Title: Risk of stroke in patients with inflammatory bowel disease: A systematic review and
meta-analysis
Version: 2 Date: 28 Dec 2024
Reviewer's report:
Luo et al. present a systematic review and meta-analysis assessing the risk of stroke in patients
with inflammatory bowel disease (IBD). The authors found that IBD patients have a 30%
increased risk of stroke compared to controls (HR 1.30 [95% CI 1.21–1.39]), with a slightly
higher risk observed in Crohn's disease (CD) patients. While the topic addresses a relevant
clinical question, the primary concern is the lack of novelty. Several systematic reviews and
meta-analyses have previously investigated this association and reached similar conclusions—a
modestly increased risk of stroke in IBD patients (PMID: 23978350, PMID: 26360973, PMID:
36863421, PMID: 37796223, PMID: 38046580, PMID: 38271615). This paper makes limited
reference to these earlier studies and does not clearly articulate how it builds upon or adds to
the existing body of evidence.
Major Comments:
1. Introduction and Discussion:
o The authors should better justify the necessity of this systematic review and meta-analysis
(SR-MA). Specifically, they should highlight its contribution to the existing literature and how
it sets itself apart from prior evidence syntheses. For instance, apart from subgroup analyses by
CD and UC, previous SR-MAs have also explored differences in stroke risk by gender and age.
Currently, the paper provides additional data but no novel insights.
2. Introduction:
o The statement, “Similarly, studies suggested a possible link between anti-TNF# therapies and
increased risk of thromboembolic events [14, 15],” is misleading. On the contrary, evidence
suggests that anti-TNFs are associated with reduced risk of venous and arterial thrombotic
events. Refer to this review for clarification: Nat Rev Gastroenterol Hepatol 2021;18(12):857–
873 (PMID: 34453143).
o The authors claim that findings on the association between IBD and cerebrovascular diseases
are inconsistent. However, previous meta-analyses have consistently demonstrated a modest
increase in risk. This point should be clarified.
3. Methods:
o The search strategies for all databases should be included as a supplementary appendix for
reproducibility.
o The Newcastle-Ottawa Scale (NOS), while commonly used, is oversimplified, lacks
granularity, and relies heavily on subjective interpretation. The ROBINS-E tool is a more robust
and rigorous option for risk of bias assessment and should be considered.
o Six of the 13 included studies were assessed as having a high risk of bias using the NOS. A
sensitivity analysis excluding these studies should be performed to assess their impact on the
findings.
o The claim that selective reporting was assessed by comparing outcomes with protocols or trial
registries is unclear, as none of the included studies are clinical trials. Please clarify whether this
was actually done and how many studies had available protocols or registries.
o Sensitivity analyses should be clearly described in the methods, including whether they were
planned a priori.
4. Results:
o Clarify whether the 10 cohort studies were prospective. Table 1 and the text should specify
whether studies were population-based or hospital-based.
o “encompassing a total sample size of over 2.6 million participants” and in the following
paragraph “Data from 13 studies with a total of 2,802,955 participants were analyzed” Please
keep it consistent.
o Provide more details on the risk of bias assessment, including a figure summarizing each
assessed domain.
o The x-axis for forest plots spans unnecessarily wide ranges, making confidence intervals hard
to interpret. Adjust the maximum HR to 4, as the highest upper bound CI is 3.41 (Keller 2014).
o Clarify whether the mean age of participants refers to age at IBD diagnosis or at the time of
events. Also, specify whether the cases were incident or prevalent.
5. Discussion:
o When discussing strengths, explicitly state what sets this SR-MA apart from prior reviews. For
example, citing a larger sample size as a strength is weak given that previous meta-analyses (e.g.,
Fan et al. Front Neurol 2023;14:1204727) included almost twice as many participants (4,495,055
individuals). Similarly, stratification by IBD subtype has been consistently performed in earlier
SR-MAs.
Minor Comments:
1. Methods:
o For heterogeneity assessment, describe how results from the I² statistic were interpreted and
which thresholds were used.
2. Results:
o Replace “Salient features of the included studies” with “Characteristics of included studies.”
3. Discussion:
o Correct typographical errors in phrases such as “various demographics that incrteases
generalizability of our results” and “Due to the lack of such granular data in the included stidies.”
4. Style:
o Avoid contractions like “didn’t” or “isn’t” to maintain formal academic tone.
Title: Risk of stroke in patients with inflammatory bowel disease: A systematic review and
meta-analysis
Version: 2 Date: 28 Dec 2024
Reviewer's report:
Luo et al. present a systematic review and meta-analysis assessing the risk of stroke in patients
with inflammatory bowel disease (IBD). The authors found that IBD patients have a 30%
increased risk of stroke compared to controls (HR 1.30 [95% CI 1.21–1.39]), with a slightly
higher risk observed in Crohn's disease (CD) patients. While the topic addresses a relevant
clinical question, the primary concern is the lack of novelty. Several systematic reviews and
meta-analyses have previously investigated this association and reached similar conclusions—a
modestly increased risk of stroke in IBD patients (PMID: 23978350, PMID: 26360973, PMID:
36863421, PMID: 37796223, PMID: 38046580, PMID: 38271615). This paper makes limited
reference to these earlier studies and does not clearly articulate how it builds upon or adds to
the existing body of evidence.
Major Comments:
1. Introduction and Discussion:
o The authors should better justify the necessity of this systematic review and meta-analysis
(SR-MA). Specifically, they should highlight its contribution to the existing literature and how
it sets itself apart from prior evidence syntheses. For instance, apart from subgroup analyses by
CD and UC, previous SR-MAs have also explored differences in stroke risk by gender and age.
Currently, the paper provides additional data but no novel insights.
2. Introduction:
o The statement, “Similarly, studies suggested a possible link between anti-TNF# therapies and
increased risk of thromboembolic events [14, 15],” is misleading. On the contrary, evidence
suggests that anti-TNFs are associated with reduced risk of venous and arterial thrombotic
events. Refer to this review for clarification: Nat Rev Gastroenterol Hepatol 2021;18(12):857–
873 (PMID: 34453143).
o The authors claim that findings on the association between IBD and cerebrovascular diseases
are inconsistent. However, previous meta-analyses have consistently demonstrated a modest
increase in risk. This point should be clarified.
3. Methods:
o The search strategies for all databases should be included as a supplementary appendix for
reproducibility.
o The Newcastle-Ottawa Scale (NOS), while commonly used, is oversimplified, lacks
granularity, and relies heavily on subjective interpretation. The ROBINS-E tool is a more robust
and rigorous option for risk of bias assessment and should be considered.
o Six of the 13 included studies were assessed as having a high risk of bias using the NOS. A
sensitivity analysis excluding these studies should be performed to assess their impact on the
findings.
o The claim that selective reporting was assessed by comparing outcomes with protocols or trial
registries is unclear, as none of the included studies are clinical trials. Please clarify whether this
was actually done and how many studies had available protocols or registries.
o Sensitivity analyses should be clearly described in the methods, including whether they were
planned a priori.
4. Results:
o Clarify whether the 10 cohort studies were prospective. Table 1 and the text should specify
whether studies were population-based or hospital-based.
o “encompassing a total sample size of over 2.6 million participants” and in the following
paragraph “Data from 13 studies with a total of 2,802,955 participants were analyzed” Please
keep it consistent.
o Provide more details on the risk of bias assessment, including a figure summarizing each
assessed domain.
o The x-axis for forest plots spans unnecessarily wide ranges, making confidence intervals hard
to interpret. Adjust the maximum HR to 4, as the highest upper bound CI is 3.41 (Keller 2014).
o Clarify whether the mean age of participants refers to age at IBD diagnosis or at the time of
events. Also, specify whether the cases were incident or prevalent.
5. Discussion:
o When discussing strengths, explicitly state what sets this SR-MA apart from prior reviews. For
example, citing a larger sample size as a strength is weak given that previous meta-analyses (e.g.,
Fan et al. Front Neurol 2023;14:1204727) included almost twice as many participants (4,495,055
individuals). Similarly, stratification by IBD subtype has been consistently performed in earlier
SR-MAs.
Minor Comments:
1. Methods:
o For heterogeneity assessment, describe how results from the I² statistic were interpreted and
which thresholds were used.
2. Results:
o Replace “Salient features of the included studies” with “Characteristics of included studies.”
3. Discussion:
o Correct typographical errors in phrases such as “various demographics that incrteases
generalizability of our results” and “Due to the lack of such granular data in the included stidies.”
4. Style:
o Avoid contractions like “didn’t” or “isn’t” to maintain formal academic tone.
