Title: Risk of Clostridioides difficile infection in inflammatory bowel disease patients
undergoing vedolizumab treatment: a systematic review and meta-analysis
Version: 1 Date: 24 Jul 2024
Reviewer's report:
The authors conduct a systematic review and meta-analysis of the risk of Clostridioides difficile
in individuals with inflammatory bowel disease (IBD) who receive vedolizumab. This is not a
very novel study as a similar study (meta-analysis) was recently published evaluating the risk
of C difficile in individuals with ulcerative colitis (PMID: 38847060). This is a well-written
manuscript with clear description of the manuscript aims, inclusion/exclusion criteria, search
strategy, and evaluation for bias. However, there are some limitations to this study including
the heterogeneity of the study in including both randomized controlled trials and observational
studies and combining ulcerative colitis and Crohn’s patients. I have the following comments
that I hope will improve the quality of the manuscript.
Major comments:
1. In the abstract, the authors note that a systematic comparison regarding the risk of C
difficile infection has not been performed. However, as mentioned above, a similar study has
been published (PMID: 38847060). The authors may want to rephrase their abstract to more
accurately describe the current state of literature on the relationship between vedolizumab use
and C difficile.
2. In the abstract, the authors note the absence of superiority or inferiority of vedolizumab in
C difficile risk in patients with IBD. However, it is important to note that this study was not
designed as a superiority or non-inferiority trial. Therefore, the authors may want to modify their
terminology to discuss that there is no association.
3. The authors noted that there was an increased risk of C difficile in individuals taking
vedolizumab with ulcerative colitis versus Crohn’s disease. However, this risk does not appear
to be isolated to vedolizumab use as ulcerative colitis has been shown to have a higher risk for
C difficile regardless of vedolizumab use.
4. The authors went above and beyond in asking investigators for data that was not reported.
Were the authors able to obtain all the information they needed after these e-mails?
5. In the methods, the authors note that “post-marketing” was a covariate. What studies fall
under the “post-marketing” designation? Further explanation would be helpful.
6. The authors performed subgroup analyses for prior abdominal surgery, current smoking
status, corticosteroid use, and other variables with disparate cut-off values. How did the authors
select their cut-off values? The numbers appear to be somewhat arbitrary as the cut-off varies
from 0.1 for smoking, 0.25 for abdominal surgery, 0.4 for immunomodulator use, and 0.5 for
corticosteroid use. Further explanation would be helpful.
7. Combining information with multiple different study designs (randomized controlled trials
and single arm/multiple arm cohort studies) introduces heterogeneity in the analysis.
8. There is a significant amount of missing data for important covariables such as 11 studies not
reporting follow-up time, which is a limitation.
9. It is important to note that many of these studies explored C difficile infection as a secondary
outcome, which could lead to underpowered estimates comparing vedolizumab use with other
agents to manage IBD.
10. C difficile testing is usually diagnosed using a 2-step technique evaluating the antigen
and toxin. However, some studies have reported an overdiagnosis of C difficile infection at
centers exclusively using PCR testing (PMID: 26348734). It would be important to account for
differences in C difficile testing modalities that could introduce heterogeneity in the data.
Minor comments:
1. The authors sometimes use the term “IBD” or “inflammatory bowel disease.” The authors may
want to either commit to use the abbreviation throughout the manuscript (after initial definition)
or not abbreviate the term at all.
2. In the list of abbreviations, the authors may want to correct their abbreviation for “UC” as it
is currently listed as “Ulcerative Not applicable”
3. In the list of abbreviations, the authors may want to correct their abbreviation for vedolizumab
as it is currently listed as “DZ”
4. On line 589, the authors should correct the spelling of “abbreviations”
5. In Figure 1 (the PRISMA flow diagram), there are asterisks (*) and (**) but no mention of
the meaning of these asterisks. The authors should either delete these asterisks or explain the
meaning of these asterisks in the figure legend.
6. In figures 2A, 3A, and 4, the authors should consider adjusting the “p < 0.01” text at the
bottom of the figure so that it does not overlap with the horizontal axis of the figure.
