Reviewer’s report  
Title: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Abdul Elkadri  
Reviewer’s report:  
The authors review the experiences and clinical phenotypes of Early Onset Inflammatory Bowel 
Disease in two large IBD centers in Europe: one in the UK and the other in Italy. They have 
looked at the differences between two different age groups in an attempt to answer the question: 
"Is earlier onset Inflammatory Bowel Disease more severe than children presenting at an older 
age?". To do so, they have b roken up their cohort into two groups: those age 5 -10, and those 
aged 11 -16. They used various outcomes and phenotypes and compared the two groups to each 
other to attempt to answer the question.  
 
In general, the manuscript tackles an important question a nd attempts to gather mainly 
descriptive data with analysis between each about a rare phenotype by combining two cohorts. 
This introduces some differences which may represent differences in the medical health care 
systems and access to medications, or diff erences in medical practice. Regardless, the authors 
come to the conclusion that there is no measurable difference between the patients presenting 
with inflammatory bowel disease between the age of 5 -10 and the patients presenting between 11 
and 16.  
 
I had hoped to read about treatment outcomes, and this topic was not covered; though it appears 
the data may be available. It is unclear whether the ethnic breakdown of each of the two groups 
is comparable as well. The supplemental tables convey a great deal o f data and should be 
considered to be included in the main manuscript in a modified form.  
 
I congratulate the authors on describing this difficult to describe population.  
 
My comments are the following:  
 
- Page 5 line 27: I don't believe that the reference used here supports the statement in this 
sentence. The paper referenced is the paper by Glocker et al describing an IL10 
deficiency patient. The paper used the age cutoff of 12 months to select a compari son 
group when looking for IL10 and IL10R defects. A better reference might be the Paris 
modification of the Montreal classification by Levine et al, among others using an older 
age group for comparison. Furthermore, The Paris modification of the Montreal 
classification uses age 10 as the cutoff between early onset and pediatric onset IBD. This 
was selected based upon the available evidence and expert opinion. Commenting on this 
fact may further justify the selection of age=11 used in this cohort, as the cu toff used in 
this manuscript was selected mainly via age distribution of the cohort.  
- Page 5 Methods paragraph: From my read, I believe what was done was an age matched 
cohort in each location with cutoffs based upon the distribution of their cohorts wi th a 
focus on the lowest quartile. 80 were selected from each institution with 40 in each age 
category was used for analysis. It's a bit unclear how the selection from the 287 was 
performed. Was it random? Was the final selected 80 comparable to the 80 fro m the 
unselected population? This hasn't been clarified as the data available appears to describe 
the 160 patients finally selected.  
 
- Supplemental table 1: British group A has a range of 2.1 -10.6. In the methodology, it is 
stated that patients 5 -10 year s old were included in Group A. I'm a bit confused that the 
range goes down to 2.1? Is this from the unselected cohort? Shouldn't the "A" cohorts 
remain between 5 -10 years old at diagnosis?  
 
- -Supplemental table 1: I would highly suggest that patients be ph enotyped using the Paris 
classification. It clarifies disease location better. Plus, it is an internationally agreed upon 
classification scheme. It allows easy comparison of this data with other datasets. Also, the 
table may look a bit more organized.  
 
- Supplemental table 1: There is a discrepancy in gender break down that requires an 
explanation by the authors. There is a higher percentage of females in the Italian cohort 
than in the British cohort. This is different than most of the literature that state s that there 
is a higher percentage of males the younger the diagnosis age.  
 
- The definition for escalation of medical therapy is missing. Would introducing enteral 
nutrition be considered escalation? Would an increase in dose for weight gain be 
consider ed escalation? Would change in therapy for personal choices be considered 
escalation?  
 
- Page 10 line 34: I would remove the word tendency. There appears to be statistical 
significance, and a high one in some cases. I use the word tendency more for p valu es 
approaching significance.  
 
- Page 10, line 45: For EIMs, I applaud the attempt at looking at Extra intestinal 
manifestations (EIM). But, inter -observer reliability has been shown to be not very strong 
for EIMs. This was shown in Dassopoulos et al (IBD V ol 13 No 8, August 2007). The 
kappa for large joint arthritis is 0.25, while small joint arthritis is 0.13. The crude inter -
rater variability was 80.1% with a wide range from 46.7 to 100 % agreement for small 
joint arthritis, while large joint had 76.2% (5 3.3-96.7). Due to this, it is difficult to 
compare two different groups potentially phenotyped by two different reviewers and this 
should be at least mentioned in the discussion.  
 
- Page 11 Line 32 -48: This paragraph is a bit difficult to follow and it is unclear what 
specifically is the difference being highlighted in the analysis. It appears that more 
patients in Group A received thiopurines in the first three months compared to group B. 
I'm not sure why there is a further breakdown when the groups overal l are different. It 
may suffice to say that this trend was not driven by one site and was seen in both. It 
becomes difficult to follow and appears repetitive.  
 
