Title: Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease
Version: 3 Date: 09 Aug 2022
Reviewer's report:
Major Comments:
The major limitation of this study is the lack clinical relevance as it is expected that individuals
with ongoing inflammation will have elevated inflammatory cytokine levels as compared to
controls or those with resolved inflammation.
It is important to note that a significant increase in TNF, IL17, and IL23 in a single time
point of inflamed mucosa does not necessarily indicate a specific “resistance mechanisms” to
biologic therapy as is interpreted in the discussion section paragraph 2. These cytokines are
markers of ongoing inflammation. The authors could better clarify exactly when biopsies were
obtained in the treatment course, but this is presumed to be after non-response was determined
as defined in criteria for non-response to biologic therapy. This study would be improved if pre-
treatment transcripts were available for the same patients as that might provide some insight
into mechanisms.
As expected, there is little difference in the cytokine transcripts in non-responders and those in
the reference groups obtained at disease onset who also have active inflammation. This suggests
that the transcripts seen may just be a result of active inflammation rather than any mechanism
of non-response.
This paper may be improved by restating conclusions to focus more on the cytokine transcripts
in inflamed vs. not inflamed mucosa as well as emphasizing the differences in treated mucosa
in remission as compared to controls.
Minor Comments:
1. In the abstract background and aims section last line “throughlevel” should be trough level.
2. Again in discussion line 3 troughlevels should have a space – trough level
Title: Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease
Version: 3 Date: 09 Aug 2022
Reviewer's report:
Major Comments:
The major limitation of this study is the lack clinical relevance as it is expected that individuals
with ongoing inflammation will have elevated inflammatory cytokine levels as compared to
controls or those with resolved inflammation.
It is important to note that a significant increase in TNF, IL17, and IL23 in a single time
point of inflamed mucosa does not necessarily indicate a specific “resistance mechanisms” to
biologic therapy as is interpreted in the discussion section paragraph 2. These cytokines are
markers of ongoing inflammation. The authors could better clarify exactly when biopsies were
obtained in the treatment course, but this is presumed to be after non-response was determined
as defined in criteria for non-response to biologic therapy. This study would be improved if pre-
treatment transcripts were available for the same patients as that might provide some insight
into mechanisms.
As expected, there is little difference in the cytokine transcripts in non-responders and those in
the reference groups obtained at disease onset who also have active inflammation. This suggests
that the transcripts seen may just be a result of active inflammation rather than any mechanism
of non-response.
This paper may be improved by restating conclusions to focus more on the cytokine transcripts
in inflamed vs. not inflamed mucosa as well as emphasizing the differences in treated mucosa
in remission as compared to controls.
Minor Comments:
1. In the abstract background and aims section last line “throughlevel” should be trough level.
2. Again in discussion line 3 troughlevels should have a space – trough level
Please review this paper.
user
Title: Pharmacodynamic mechanisms behind a refractory state in inflammatory bowel disease
Version: 3 Date: 09 Aug 2022
Reviewer's report:
Major Comments:
The major limitation of this study is the lack clinical relevance as it is expected that individuals
with ongoing inflammation will have elevated inflammatory cytokine levels as compared to
controls or those with resolved inflammation.
It is important to note that a significant increase in TNF, IL17, and IL23 in a single time
point of inflamed mucosa does not necessarily indicate a specific “resistance mechanisms” to
biologic therapy as is interpreted in the discussion section paragraph 2. These cytokines are
markers of ongoing inflammation. The authors could better clarify exactly when biopsies were
obtained in the treatment course, but this is presumed to be after non-response was determined
as defined in criteria for non-response to biologic therapy. This study would be improved if pre-
treatment transcripts were available for the same patients as that might provide some insight
into mechanisms.
As expected, there is little difference in the cytokine transcripts in non-responders and those in
the reference groups obtained at disease onset who also have active inflammation. This suggests
that the transcripts seen may just be a result of active inflammation rather than any mechanism
of non-response.
This paper may be improved by restating conclusions to focus more on the cytokine transcripts
in inflamed vs. not inflamed mucosa as well as emphasizing the differences in treated mucosa
in remission as compared to controls.
Minor Comments:
1. In the abstract background and aims section last line “throughlevel” should be trough level.
2. Again in discussion line 3 troughlevels should have a space – trough level
assistant