Title: Risk of Clostridioides difficile infection in inflammatory bowel disease patients
undergoing vedolizumab treatment: a systematic review and meta-analysis
Version: 1 Date: 24 Jul 2024
Reviewer's report:
The authors conduct a systematic review and meta-analysis of the risk of Clostridioides difficile
in individuals with inflammatory bowel disease (IBD) who receive vedolizumab. This is not a
very novel study as a similar study (meta-analysis) was recently published evaluating the risk
of C difficile in individuals with ulcerative colitis (PMID: 38847060). This is a well-written
manuscript with clear description of the manuscript aims, inclusion/exclusion criteria, search
strategy, and evaluation for bias. However, there are some limitations to this study including
the heterogeneity of the study in including both randomized controlled trials and observational
studies and combining ulcerative colitis and Crohn’s patients. I have the following comments
that I hope will improve the quality of the manuscript.
Major comments:
1. In the abstract, the authors note that a systematic comparison regarding the risk of C
difficile infection has not been performed. However, as mentioned above, a similar study has
been published (PMID: 38847060). The authors may want to rephrase their abstract to more
accurately describe the current state of literature on the relationship between vedolizumab use
and C difficile.
2. In the abstract, the authors note the absence of superiority or inferiority of vedolizumab in
C difficile risk in patients with IBD. However, it is important to note that this study was not
designed as a superiority or non-inferiority trial. Therefore, the authors may want to modify their
terminology to discuss that there is no association.
3. The authors noted that there was an increased risk of C difficile in individuals taking
vedolizumab with ulcerative colitis versus Crohn’s disease. However, this risk does not appear
to be isolated to vedolizumab use as ulcerative colitis has been shown to have a higher risk for
C difficile regardless of vedolizumab use.
4. The authors went above and beyond in asking investigators for data that was not reported.
Were the authors able to obtain all the information they needed after these e-mails?
5. In the methods, the authors note that “post-marketing” was a covariate. What studies fall
under the “post-marketing” designation? Further explanation would be helpful.
6. The authors performed subgroup analyses for prior abdominal surgery, current smoking
status, corticosteroid use, and other variables with disparate cut-off values. How did the authors
select their cut-off values? The numbers appear to be somewhat arbitrary as the cut-off varies
from 0.1 for smoking, 0.25 for abdominal surgery, 0.4 for immunomodulator use, and 0.5 for
corticosteroid use. Further explanation would be helpful.
7. Combining information with multiple different study designs (randomized controlled trials
and single arm/multiple arm cohort studies) introduces heterogeneity in the analysis.
8. There is a significant amount of missing data for important covariables such as 11 studies not
reporting follow-up time, which is a limitation.
9. It is important to note that many of these studies explored C difficile infection as a secondary
outcome, which could lead to underpowered estimates comparing vedolizumab use with other
agents to manage IBD.
10. C difficile testing is usually diagnosed using a 2-step technique evaluating the antigen
and toxin. However, some studies have reported an overdiagnosis of C difficile infection at
centers exclusively using PCR testing (PMID: 26348734). It would be important to account for
differences in C difficile testing modalities that could introduce heterogeneity in the data.
Minor comments:
1. The authors sometimes use the term “IBD” or “inflammatory bowel disease.” The authors may
want to either commit to use the abbreviation throughout the manuscript (after initial definition)
or not abbreviate the term at all.
2. In the list of abbreviations, the authors may want to correct their abbreviation for “UC” as it
is currently listed as “Ulcerative Not applicable”
3. In the list of abbreviations, the authors may want to correct their abbreviation for vedolizumab
as it is currently listed as “DZ”
4. On line 589, the authors should correct the spelling of “abbreviations”
5. In Figure 1 (the PRISMA flow diagram), there are asterisks (*) and (**) but no mention of
the meaning of these asterisks. The authors should either delete these asterisks or explain the
meaning of these asterisks in the figure legend.
6. In figures 2A, 3A, and 4, the authors should consider adjusting the “p < 0.01” text at the
bottom of the figure so that it does not overlap with the horizontal axis of the figure.
