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: 13 Jun 2017 
 
Reviewer:  Karmiris  Konstantinos  
 
Reviewer’s report:  
 
This is a prospective cohort study investigating the necessity of TDM of adalimumab therapy in 
IBD patients for predicting loss of response. The authors conclude that anti -drug antibody 
development, low trough level and need for dose intensification were frequent during 
adalimumab therapy and support the use of TDM in IBD patients treated with adalimumab. Their 
results are intriguing.  However, there are certain issues that need to be addressed:  
 
 
Major comments  
 
1. Adalimumab is a subcutaneously administered monoclonal antibody. As such, it is difficult to 
apply "classic" PK one compartment models with first order absorption. Commercial ly available 
ELISAs usually use such models in an attempt to simulate PK properties of a subcutaneously to 
those of an intravenously administered antibody, where PK can be calculated more accurately. 
As a consequence, measurement of drug's concentration wi th an ELISA could produce 
inaccurate values. The authors should comment on this issue.  
 
2. It is very difficult to measure drug's concentration when this is administered subcutaneously 
although several laboratorial techniques have been proposed. Moreover, experts in pharmacology 
even doubt that using the term "trough levels" for a drug that is injected by this route is 
appropriate claiming that there is a relatively stable concentration of the drug throughout the 
interval between two consecutive injections.  The authors should also comment on this issue.  
 
3. ELISAs usually produce lower title of antibodies against a drug when the latter has a certain 
concentration in the specimen. The authors do not describe in the "Methods" section if their 
ELISA had such a cut-off value of adalimumab concentration above which measurement of anti -
drug antibodies was not feasible.      
 
4. Previous expose to anti -TNF could affect anti -drug antibody measurement and also TL 
according to existing literature. The authors found no a ssociation. No explanation is given for 
this result.   
 
5. Low TL have been clearly associated with LOR at least for intravenously administered anti -
TNF agents. That's why respective algorithms propose dose intensification in patients with low 
TR and absenc e of ADA who lose response for regaining it. However, no association was found 
in this study. Perhaps because "TL" is not a proper term to use/concentration to measure in 
subcutaneously administered agents? On the other hand, the titer of ADA was not assoc iated 
with LOR meaning that only positivity is important clinically.  
 
6. How do the authors explain that transient ADA were associated with LOR (albeit marginally 
non significantly)?  
 
7. It is already known that LOR is more frequent in patients receiving do se intensification since 
these represent a sub -group with a more refractory disease. Thus, no particular scientific interest 
is added in the respective text and this part could be omitted.  
 
8. The authors do not define adalimumab dose intensification and a lso if this intervention was 
based on TDM or treating physician's clinical assessment or both. Also they do not mention if 
other interventions (i.e AZA or steroids administration as add -on therapy) took place.  
 
 
Minor comments   
 
1. Results, lines 181,182: i t is not clear if annual percentages of ADA positivity and low TL rate 
refer to those patients who exhibit both outcomes or reflect patients that had at least one of these 
two characteristics.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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 recommend additional stati stical 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 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: 13 Jun 2017 
 
Reviewer:  Karmiris  Konstantinos  
 
Reviewer’s report:  
 
This is a prospective cohort study investigating the necessity of TDM of adalimumab therapy in 
IBD patients for predicting loss of response. The authors conclude that anti -drug antibody 
development, low trough level and need for dose intensification were frequent during 
adalimumab therapy and support the use of TDM in IBD patients treated with adalimumab. Their 
results are intriguing.  However, there are certain issues that need to be addressed:  
 
 
Major comments  
 
1. Adalimumab is a subcutaneously administered monoclonal antibody. As such, it is difficult to 
apply "classic" PK one compartment models with first order absorption. Commercial ly available 
ELISAs usually use such models in an attempt to simulate PK properties of a subcutaneously to 
those of an intravenously administered antibody, where PK can be calculated more accurately. 
As a consequence, measurement of drug's concentration wi th an ELISA could produce 
inaccurate values. The authors should comment on this issue.  
 
2. It is very difficult to measure drug's concentration when this is administered subcutaneously 
although several laboratorial techniques have been proposed. Moreover, experts in pharmacology 
even doubt that using the term "trough levels" for a drug that is injected by this route is 
appropriate claiming that there is a relatively stable concentration of the drug throughout the 
interval between two consecutive injections.  The authors should also comment on this issue.  
 
3. ELISAs usually produce lower title of antibodies against a drug when the latter has a certain 
concentration in the specimen. The authors do not describe in the "Methods" section if their 
ELISA had such a cut-off value of adalimumab concentration above which measurement of anti -
drug antibodies was not feasible.      
 
