Reviewer’ s report
Title: Efficacy, Safety and Drug Survival of Thioguanine as Maintenance Treatment for
Inflammatory Bowel Disease: A Retrospective Multi-Centre Study in the United Kingdom
Version: 1Date: 26 Mar 2020
Reviewer: Patricia V Hernandez
Reviewer's report:
This is a well written multicenter study, however I have some concerns:
- The main concern is that the study is not randomized and there is no control group to compareresults with thioguanine (TG). Although it was found that "no statistical difference in responserates was seen between the group using TG and concurrent biological therapy", given the absenceof a formal randomization in the study, it is not possible to assume that both treatment do not differin regards to results- You may want to consider stratifying cohort in Crohn's, ulcerative colitis, and IBD-unclassified.In addition, you would consider the severity of the disease before comparing. For instance, thosepatients with history of bowel election or pancolitis had the same result after TG therapy thanpatients with nonstricturing and nonpenetrating disease?- Would you explain better what biological therapy was used, dosage and duration of treatment?How come was this treatment stopped?- Was there a washout between azathioprine/mercaptopurine treatment and TG?- What was the dosage of azathiaprine/mercaptopurine at which patients present resistance/ noresponse?- In a per-protocol analysis, how is the effectiveness of thioguanine, considering that 46%
discontinued follow-up?
- As acknowledged by the authors, the lack of information about clinical and endoscopic responseto the treatment is a limitation of the study as well as not standardized definition of splenomegaly,hepatomegaly, and signs of nodular regenerative hyperplasia- The retrospective design of the study and the lack of control group prevent the conclusion "...low-dose TH (≤40 mg/day) was effective..." I would recommend to replace with "suggests"
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
NoDoes the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
NoAre the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you 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 furtherassessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, either now or in the future?
2. Do you hold any stocks or shares 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 received 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 interestsI 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 reportincluding 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 CommonsCC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any commentswhich I do not wish to be included 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
Reviewer’ s report
Title: Efficacy, Safety and Drug Survival of Thioguanine as Maintenance Treatment for
Inflammatory Bowel Disease: A Retrospective Multi-Centre Study in the United Kingdom
Version: 1Date: 26 Mar 2020
Reviewer: Patricia V Hernandez
Reviewer's report:
This is a well written multicenter study, however I have some concerns:
- The main concern is that the study is not randomized and there is no control group to compareresults with thioguanine (TG). Although it was found that "no statistical difference in responserates was seen between the group using TG and concurrent biological therapy", given the absenceof a formal randomization in the study, it is not possible to assume that both treatment do not differin regards to results- You may want to consider stratifying cohort in Crohn's, ulcerative colitis, and IBD-unclassified.In addition, you would consider the severity of the disease before comparing. For instance, thosepatients with history of bowel election or pancolitis had the same result after TG therapy thanpatients with nonstricturing and nonpenetrating disease?- Would you explain better what biological therapy was used, dosage and duration of treatment?How come was this treatment stopped?- Was there a washout between azathioprine/mercaptopurine treatment and TG?- What was the dosage of azathiaprine/mercaptopurine at which patients present resistance/ noresponse?- In a per-protocol analysis, how is the effectiveness of thioguanine, considering that 46%
discontinued follow-up?
- As acknowledged by the authors, the lack of information about clinical and endoscopic responseto the treatment is a limitation of the study as well as not standardized definition of splenomegaly,hepatomegaly, and signs of nodular regenerative hyperplasia- The retrospective design of the study and the lack of control group prevent the conclusion "...low-dose TH (≤40 mg/day) was effective..." I would recommend to replace with "suggests"
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
NoDoes the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
NoAre the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you 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 furtherassessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, either now or in the future?
2. Do you hold any stocks or shares 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 received 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 interestsI 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 reportincluding 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 CommonsCC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any commentswhich I do not wish to be included 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
Reviewer’ s report
Title: Efficacy, Safety and Drug Survival of Thioguanine as Maintenance Treatment for
Inflammatory Bowel Disease: A Retrospective Multi-Centre Study in the United Kingdom
Version: 1Date: 26 Mar 2020
Reviewer: Patricia V Hernandez
Reviewer's report:
This is a well written multicenter study, however I have some concerns:
- The main concern is that the study is not randomized and there is no control group to compareresults with thioguanine (TG). Although it was found that "no statistical difference in responserates was seen between the group using TG and concurrent biological therapy", given the absenceof a formal randomization in the study, it is not possible to assume that both treatment do not differin regards to results- You may want to consider stratifying cohort in Crohn's, ulcerative colitis, and IBD-unclassified.In addition, you would consider the severity of the disease before comparing. For instance, thosepatients with history of bowel election or pancolitis had the same result after TG therapy thanpatients with nonstricturing and nonpenetrating disease?- Would you explain better what biological therapy was used, dosage and duration of treatment?How come was this treatment stopped?- Was there a washout between azathioprine/mercaptopurine treatment and TG?- What was the dosage of azathiaprine/mercaptopurine at which patients present resistance/ noresponse?- In a per-protocol analysis, how is the effectiveness of thioguanine, considering that 46%
discontinued follow-up?
- As acknowledged by the authors, the lack of information about clinical and endoscopic responseto the treatment is a limitation of the study as well as not standardized definition of splenomegaly,hepatomegaly, and signs of nodular regenerative hyperplasia- The retrospective design of the study and the lack of control group prevent the conclusion "...low-dose TH (≤40 mg/day) was effective..." I would recommend to replace with "suggests"
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
NoDoes the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
NoAre the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you 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 furtherassessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
AcceptableDeclaration 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 thismanuscript, either now or in the future?
2. Do you hold any stocks or shares 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 received 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 interestsI 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 reportincluding 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 CommonsCC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any commentswhich I do not wish to be included 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