Please review this paper.
user
Title: Risk of Clostridioides difficile infection in inflammatory bowel disease patients
undergoing vedolizumab treatment: a systematic review and meta-analysis
Version: 1 Date: 24 Jul 2024
Reviewer's report:
The authors conduct a systematic review and meta-analysis of the risk of Clostridioides difficile
in individuals with inflammatory bowel disease (IBD) who receive vedolizumab. This is not a
very novel study as a similar study (meta-analysis) was recently published evaluating the risk
of C difficile in individuals with ulcerative colitis (PMID: 38847060). This is a well-written
manuscript with clear description of the manuscript aims, inclusion/exclusion criteria, search
strategy, and evaluation for bias. However, there are some limitations to this study including
the heterogeneity of the study in including both randomized controlled trials and observational
studies and combining ulcerative colitis and Crohn’s patients. I have the following comments
that I hope will improve the quality of the manuscript.
Major comments:
1. In the abstract, the authors note that a systematic comparison regarding the risk of C
difficile infection has not been performed. However, as mentioned above, a similar study has
been published (PMID: 38847060). The authors may want to rephrase their abstract to more
accurately describe the current state of literature on the relationship between vedolizumab use
and C difficile.
2. In the abstract, the authors note the absence of superiority or inferiority of vedolizumab in
C difficile risk in patients with IBD. However, it is important to note that this study was not
designed as a superiority or non-inferiority trial. Therefore, the authors may want to modify their
terminology to discuss that there is no association.
3. The authors noted that there was an increased risk of C difficile in individuals taking
vedolizumab with ulcerative colitis versus Crohn’s disease. However, this risk does not appear
to be isolated to vedolizumab use as ulcerative colitis has been shown to have a higher risk for
C difficile regardless of vedolizumab use.
4. The authors went above and beyond in asking investigators for data that was not reported.
Were the authors able to obtain all the information they needed after these e-mails?
5. In the methods, the authors note that “post-marketing” was a covariate. What studies fall
under the “post-marketing” designation? Further explanation would be helpful.
6. The authors performed subgroup analyses for prior abdominal surgery, current smoking
status, corticosteroid use, and other variables with disparate cut-off values. How did the authors
select their cut-off values? The numbers appear to be somewhat arbitrary as the cut-off varies
from 0.1 for smoking, 0.25 for abdominal surgery, 0.4 for immunomodulator use, and 0.5 for
corticosteroid use. Further explanation would be helpful.
7. Combining information with multiple different study designs (randomized controlled trials
and single arm/multiple arm cohort studies) introduces heterogeneity in the analysis.
8. There is a significant amount of missing data for important covariables such as 11 studies not
reporting follow-up time, which is a limitation.
9. It is important to note that many of these studies explored C difficile infection as a secondary
outcome, which could lead to underpowered estimates comparing vedolizumab use with other
agents to manage IBD.
10. C difficile testing is usually diagnosed using a 2-step technique evaluating the antigen
and toxin. However, some studies have reported an overdiagnosis of C difficile infection at
centers exclusively using PCR testing (PMID: 26348734). It would be important to account for
differences in C difficile testing modalities that could introduce heterogeneity in the data.
Minor comments:
1. The authors sometimes use the term “IBD” or “inflammatory bowel disease.” The authors may
want to either commit to use the abbreviation throughout the manuscript (after initial definition)
or not abbreviate the term at all.
2. In the list of abbreviations, the authors may want to correct their abbreviation for “UC” as it
is currently listed as “Ulcerative Not applicable”
3. In the list of abbreviations, the authors may want to correct their abbreviation for vedolizumab
as it is currently listed as “DZ”
4. On line 589, the authors should correct the spelling of “abbreviations”
5. In Figure 1 (the PRISMA flow diagram), there are asterisks (*) and (**) but no mention of
the meaning of these asterisks. The authors should either delete these asterisks or explain the
meaning of these asterisks in the figure legend.
6. In figures 2A, 3A, and 4, the authors should consider adjusting the “p < 0.01” text at the
bottom of the figure so that it does not overlap with the horizontal axis of the figure.
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