4. Previous expose to anti -TNF could affect anti -drug antibody measurement and also TL 
according to existing literature. The authors found no a ssociation. No explanation is given for 
this result.   
 
5. Low TL have been clearly associated with LOR at least for intravenously administered anti -
TNF agents. That's why respective algorithms propose dose intensification in patients with low 
TR and absenc e of ADA who lose response for regaining it. However, no association was found 
in this study. Perhaps because "TL" is not a proper term to use/concentration to measure in 
subcutaneously administered agents? On the other hand, the titer of ADA was not assoc iated 
with LOR meaning that only positivity is important clinically.  
 
6. How do the authors explain that transient ADA were associated with LOR (albeit marginally 
non significantly)?  
 
7. It is already known that LOR is more frequent in patients receiving do se intensification since 
these represent a sub -group with a more refractory disease. Thus, no particular scientific interest 
is added in the respective text and this part could be omitted.  
 
8. The authors do not define adalimumab dose intensification and a lso if this intervention was 
based on TDM or treating physician's clinical assessment or both. Also they do not mention if 
other interventions (i.e AZA or steroids administration as add -on therapy) took place.  
 
 
Minor comments   
 
1. Results, lines 181,182: i t is not clear if annual percentages of ADA positivity and low TL rate 
refer to those patients who exhibit both outcomes or reflect patients that had at least one of these 
two characteristics.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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 recommend additional stati stical 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 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: 13 Jun 2017 
 
Reviewer:  Karmiris  Konstantinos  
 
Reviewer’s report:  
 
This is a prospective cohort study investigating the necessity of TDM of adalimumab therapy in 
IBD patients for predicting loss of response. The authors conclude that anti -drug antibody 
development, low trough level and need for dose intensification were frequent during 
adalimumab therapy and support the use of TDM in IBD patients treated with adalimumab. Their 
results are intriguing.  However, there are certain issues that need to be addressed:  
 
 
Major comments  
 
1. Adalimumab is a subcutaneously administered monoclonal antibody. As such, it is difficult to 
apply "classic" PK one compartment models with first order absorption. Commercial ly available 
ELISAs usually use such models in an attempt to simulate PK properties of a subcutaneously to 
those of an intravenously administered antibody, where PK can be calculated more accurately. 
As a consequence, measurement of drug's concentration wi th an ELISA could produce 
inaccurate values. The authors should comment on this issue.  
 
2. It is very difficult to measure drug's concentration when this is administered subcutaneously 
although several laboratorial techniques have been proposed. Moreover, experts in pharmacology 
even doubt that using the term "trough levels" for a drug that is injected by this route is 
appropriate claiming that there is a relatively stable concentration of the drug throughout the 
interval between two consecutive injections.  The authors should also comment on this issue.  
 
3. ELISAs usually produce lower title of antibodies against a drug when the latter has a certain 
concentration in the specimen. The authors do not describe in the "Methods" section if their 
ELISA had such a cut-off value of adalimumab concentration above which measurement of anti -
drug antibodies was not feasible.      
 
4. Previous expose to anti -TNF could affect anti -drug antibody measurement and also TL 
according to existing literature. The authors found no a ssociation. No explanation is given for 
this result.   
 
5. Low TL have been clearly associated with LOR at least for intravenously administered anti -
TNF agents. That's why respective algorithms propose dose intensification in patients with low 
TR and absenc e of ADA who lose response for regaining it. However, no association was found 
in this study. Perhaps because "TL" is not a proper term to use/concentration to measure in 
subcutaneously administered agents? On the other hand, the titer of ADA was not assoc iated 
with LOR meaning that only positivity is important clinically.  
 
6. How do the authors explain that transient ADA were associated with LOR (albeit marginally 
non significantly)?  
 
7. It is already known that LOR is more frequent in patients receiving do se intensification since 
these represent a sub -group with a more refractory disease. Thus, no particular scientific interest 
is added in the respective text and this part could be omitted.  
 
8. The authors do not define adalimumab dose intensification and a lso if this intervention was 
based on TDM or treating physician's clinical assessment or both. Also they do not mention if 
other interventions (i.e AZA or steroids administration as add -on therapy) took place.  
 
 
Minor comments   
 
1. Results, lines 181,182: i t is not clear if annual percentages of ADA positivity and low TL rate 
refer to those patients who exhibit both outcomes or reflect patients that had at least one of these 
two characteristics.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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 recommend additional stati stical 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 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