Reviewer ’s report  
 
Title: The culprit of mesalamine intolerance: ca se series and literature review  
 
Version: 0 Date: 05 May 2019  
 
Reviewer: Praveen Kumar  
 
Reviewer's report:  
 
Please incl ude all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a  text format.  
Please overwrite this text when adding your comments to the authors.  
 
The author in this case series describe the 2 cases in their routine practice; one patient faced 
adverse drug reaction supposedly due to mesalamine intolerance another was due to excipient 
intolerance. Hence, the authors are presenting these 2 cases in this case series to enable other 
treating physician of the possibility of occurrence of such an event. It has furthermore rightly 
highlighted that such misdiagnosis might lead  to the prescription of an alternate regimen such as 
steroid, immunosuppressant or costly biologics for induction and maintenance of remission 
which have more propensity to cause adverse drug reaction by itself and are economically more 
demanding.  
Major P oints  
What was the excipient in Salofalk and Pentasa? Is the excipient of the two preparations same or 
different?.  If the details of the excipient of Salofalk and Pentasa not available was the drug 
tested for the excipient in a drug testing laboratory. Ev ent the company of both the preparation 
could have been contacted to get a piece of knowledge about the excipient. This is the critical 
question to be answered to go ahead with confirmation that the excipient was responsible for the 
adverse event. Suppose if the excipient of Salofalk and Pentasa are same, then how can we 
attribute to excipient intolerance. The author basis of saying that excipient was the reason was 
solely due to the lack of reaction on the re -administration of mesalamine suppositories and 
mesalamine slow release tablets to the case 2 patient. Also, the clinical sensitivity test for the 
excipient was also not performed.  
For case 2, reintroduction is a critical aspect missed. For case 1, the reintroduction was 
performed. So a discrepant appr oach was practiced by the Physician, where reintroduction was 
performed for case 1 but not for case 2. It is furthermore amusing that the reintroduction was 
attempted to case 1 - even -though the adverse reaction of case 1 is more prudent (fever over 
40°C, worse abdominal pain and bloody diarrhea with 10 -20 stools movements per day two 
hours) in nature as compared to that of case 2 (skin rash over the trunk and limbs with pruritus). 
As highlighted in my first statement, was any effort made in testing the con stituents of the two 
preparation in a drug testing laboratory?  
The author writes that "Subsequently, the patient was admitted to our department for further 
management. Laboratory examinations revealed…." The values of CRP, ESR presented are 
during adverse  event or following its resolution?  
Though the possibility of excipient based intolerance is present, the conclusion is very broad . 
Especially the word "considered together" in conclusion could create confusion among the 
treating physicians to look out fo r excipient intolerance for every case (though the possibility as 
highlighted may be present).  
The naming of mesalamine preparations is not uniform. Sometimes the author refers to the brand 
name and sometimes to the preparation names.  
Minor Points:  
The i leocolonoscopy was not performed for the first case initially due to arrhythmia. What kind 
of arrhythmia was present?  
The definition of excipient should be added in the introduction segment of the manuscript.  
The authors have mentioned the list of a prev iously known adverse event with excipient in the 
manuscript. In that case, what was the search strategy? (Though this is not a systematic review, 
this information would be essential to understand the gravity of the situation).  
Clinical photography of the skin rashes of case 2 should be included with the manuscript.  
References need to be made more uniform.  
Though the overall language is right, typos are present and need to be corrected. E.g. the spelling 
of mesalamine had been written "melamine" in line n umber 1 page number 6.  
 
 
 
 
 
 
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 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.  
 
Yes 
 
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.  
 
Not relevant to this manuscript  
 
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 r elation 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 websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY licen se (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: The culprit of mesalamine intolerance: ca se series and literature review  
 
Version: 0 Date: 05 May 2019  
 
Reviewer: Praveen Kumar  
 
Reviewer's report:  
 
Please incl ude all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a  text format.  
Please overwrite this text when adding your comments to the authors.  
 
The author in this case series describe the 2 cases in their routine practice; one patient faced 
adverse drug reaction supposedly due to mesalamine intolerance another was due to excipient 
intolerance. Hence, the authors are presenting these 2 cases in this case series to enable other 
treating physician of the possibility of occurrence of such an event. It has furthermore rightly 
highlighted that such misdiagnosis might lead  to the prescription of an alternate regimen such as 
steroid, immunosuppressant or costly biologics for induction and maintenance of remission 
which have more propensity to cause adverse drug reaction by itself and are economically more 
demanding.  
Major P oints  
What was the excipient in Salofalk and Pentasa? Is the excipient of the two preparations same or 
different?.  If the details of the excipient of Salofalk and Pentasa not available was the drug 
tested for the excipient in a drug testing laboratory. Ev ent the company of both the preparation 
could have been contacted to get a piece of knowledge about the excipient. This is the critical 
question to be answered to go ahead with confirmation that the excipient was responsible for the 
adverse event. Suppose if the excipient of Salofalk and Pentasa are same, then how can we 
attribute to excipient intolerance. The author basis of saying that excipient was the reason was 
solely due to the lack of reaction on the re -administration of mesalamine suppositories and 
mesalamine slow release tablets to the case 2 patient. Also, the clinical sensitivity test for the 
excipient was also not performed.  
For case 2, reintroduction is a critical aspect missed. For case 1, the reintroduction was 
performed. So a discrepant appr oach was practiced by the Physician, where reintroduction was 
performed for case 1 but not for case 2. It is furthermore amusing that the reintroduction was 
attempted to case 1 - even -though the adverse reaction of case 1 is more prudent (fever over 
40°C, worse abdominal pain and bloody diarrhea with 10 -20 stools movements per day two 
hours) in nature as compared to that of case 2 (skin rash over the trunk and limbs with pruritus). 
As highlighted in my first statement, was any effort made in testing the con stituents of the two 
preparation in a drug testing laboratory?  
The author writes that "Subsequently, the patient was admitted to our department for further 
management. Laboratory examinations revealed…." The values of CRP, ESR presented are 
during adverse  event or following its resolution?  
Though the possibility of excipient based intolerance is present, the conclusion is very broad . 
Especially the word "considered together" in conclusion could create confusion among the 
treating physicians to look out fo r excipient intolerance for every case (though the possibility as 
highlighted may be present).  
The naming of mesalamine preparations is not uniform. Sometimes the author refers to the brand 
name and sometimes to the preparation names.  
Minor Points:  
The i leocolonoscopy was not performed for the first case initially due to arrhythmia. What kind 
of arrhythmia was present?  
The definition of excipient should be added in the introduction segment of the manuscript.  
The authors have mentioned the list of a prev iously known adverse event with excipient in the 
manuscript. In that case, what was the search strategy? (Though this is not a systematic review, 
this information would be essential to understand the gravity of the situation).  
Clinical photography of the skin rashes of case 2 should be included with the manuscript.  
References need to be made more uniform.  
Though the overall language is right, typos are present and need to be corrected. E.g. the spelling 
of mesalamine had been written "melamine" in line n umber 1 page number 6.  
 
 
 
 
 
 
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 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.  
 
Yes 
 
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.  
 
Not relevant to this manuscript  
 
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 r elation 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 websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY licen se (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: The culprit of mesalamine intolerance: ca se series and literature review  
 
Version: 0 Date: 05 May 2019  
 
Reviewer: Praveen Kumar  
 
Reviewer's report:  
 
Please incl ude all comments for the authors in this box rather than uploading your report as an 
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, 
supporting materials or other aspects of your report which cannot be included in a  text format.  
Please overwrite this text when adding your comments to the authors.  
 
The author in this case series describe the 2 cases in their routine practice; one patient faced 
adverse drug reaction supposedly due to mesalamine intolerance another was due to excipient 
intolerance. Hence, the authors are presenting these 2 cases in this case series to enable other 
treating physician of the possibility of occurrence of such an event. It has furthermore rightly 
highlighted that such misdiagnosis might lead  to the prescription of an alternate regimen such as 
steroid, immunosuppressant or costly biologics for induction and maintenance of remission 
which have more propensity to cause adverse drug reaction by itself and are economically more 
demanding.  
Major P oints  
What was the excipient in Salofalk and Pentasa? Is the excipient of the two preparations same or 
different?.  If the details of the excipient of Salofalk and Pentasa not available was the drug 
tested for the excipient in a drug testing laboratory. Ev ent the company of both the preparation 
could have been contacted to get a piece of knowledge about the excipient. This is the critical 
question to be answered to go ahead with confirmation that the excipient was responsible for the 
adverse event. Suppose if the excipient of Salofalk and Pentasa are same, then how can we 
attribute to excipient intolerance. The author basis of saying that excipient was the reason was 
solely due to the lack of reaction on the re -administration of mesalamine suppositories and 
mesalamine slow release tablets to the case 2 patient. Also, the clinical sensitivity test for the 
excipient was also not performed.  
For case 2, reintroduction is a critical aspect missed. For case 1, the reintroduction was 
performed. So a discrepant appr oach was practiced by the Physician, where reintroduction was 
performed for case 1 but not for case 2. It is furthermore amusing that the reintroduction was 
attempted to case 1 - even -though the adverse reaction of case 1 is more prudent (fever over 
40°C, worse abdominal pain and bloody diarrhea with 10 -20 stools movements per day two 
hours) in nature as compared to that of case 2 (skin rash over the trunk and limbs with pruritus). 
As highlighted in my first statement, was any effort made in testing the con stituents of the two 
preparation in a drug testing laboratory?  
The author writes that "Subsequently, the patient was admitted to our department for further 
management. Laboratory examinations revealed…." The values of CRP, ESR presented are 
during adverse  event or following its resolution?  
Though the possibility of excipient based intolerance is present, the conclusion is very broad . 
Especially the word "considered together" in conclusion could create confusion among the 
treating physicians to look out fo r excipient intolerance for every case (though the possibility as 
highlighted may be present).  
The naming of mesalamine preparations is not uniform. Sometimes the author refers to the brand 
name and sometimes to the preparation names.  
Minor Points:  
The i leocolonoscopy was not performed for the first case initially due to arrhythmia. What kind 
of arrhythmia was present?  
The definition of excipient should be added in the introduction segment of the manuscript.  
The authors have mentioned the list of a prev iously known adverse event with excipient in the 
manuscript. In that case, what was the search strategy? (Though this is not a systematic review, 
this information would be essential to understand the gravity of the situation).  
Clinical photography of the skin rashes of case 2 should be included with the manuscript.  
References need to be made more uniform.  
Though the overall language is right, typos are present and need to be corrected. E.g. the spelling 
of mesalamine had been written "melamine" in line n umber 1 page number 6.  
 
 
 
 
 
 
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 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.  
 
Yes 
 
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.  
 
Not relevant to this manuscript  
 
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 r elation 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 websi te along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY licen se (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