Please review this paper.
user
Title: Risk of stroke in patients with inflammatory bowel disease: A systematic review and
meta-analysis
Version: 2 Date: 28 Dec 2024
Reviewer's report:
Luo et al. present a systematic review and meta-analysis assessing the risk of stroke in patients
with inflammatory bowel disease (IBD). The authors found that IBD patients have a 30%
increased risk of stroke compared to controls (HR 1.30 [95% CI 1.21–1.39]), with a slightly
higher risk observed in Crohn's disease (CD) patients. While the topic addresses a relevant
clinical question, the primary concern is the lack of novelty. Several systematic reviews and
meta-analyses have previously investigated this association and reached similar conclusions—a
modestly increased risk of stroke in IBD patients (PMID: 23978350, PMID: 26360973, PMID:
36863421, PMID: 37796223, PMID: 38046580, PMID: 38271615). This paper makes limited
reference to these earlier studies and does not clearly articulate how it builds upon or adds to
the existing body of evidence.
Major Comments:
1. Introduction and Discussion:
o The authors should better justify the necessity of this systematic review and meta-analysis
(SR-MA). Specifically, they should highlight its contribution to the existing literature and how
it sets itself apart from prior evidence syntheses. For instance, apart from subgroup analyses by
CD and UC, previous SR-MAs have also explored differences in stroke risk by gender and age.
Currently, the paper provides additional data but no novel insights.
2. Introduction:
o The statement, “Similarly, studies suggested a possible link between anti-TNF# therapies and
increased risk of thromboembolic events [14, 15],” is misleading. On the contrary, evidence
suggests that anti-TNFs are associated with reduced risk of venous and arterial thrombotic
events. Refer to this review for clarification: Nat Rev Gastroenterol Hepatol 2021;18(12):857–
873 (PMID: 34453143).
o The authors claim that findings on the association between IBD and cerebrovascular diseases
are inconsistent. However, previous meta-analyses have consistently demonstrated a modest
increase in risk. This point should be clarified.
3. Methods:
o The search strategies for all databases should be included as a supplementary appendix for
reproducibility.
o The Newcastle-Ottawa Scale (NOS), while commonly used, is oversimplified, lacks
granularity, and relies heavily on subjective interpretation. The ROBINS-E tool is a more robust
and rigorous option for risk of bias assessment and should be considered.
o Six of the 13 included studies were assessed as having a high risk of bias using the NOS. A
sensitivity analysis excluding these studies should be performed to assess their impact on the
findings.
o The claim that selective reporting was assessed by comparing outcomes with protocols or trial
registries is unclear, as none of the included studies are clinical trials. Please clarify whether this
was actually done and how many studies had available protocols or registries.
o Sensitivity analyses should be clearly described in the methods, including whether they were
planned a priori.
4. Results:
o Clarify whether the 10 cohort studies were prospective. Table 1 and the text should specify
whether studies were population-based or hospital-based.
o “encompassing a total sample size of over 2.6 million participants” and in the following
paragraph “Data from 13 studies with a total of 2,802,955 participants were analyzed” Please
keep it consistent.
o Provide more details on the risk of bias assessment, including a figure summarizing each
assessed domain.
o The x-axis for forest plots spans unnecessarily wide ranges, making confidence intervals hard
to interpret. Adjust the maximum HR to 4, as the highest upper bound CI is 3.41 (Keller 2014).
o Clarify whether the mean age of participants refers to age at IBD diagnosis or at the time of
events. Also, specify whether the cases were incident or prevalent.
5. Discussion:
o When discussing strengths, explicitly state what sets this SR-MA apart from prior reviews. For
example, citing a larger sample size as a strength is weak given that previous meta-analyses (e.g.,
Fan et al. Front Neurol 2023;14:1204727) included almost twice as many participants (4,495,055
individuals). Similarly, stratification by IBD subtype has been consistently performed in earlier
SR-MAs.
Minor Comments:
1. Methods:
o For heterogeneity assessment, describe how results from the I² statistic were interpreted and
which thresholds were used.
2. Results:
o Replace “Salient features of the included studies” with “Characteristics of included studies.”
3. Discussion:
o Correct typographical errors in phrases such as “various demographics that incrteases
generalizability of our results” and “Due to the lack of such granular data in the included stidies.”
4. Style:
o Avoid contractions like “didn’t” or “isn’t” to maintain formal academic tone.
assistant