Reviewer ’s report  
 
Title: An Open -Label Prospective Randomized Multicenter Study of Intensive versus Weekly  
Granulocyte and Monocyte Apheresi s in Active Crohn's Disease  
 
Version: 0 Date: 22 Sep 2015  
 
Reviewer: BONAZ  Bruno  
 
Reviewe r's report:  
In this study the authors assessed clinical efficacy and safety of intensive  GMA (10 sessions) 
versus regular (5 sessions) granulocyte -monocyte apheresis (GMA), as classically performed in 
clinical practice, in patients with active Crohn's disease (CD). They showed that intensive GMA 
(2 sessions per week during 5 weeks) was not su perior to weekly (for 5 weeks) GMA, but the 
time to remission was significantly shorter in the intensive GMA without increasing the 
incidence of side effects.  
This is an interesting study on a non -pharmacological and safe treatment of CD which is 
currently  used in Japan in the treatment of UC. GMA is not so much used in clinical practice in 
the treatment of IBD in Europe while patients are more and more reluctant to the side -effects of 
drug currently used in IBD. GMA could be an alternative therapeutic in s pecific conditions. I 
have some points which need to be addressed by the authors:  
- To my knowledge, GMA is more used for UC (more data) than CD (60 citations in 
PubMed for UC versus 21 for CD), consequently such a study will improve the indication 
of such  a technic.  
- A quite similar study has been done in UC where five or ten cycles of GMA showed 
equivalent efficacy and safety in in steroid -refractory or -dependent ulcerative colitis 
(UC) (Dignass AU et al. Aliment Pharmacol Ther 2010; 31: 1286 -1295). The  authors did 
not reference this study and need to add it for comparison and discussion.  
- This is an uncontrolled study.  
- Specify that lymphocytes are not depleted with GMA.  
- Was there an upper limit of age for inclusion? This is not specified in the manuscript.  
- The phenotype of CD is not specified in the manuscript. This is important since one can 
wonder that GMA is perhaps less efficient in stenosis and/or penetrating CD which are 
advance formed of CD.  
- I suppose that patients with ano -perineal CD as well as with involvement of the upper 
digestive tract were excluded from the study? Same question for parenteral nutrition or 
enteral feeding. Did the authors included patien t with only ileal disease. The surgical 
status of the patients needs to be specified.  
- The blood access of the patients (at the antecubital vein) is often a limit to perform GMA. 
What was the screen failure percentage for such a reason?  
- CDAI is a very s ubjective marker since the principal components of this score 
(abdominal pain, diarrhea, and general well -being) are sensitive to stress, anxiety, 
depression… I suppose that no psychological evaluation of the patients was performed in 
this study. The autho rs need to comment on that. The authors have perhaps included 
patients with irritable bowel syndrome on IBD, as frequently observed in clinical 
practice. The classical lower level of CDAI currently used in clinical research is 220. In 
the inclusion criteri a, did the authors looked at fecal calprotectin which is a good marker 
of inflammation (CRP is normal in 20 -30% of CD with flare), as well as morphological 
level (ultrasonography, MRI, endocopy). In particular, there are no data on the efficacy of 
GMA on m ucosal healing which is presently the gold standard.  
- The authors did not perform maintenance treatment with apheresis after 10 or 5 sessions. 
Did they have any data on that?  
- The basal leucocyte count could be biased by the use of corticosteroids. Spec ify the 
normal values of CRP and ESR.  
- In the discussion, the authors did not discuss the limits of their study.  
 
Minor:  
- Abstract, background: This study was performed…..  
- Abstract, background: specify the upper level of CDAI (450?)  
- Abstract, result s: Remission (CDAI<150)….  
- Abstract, results: ..(32.5%) in the intensive GMA (NS).  
- Abstract, results: replace GAM by GMA in the last sentence  
- Page 8, primary efficacy outcome: specify clinical remission (achieved clinical 
remission).  
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, please specify which controls are required in your comments to the  authors.  
 
