Reviewe r’s report  
 
Title: Inflammatory Bowel Disease (IBD) Pharmacotherapy and the Risk of Serious Infection:  
A Systemati c Review and Network Meta -Analysis  
 
Version: 0 Date: 31 Dec 2016  
 
Reviewer: Dominik Bettenworth  
 
Reviewer's report:  
 
Wheat and coworkers provide a systematic review and networt meta -analysis (NMA) on the 
(potential) association between pharmacotherapy and the occurrence of serious infections in 
adult IBD patients. The analysis is based o n a comprehensive literature search including 
PubMed, Cochrane, EMBASE and other libraries. The analysis comprises 38 randomized 
controlled trials evaluating 24 different treatment regimens.  The authors found no increased risk 
for serious infection to be associated with any of the different medical treatment regimes, 
including combo therapy with anti -TNF agents and immunomodulators.  
The study shows some weaknesses, e.g. heterogeneous duration of treatment and follow -up 
period, no inclusion of "real -world"  registry data, low published evidence for novel treatment 
agents and others. Nevertheless, the work presented by Wheat et al. touches an important aspect 
of the medical treatment of IBD patients. Due to the chronic remittent (progressive) character of 
Crohn's disease and ulcerative colitis, long -term medical treatment is required in the vast 
majority of patients. However, infections as a frequent side -effect of anti -inflammatory treatment 
may significantly impact/limit medical therapy. In the absence of di rect head - to-head studies 
comparing the risk for serious infection to be associated with different anti -inflammatory drugs, 
the approach of a network -Meta -Analysis appears reasonable for risk estimation.  
The authors integrate the following remarks in a r evised version of their manuscript:  
 
Major:  
The results presented here are in contrast to earlier studies (e.g Toruner Gastroenterology 2009) 
reporting an increased risk of (opportunistic) infections for IBD patients being treated with 
(combined) immunosuppressive therapy. Similarly, most recently p ublished data from the large 
prospective 5 -year ENCORE registry trial demonstrate an increased risk of serious infection for 
patients being treated with infliximab (D'Haens JCC 2016). The authors should comment on this 
contradiction in more details. May th eir results be transferred to the daily -clinical practice/"real -
world" patient if the analysis only includes data from randomized controlled trials??  
The number of patients in different treatment arms of included individual studies is ranging from 
6 (Ref#2 003) to 967 (Ref#40). Did the authors perform weighting of the study results before 
performing their analyses?  
The authors used a design -by-treatment interaction model to assess inconsistency in NMA with 
multi -arm studies. Did the authors additionally use  models to account for heterogeneity between 
different studies?  
 
Minor:  
Table 1: The dosage of the applied drug should be added (if data is available from included 
studies)  
The authors state in the abstract that 1 study out of 39 studies (fulfilling the inclusion criteria) 
was excluded from the further analysis. This information may be added to the PRISMA 
flowchart.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are y ou able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recomm end additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or share s in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you rece ived reimbursements, fees, funding, or salary from an organization that 
holds   or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be include d in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewe r’s report  
 
Title: Inflammatory Bowel Disease (IBD) Pharmacotherapy and the Risk of Serious Infection:  
A Systemati c Review and Network Meta -Analysis  
 
Version: 0 Date: 31 Dec 2016  
 
Reviewer: Dominik Bettenworth  
 
Reviewer's report:  
 
Wheat and coworkers provide a systematic review and networt meta -analysis (NMA) on the 
(potential) association between pharmacotherapy and the occurrence of serious infections in 
adult IBD patients. The analysis is based o n a comprehensive literature search including 
PubMed, Cochrane, EMBASE and other libraries. The analysis comprises 38 randomized 
controlled trials evaluating 24 different treatment regimens.  The authors found no increased risk 
for serious infection to be associated with any of the different medical treatment regimes, 
including combo therapy with anti -TNF agents and immunomodulators.  
The study shows some weaknesses, e.g. heterogeneous duration of treatment and follow -up 
period, no inclusion of "real -world"  registry data, low published evidence for novel treatment 
agents and others. Nevertheless, the work presented by Wheat et al. touches an important aspect 
of the medical treatment of IBD patients. Due to the chronic remittent (progressive) character of 
Crohn's disease and ulcerative colitis, long -term medical treatment is required in the vast 
majority of patients. However, infections as a frequent side -effect of anti -inflammatory treatment 
may significantly impact/limit medical therapy. In the absence of di rect head - to-head studies 
comparing the risk for serious infection to be associated with different anti -inflammatory drugs, 
the approach of a network -Meta -Analysis appears reasonable for risk estimation.  
The authors integrate the following remarks in a r evised version of their manuscript:  
 
