Reviewer ’s report  
 
Title:  Drug persistence and need  for dose intensification to adalimumab therapy; the importance 
of therapeutic drug monitoring in inflammatory bowel diseases  
 
Version: 0 Date: 06 Jun 2017 
 
Reviewer:  Brain  Bressler  
 
Reviewer’s report:  
 
The clinical state of the patients when TDM was ordered is not clear.  The authors mention an 
objective of the study was to determine whether TDM can predict LOR.  If indeed that was 
looked at I woul d assume TDM was performed when patients where in remission before they 
flared.  If TDM was done at time of LOR then an association could be looked for as opposed to 
the value of TDM to predict clinical course.  
 
If the hypothesis remains that ADAs are drug  neutralizing, why does approx. 10% of the cohort 
have 'normal' TL with 'high' ADAs?  
 
As these patients were prospectively followed, further evaluation of them after TDM was 
collected and a clinical decision/change of therapy was done would be helpful  
 
Specify why the cut -off values were chosen for the anti -drug antibodies. I am assuming they are 
the limit of the ELISA test they were using? I've seen the lower limit in one other paper, but not 
200ng/mL.  
 
Line 98: I'm not sure what the word "Twit" means i n this context  
 
Line 196 -197: for association between TL and ADA positivity, considering that the p -value 
>0.05 and CI crosses 1 for the OR, the authors should state "though not statistically significant, 
there may be an trend towards…"  
 
I am not sure why the Cox regression analysis was performed in the final results, as I do not see 
estimated HR for the possible significant variables. Would a multivariate logistic regression on 
the significant variable be useful in terms of confirming the relevance of each  of the variables 
found significant on what I assume is univariate analysis?  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are 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 further 
assessment 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:  
 
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 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 interests  
 
I agree to th e 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 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:  Drug persistence and need  for dose intensification to adalimumab therapy; the importance 
of therapeutic drug monitoring in inflammatory bowel diseases  
 
Version: 0 Date: 06 Jun 2017 
 
Reviewer:  Brain  Bressler  
 
Reviewer’s report:  
 
The clinical state of the patients when TDM was ordered is not clear.  The authors mention an 
objective of the study was to determine whether TDM can predict LOR.  If indeed that was 
looked at I woul d assume TDM was performed when patients where in remission before they 
flared.  If TDM was done at time of LOR then an association could be looked for as opposed to 
the value of TDM to predict clinical course.  
 
If the hypothesis remains that ADAs are drug  neutralizing, why does approx. 10% of the cohort 
have 'normal' TL with 'high' ADAs?  
 
As these patients were prospectively followed, further evaluation of them after TDM was 
collected and a clinical decision/change of therapy was done would be helpful  
 
Specify why the cut -off values were chosen for the anti -drug antibodies. I am assuming they are 
the limit of the ELISA test they were using? I've seen the lower limit in one other paper, but not 
200ng/mL.  
 
Line 98: I'm not sure what the word "Twit" means i n this context  
 
Line 196 -197: for association between TL and ADA positivity, considering that the p -value 
>0.05 and CI crosses 1 for the OR, the authors should state "though not statistically significant, 
there may be an trend towards…"  
 
I am not sure why the Cox regression analysis was performed in the final results, as I do not see 
estimated HR for the possible significant variables. Would a multivariate logistic regression on 
the significant variable be useful in terms of confirming the relevance of each  of the variables 
found significant on what I assume is univariate analysis?  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are 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 further 
assessment 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:  
 
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 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 interests  
 
I agree to th e 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 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:  Drug persistence and need  for dose intensification to adalimumab therapy; the importance 
of therapeutic drug monitoring in inflammatory bowel diseases  
 
Version: 0 Date: 06 Jun 2017 
 
Reviewer:  Brain  Bressler  
 
Reviewer’s report:  
 
The clinical state of the patients when TDM was ordered is not clear.  The authors mention an 
objective of the study was to determine whether TDM can predict LOR.  If indeed that was 
looked at I woul d assume TDM was performed when patients where in remission before they 
flared.  If TDM was done at time of LOR then an association could be looked for as opposed to 
the value of TDM to predict clinical course.  
 
If the hypothesis remains that ADAs are drug  neutralizing, why does approx. 10% of the cohort 
have 'normal' TL with 'high' ADAs?  
 
As these patients were prospectively followed, further evaluation of them after TDM was 
collected and a clinical decision/change of therapy was done would be helpful  
 
Specify why the cut -off values were chosen for the anti -drug antibodies. I am assuming they are 
the limit of the ELISA test they were using? I've seen the lower limit in one other paper, but not 
200ng/mL.  
 
Line 98: I'm not sure what the word "Twit" means i n this context  
 
Line 196 -197: for association between TL and ADA positivity, considering that the p -value 
>0.05 and CI crosses 1 for the OR, the authors should state "though not statistically significant, 
there may be an trend towards…"  
 
I am not sure why the Cox regression analysis was performed in the final results, as I do not see 
estimated HR for the possible significant variables. Would a multivariate logistic regression on 
the significant variable be useful in terms of confirming the relevance of each  of the variables 
found significant on what I assume is univariate analysis?  
 
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 nec essary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are 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 further 
assessment 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:  
 
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 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 interests  
 
I agree to th e 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 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