No 
 
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.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscr ipt: 
 
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, fundin g, 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 f rom 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 o rganization 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.  
NO competing in terest.  
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 upl oad 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: An Open -Label Prospective Randomized Multicenter Study of Intensive versus Weekly  
Granulocyte and Monocyte Apheresi s in Active Crohn's Disease  
 
Version: 0 Date: 22 Sep 2015  
 
Reviewer: BONAZ  Bruno  
 
Reviewe r's report:  
In this study the authors assessed clinical efficacy and safety of intensive  GMA (10 sessions) 
versus regular (5 sessions) granulocyte -monocyte apheresis (GMA), as classically performed in 
clinical practice, in patients with active Crohn's disease (CD). They showed that intensive GMA 
(2 sessions per week during 5 weeks) was not su perior to weekly (for 5 weeks) GMA, but the 
time to remission was significantly shorter in the intensive GMA without increasing the 
incidence of side effects.  
This is an interesting study on a non -pharmacological and safe treatment of CD which is 
currently  used in Japan in the treatment of UC. GMA is not so much used in clinical practice in 
the treatment of IBD in Europe while patients are more and more reluctant to the side -effects of 
drug currently used in IBD. GMA could be an alternative therapeutic in s pecific conditions. I 
have some points which need to be addressed by the authors:  
- To my knowledge, GMA is more used for UC (more data) than CD (60 citations in 
PubMed for UC versus 21 for CD), consequently such a study will improve the indication 
of such  a technic.  
- A quite similar study has been done in UC where five or ten cycles of GMA showed 
equivalent efficacy and safety in in steroid -refractory or -dependent ulcerative colitis 
(UC) (Dignass AU et al. Aliment Pharmacol Ther 2010; 31: 1286 -1295). The  authors did 
not reference this study and need to add it for comparison and discussion.  
- This is an uncontrolled study.  
- Specify that lymphocytes are not depleted with GMA.  
- Was there an upper limit of age for inclusion? This is not specified in the manuscript.  
- The phenotype of CD is not specified in the manuscript. This is important since one can 
wonder that GMA is perhaps less efficient in stenosis and/or penetrating CD which are 
advance formed of CD.  
- I suppose that patients with ano -perineal CD as well as with involvement of the upper 
digestive tract were excluded from the study? Same question for parenteral nutrition or 
enteral feeding. Did the authors included patien t with only ileal disease. The surgical 
status of the patients needs to be specified.  
- The blood access of the patients (at the antecubital vein) is often a limit to perform GMA. 
What was the screen failure percentage for such a reason?  
- CDAI is a very s ubjective marker since the principal components of this score 
(abdominal pain, diarrhea, and general well -being) are sensitive to stress, anxiety, 
depression… I suppose that no psychological evaluation of the patients was performed in 
this study. The autho rs need to comment on that. The authors have perhaps included 
patients with irritable bowel syndrome on IBD, as frequently observed in clinical 
practice. The classical lower level of CDAI currently used in clinical research is 220. In 
the inclusion criteri a, did the authors looked at fecal calprotectin which is a good marker 
of inflammation (CRP is normal in 20 -30% of CD with flare), as well as morphological 
level (ultrasonography, MRI, endocopy). In particular, there are no data on the efficacy of 
GMA on m ucosal healing which is presently the gold standard.  
- The authors did not perform maintenance treatment with apheresis after 10 or 5 sessions. 
Did they have any data on that?  
- The basal leucocyte count could be biased by the use of corticosteroids. Spec ify the 
normal values of CRP and ESR.  
- In the discussion, the authors did not discuss the limits of their study.  
 
Minor:  
- Abstract, background: This study was performed…..  
- Abstract, background: specify the upper level of CDAI (450?)  
- Abstract, result s: Remission (CDAI<150)….  
- Abstract, results: ..(32.5%) in the intensive GMA (NS).  
- Abstract, results: replace GAM by GMA in the last sentence  
- Page 8, primary efficacy outcome: specify clinical remission (achieved clinical 
remission).  
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, please specify which controls are required in your comments to the  authors.  
 
No 
 
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.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscr ipt: 
 
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, fundin g, 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 f rom 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 o rganization 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.  
NO competing in terest.  
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 upl oad 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: An Open -Label Prospective Randomized Multicenter Study of Intensive versus Weekly  
Granulocyte and Monocyte Apheresi s in Active Crohn's Disease  
 
Version: 0 Date: 22 Sep 2015  
 
Reviewer: BONAZ  Bruno  
 
Reviewe r's report:  
In this study the authors assessed clinical efficacy and safety of intensive  GMA (10 sessions) 
versus regular (5 sessions) granulocyte -monocyte apheresis (GMA), as classically performed in 
clinical practice, in patients with active Crohn's disease (CD). They showed that intensive GMA 
(2 sessions per week during 5 weeks) was not su perior to weekly (for 5 weeks) GMA, but the 
time to remission was significantly shorter in the intensive GMA without increasing the 
incidence of side effects.  
This is an interesting study on a non -pharmacological and safe treatment of CD which is 
currently  used in Japan in the treatment of UC. GMA is not so much used in clinical practice in 
the treatment of IBD in Europe while patients are more and more reluctant to the side -effects of 
drug currently used in IBD. GMA could be an alternative therapeutic in s pecific conditions. I 
have some points which need to be addressed by the authors:  
- To my knowledge, GMA is more used for UC (more data) than CD (60 citations in 
PubMed for UC versus 21 for CD), consequently such a study will improve the indication 
of such  a technic.  
- A quite similar study has been done in UC where five or ten cycles of GMA showed 
equivalent efficacy and safety in in steroid -refractory or -dependent ulcerative colitis 
(UC) (Dignass AU et al. Aliment Pharmacol Ther 2010; 31: 1286 -1295). The  authors did 
not reference this study and need to add it for comparison and discussion.  
- This is an uncontrolled study.  
- Specify that lymphocytes are not depleted with GMA.  
- Was there an upper limit of age for inclusion? This is not specified in the manuscript.  
- The phenotype of CD is not specified in the manuscript. This is important since one can 
wonder that GMA is perhaps less efficient in stenosis and/or penetrating CD which are 
advance formed of CD.  
- I suppose that patients with ano -perineal CD as well as with involvement of the upper 
digestive tract were excluded from the study? Same question for parenteral nutrition or 
enteral feeding. Did the authors included patien t with only ileal disease. The surgical 
status of the patients needs to be specified.  
- The blood access of the patients (at the antecubital vein) is often a limit to perform GMA. 
What was the screen failure percentage for such a reason?  
- CDAI is a very s ubjective marker since the principal components of this score 
(abdominal pain, diarrhea, and general well -being) are sensitive to stress, anxiety, 
depression… I suppose that no psychological evaluation of the patients was performed in 
this study. The autho rs need to comment on that. The authors have perhaps included 
patients with irritable bowel syndrome on IBD, as frequently observed in clinical 
practice. The classical lower level of CDAI currently used in clinical research is 220. In 
the inclusion criteri a, did the authors looked at fecal calprotectin which is a good marker 
of inflammation (CRP is normal in 20 -30% of CD with flare), as well as morphological 
level (ultrasonography, MRI, endocopy). In particular, there are no data on the efficacy of 
GMA on m ucosal healing which is presently the gold standard.  
- The authors did not perform maintenance treatment with apheresis after 10 or 5 sessions. 
Did they have any data on that?  
- The basal leucocyte count could be biased by the use of corticosteroids. Spec ify the 
normal values of CRP and ESR.  
- In the discussion, the authors did not discuss the limits of their study.  
 
Minor:  
- Abstract, background: This study was performed…..  
- Abstract, background: specify the upper level of CDAI (450?)  
- Abstract, result s: Remission (CDAI<150)….  
- Abstract, results: ..(32.5%) in the intensive GMA (NS).  
- Abstract, results: replace GAM by GMA in the last sentence  
- Page 8, primary efficacy outcome: specify clinical remission (achieved clinical 
remission).  
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, please specify which controls are required in your comments to the  authors.  
 
No 
 
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.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscr ipt: 
 
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, fundin g, 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 f rom 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 o rganization 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.  
NO competing in terest.  
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 upl oad 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