the production
and secretion of proinflammatory cytokines, including TNF-alpha. It is unclear whether similar
results would be demonstrated when treated with vedolizumab or JAK inhibitors, which have
different mechanisms of action. Therefore, additional comments regarding limitation are needed.
assistant