Major:  
The results presented here are in contrast to earlier studies (e.g Toruner Gastroenterology 2009) 
reporting an increased risk of (opportunistic) infections for IBD patients being treated with 
(combined) immunosuppressive therapy. Similarly, most recently p ublished data from the large 
prospective 5 -year ENCORE registry trial demonstrate an increased risk of serious infection for 
patients being treated with infliximab (D'Haens JCC 2016). The authors should comment on this 
contradiction in more details. May th eir results be transferred to the daily -clinical practice/"real -
world" patient if the analysis only includes data from randomized controlled trials??  
The number of patients in different treatment arms of included individual studies is ranging from 
6 (Ref#2 003) to 967 (Ref#40). Did the authors perform weighting of the study results before 
performing their analyses?  
The authors used a design -by-treatment interaction model to assess inconsistency in NMA with 
multi -arm studies. Did the authors additionally use  models to account for heterogeneity between 
different studies?  
 
Minor:  
Table 1: The dosage of the applied drug should be added (if data is available from included 
studies)  
The authors state in the abstract that 1 study out of 39 studies (fulfilling the inclusion criteria) 
was excluded from the further analysis. This information may be added to the PRISMA 
flowchart.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are y ou able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recomm end additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or share s in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you rece ived reimbursements, fees, funding, or salary from an organization that 
holds   or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be include d in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewe r’s report  
 
Title: Inflammatory Bowel Disease (IBD) Pharmacotherapy and the Risk of Serious Infection:  
A Systemati c Review and Network Meta -Analysis  
 
Version: 0 Date: 31 Dec 2016  
 
Reviewer: Dominik Bettenworth  
 
Reviewer's report:  
 
Wheat and coworkers provide a systematic review and networt meta -analysis (NMA) on the 
(potential) association between pharmacotherapy and the occurrence of serious infections in 
adult IBD patients. The analysis is based o n a comprehensive literature search including 
PubMed, Cochrane, EMBASE and other libraries. The analysis comprises 38 randomized 
controlled trials evaluating 24 different treatment regimens.  The authors found no increased risk 
for serious infection to be associated with any of the different medical treatment regimes, 
including combo therapy with anti -TNF agents and immunomodulators.  
The study shows some weaknesses, e.g. heterogeneous duration of treatment and follow -up 
period, no inclusion of "real -world"  registry data, low published evidence for novel treatment 
agents and others. Nevertheless, the work presented by Wheat et al. touches an important aspect 
of the medical treatment of IBD patients. Due to the chronic remittent (progressive) character of 
Crohn's disease and ulcerative colitis, long -term medical treatment is required in the vast 
majority of patients. However, infections as a frequent side -effect of anti -inflammatory treatment 
may significantly impact/limit medical therapy. In the absence of di rect head - to-head studies 
comparing the risk for serious infection to be associated with different anti -inflammatory drugs, 
the approach of a network -Meta -Analysis appears reasonable for risk estimation.  
The authors integrate the following remarks in a r evised version of their manuscript:  
 
Major:  
The results presented here are in contrast to earlier studies (e.g Toruner Gastroenterology 2009) 
reporting an increased risk of (opportunistic) infections for IBD patients being treated with 
(combined) immunosuppressive therapy. Similarly, most recently p ublished data from the large 
prospective 5 -year ENCORE registry trial demonstrate an increased risk of serious infection for 
patients being treated with infliximab (D'Haens JCC 2016). The authors should comment on this 
contradiction in more details. May th eir results be transferred to the daily -clinical practice/"real -
world" patient if the analysis only includes data from randomized controlled trials??  
The number of patients in different treatment arms of included individual studies is ranging from 
6 (Ref#2 003) to 967 (Ref#40). Did the authors perform weighting of the study results before 
performing their analyses?  
The authors used a design -by-treatment interaction model to assess inconsistency in NMA with 
multi -arm studies. Did the authors additionally use  models to account for heterogeneity between 
different studies?  
 
Minor:  
Table 1: The dosage of the applied drug should be added (if data is available from included 
studies)  
The authors state in the abstract that 1 study out of 39 studies (fulfilling the inclusion criteria) 
was excluded from the further analysis. This information may be added to the PRISMA 
flowchart.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are y ou able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recomm end additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or share s in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you rece ived reimbursements, fees, funding, or salary from an organization that 
holds   or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors ' 
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be include d in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant