Reviewer ’s report  
 
Title: Suspected Drug -induced Liver Injury Associated with Iguratimod: A Case Report and  
Review of the Literature  
 
Version: 1 Date: 22 Dec 2017  
 
Reviewer: Hans Ludger Tillmann  
 
Reviewer's report:  
Review on BMC -Gastro D -17-00337R1  
 
The article describes a case of pati ent developing severe liver injury while being exposed to 
iguratimod.  
 
The English may needs some attention, i.e. "her liver and spleen was untouched" instead of her 
liver and spleen was not enlarged palpable"  
Or  
"Besides, her limbs had no pitting edema. " Does this mean "she had edema in her limbs but not 
anywhere else", or, does it mean, "that she had no edema".  
 
The authors state the case has iguratimod DILI, given the lack of a true diagnosis in DILI, I 
recommend to use the term suspected DILI.  
 
I kno w that INR is not ideal for liver assessment; still it's used as more established criteria 
nowadays, and should be given for easier understanding if clotting was prolonged.  
 
Did the patient take any co -medication? If so can you give their start and stop da tes. 
 
Can you give as supplement your Rucam scoring for this case?  
 
What is "G and GM tests"  
 
It appears liver enzymes were more frequently found normal at week 2 and elevated at week 4, 
followed by adaptation in several patients per "Hara M, Abe T, Sugaw ara S, Mizushima Y, 
Hoshi K, Irimajiri S, Hashimoto H, Yoshino S, Matsui N, Nobunaga M. Long -term safety study 
of iguratimod in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(1):10 -6. Epub 2007 
Feb 20. PubMed PMID: 17278016."  
Can you comment on  elevations of liver enzymes timing in the previous ex  
 
Discussion should be more focused.  
 
Please give reference for your statements:  
 
i.e. "It has been reported one case that iguratimod could cause reversible increase in liver 
enzymes in China"  
 
 "The acute DILI accounts for about 20% of hospitalized patients with acute liver injury in 
China."  
 
The risk of factors for DILI is influenced by multiple, such as drug regimen, gender, age, 
malnutrition, diabetes, alcohol drinking and hepatitis B or C ch ronic infection.  
 
Moreover, genetic factors for drug metabolism, such as polymorphisms of cytochrome P (CYP) 
450 or deficiency of N -acetytransferse, have also been reported to contribute to DILI.  
 
Not sure I agree with this statement: "Understanding the p athogenesis of DILI has greatly 
advanced in recent years largely benefit from genetic studies and improved animal models." You 
probably need to have a number of good references. I don't think that in clinical practice we are 
much further than we were in 19 78, as I am not sure that we have clinical useful predictions for 
who develops DILI.  
 
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, p lease 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 i n 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:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questio ns: 
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 sh ares 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 r eceived 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 intere sts 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.  
no COI  
I agree to the open p eer 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 aut hors' 
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: Suspected Drug -induced Liver Injury Associated with Iguratimod: A Case Report and  
Review of the Literature  
 
Version: 1 Date: 22 Dec 2017  
 
Reviewer: Hans Ludger Tillmann  
 
Reviewer's report:  
Review on BMC -Gastro D -17-00337R1  
 
The article describes a case of pati ent developing severe liver injury while being exposed to 
iguratimod.  
 
The English may needs some attention, i.e. "her liver and spleen was untouched" instead of her 
liver and spleen was not enlarged palpable"  
Or  
"Besides, her limbs had no pitting edema. " Does this mean "she had edema in her limbs but not 
anywhere else", or, does it mean, "that she had no edema".  
 
The authors state the case has iguratimod DILI, given the lack of a true diagnosis in DILI, I 
recommend to use the term suspected DILI.  
 
I kno w that INR is not ideal for liver assessment; still it's used as more established criteria 
nowadays, and should be given for easier understanding if clotting was prolonged.  
 
Did the patient take any co -medication? If so can you give their start and stop da tes. 
 
Can you give as supplement your Rucam scoring for this case?  
 
What is "G and GM tests"  
 
It appears liver enzymes were more frequently found normal at week 2 and elevated at week 4, 
followed by adaptation in several patients per "Hara M, Abe T, Sugaw ara S, Mizushima Y, 
Hoshi K, Irimajiri S, Hashimoto H, Yoshino S, Matsui N, Nobunaga M. Long -term safety study 
of iguratimod in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(1):10 -6. Epub 2007 
Feb 20. PubMed PMID: 17278016."  
Can you comment on  elevations of liver enzymes timing in the previous ex  
 
Discussion should be more focused.  
 
Please give reference for your statements:  
 
i.e. "It has been reported one case that iguratimod could cause reversible increase in liver 
enzymes in China"  
 
 "The acute DILI accounts for about 20% of hospitalized patients with acute liver injury in 
China."  
 
The risk of factors for DILI is influenced by multiple, such as drug regimen, gender, age, 
malnutrition, diabetes, alcohol drinking and hepatitis B or C ch ronic infection.  
 
Moreover, genetic factors for drug metabolism, such as polymorphisms of cytochrome P (CYP) 
450 or deficiency of N -acetytransferse, have also been reported to contribute to DILI.  
 
Not sure I agree with this statement: "Understanding the p athogenesis of DILI has greatly 
advanced in recent years largely benefit from genetic studies and improved animal models." You 
probably need to have a number of good references. I don't think that in clinical practice we are 
much further than we were in 19 78, as I am not sure that we have clinical useful predictions for 
who develops DILI.  
 
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, p lease 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 i n 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:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questio ns: 
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 sh ares 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 r eceived 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 intere sts 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.  
no COI  
I agree to the open p eer 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 aut hors' 
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: Suspected Drug -induced Liver Injury Associated with Iguratimod: A Case Report and  
Review of the Literature  
 
Version: 1 Date: 22 Dec 2017  
 
Reviewer: Hans Ludger Tillmann  
 
Reviewer's report:  
Review on BMC -Gastro D -17-00337R1  
 
The article describes a case of pati ent developing severe liver injury while being exposed to 
iguratimod.  
 
The English may needs some attention, i.e. "her liver and spleen was untouched" instead of her 
liver and spleen was not enlarged palpable"  
Or  
"Besides, her limbs had no pitting edema. " Does this mean "she had edema in her limbs but not 
anywhere else", or, does it mean, "that she had no edema".  
 
The authors state the case has iguratimod DILI, given the lack of a true diagnosis in DILI, I 
recommend to use the term suspected DILI.  
 
I kno w that INR is not ideal for liver assessment; still it's used as more established criteria 
nowadays, and should be given for easier understanding if clotting was prolonged.  
 
Did the patient take any co -medication? If so can you give their start and stop da tes. 
 
Can you give as supplement your Rucam scoring for this case?  
 
What is "G and GM tests"  
 
It appears liver enzymes were more frequently found normal at week 2 and elevated at week 4, 
followed by adaptation in several patients per "Hara M, Abe T, Sugaw ara S, Mizushima Y, 
Hoshi K, Irimajiri S, Hashimoto H, Yoshino S, Matsui N, Nobunaga M. Long -term safety study 
of iguratimod in patients with rheumatoid arthritis. Mod Rheumatol. 2007;17(1):10 -6. Epub 2007 
Feb 20. PubMed PMID: 17278016."  
Can you comment on  elevations of liver enzymes timing in the previous ex  
 
Discussion should be more focused.  
 
Please give reference for your statements:  
 
i.e. "It has been reported one case that iguratimod could cause reversible increase in liver 
enzymes in China"  
 
 "The acute DILI accounts for about 20% of hospitalized patients with acute liver injury in 
China."  
 
The risk of factors for DILI is influenced by multiple, such as drug regimen, gender, age, 
malnutrition, diabetes, alcohol drinking and hepatitis B or C ch ronic infection.  
 
Moreover, genetic factors for drug metabolism, such as polymorphisms of cytochrome P (CYP) 
450 or deficiency of N -acetytransferse, have also been reported to contribute to DILI.  
 
Not sure I agree with this statement: "Understanding the p athogenesis of DILI has greatly 
advanced in recent years largely benefit from genetic studies and improved animal models." You 
probably need to have a number of good references. I don't think that in clinical practice we are 
much further than we were in 19 78, as I am not sure that we have clinical useful predictions for 
who develops DILI.  
 
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, p lease 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 i n 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:  
Needs some language corrections before being published  
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questio ns: 
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 sh ares 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 r eceived 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 intere sts 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.  
no COI  
I agree to the open p eer 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 aut hors' 
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