- Page 12 Paragraph starting at line 6: The data for the second half of the statement is not 
available within the supplementary data (at least from what I could find). From what is 
available to me at this time, there is no data presented for IFX use at diagnosis.  
 
- Page 13 line 44: I agree with the comment here, but an analysis based upon those 
differences between the two countries may be highlighting the differences between the 
two with regards to treatment pathways used at the institution. To extend this conclusion 
to a difference between the age groups due to which country they come from is diff icult 
and possibly confounded.   
 
- Page 13, line 48 -57. It is stated that for the analysis, there was weighting of the analysis 
to take into account the effect of the country. I believe this is the first time that this is 
mentioned in the manuscript. It's  unclear how this was ascertained or performed and 
should be explained as the weighting changes the multivariate analysis greatly.  
 
- -Page 14, line 37: I found this quite interesting. If there was a difference between the two 
groups in top down vs bottom u p therapy, can the clinical outcomes be compared? I 
understand that this would be difficult to do, but this would be very interesting to see 
whether there is any difference in the method or approach to treatment when it comes to 
outcomes.  
 
- Page 14, line 39: Is the difference between the two units (UK and Italy) in the rates of 
Infliximab usage due to differences in access to biological therapy? This should be 
commented upon.  
 
- Page 15: line 21: I have to disagree with this comment, speci fically with the word 
"impossible". There are situations where a recognized phenotype presents with severe 
disease that predicts poor outcome. Acute severe UC with severe hypoalbuminemia and 
toxic megacolon and extensive Crohn's with perianal disease, EIMs , fever and low 
hemoglobin for example are cases where the disease course is considered to be more 
likely to be complicated and hence naturally leads to a push to use aggressive therapy 
earlier. I would suggest saying that it is difficult or that it isn't clear rather than using the 
word impossible.  
 
- Figure 1B: The analysis between Brit Group A and B is missing.  
 
- Figure 1: Would it be possible to include a figure for infliximab usage? The data should 
be available to do so.  
 
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 spe cify 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.  
 
No 
 
Are you able to assess any statistics in the manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
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, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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 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 inc luded 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: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Abdul Elkadri  
Reviewer’s report:  
The authors review the experiences and clinical phenotypes of Early Onset Inflammatory Bowel 
Disease in two large IBD centers in Europe: one in the UK and the other in Italy. They have 
looked at the differences between two different age groups in an attempt to answer the question: 
"Is earlier onset Inflammatory Bowel Disease more severe than children presenting at an older 
age?". To do so, they have b roken up their cohort into two groups: those age 5 -10, and those 
aged 11 -16. They used various outcomes and phenotypes and compared the two groups to each 
other to attempt to answer the question.  
 
In general, the manuscript tackles an important question a nd attempts to gather mainly 
descriptive data with analysis between each about a rare phenotype by combining two cohorts. 
This introduces some differences which may represent differences in the medical health care 
systems and access to medications, or diff erences in medical practice. Regardless, the authors 
come to the conclusion that there is no measurable difference between the patients presenting 
with inflammatory bowel disease between the age of 5 -10 and the patients presenting between 11 
and 16.  
 
I had hoped to read about treatment outcomes, and this topic was not covered; though it appears 
the data may be available. It is unclear whether the ethnic breakdown of each of the two groups 
is comparable as well. The supplemental tables convey a great deal o f data and should be 
considered to be included in the main manuscript in a modified form.  
 
I congratulate the authors on describing this difficult to describe population.  
 
My comments are the following:  
 
- Page 5 line 27: I don't believe that the reference used here supports the statement in this 
sentence. The paper referenced is the paper by Glocker et al describing an IL10 
deficiency patient. The paper used the age cutoff of 12 months to select a compari son 
group when looking for IL10 and IL10R defects. A better reference might be the Paris 
modification of the Montreal classification by Levine et al, among others using an older 
age group for comparison. Furthermore, The Paris modification of the Montreal 
classification uses age 10 as the cutoff between early onset and pediatric onset IBD. This 
was selected based upon the available evidence and expert opinion. Commenting on this 
fact may further justify the selection of age=11 used in this cohort, as the cu toff used in 
this manuscript was selected mainly via age distribution of the cohort.  
- Page 5 Methods paragraph: From my read, I believe what was done was an age matched 
cohort in each location with cutoffs based upon the distribution of their cohorts wi th a 
focus on the lowest quartile. 80 were selected from each institution with 40 in each age 
category was used for analysis. It's a bit unclear how the selection from the 287 was 
performed. Was it random? Was the final selected 80 comparable to the 80 fro m the 
unselected population? This hasn't been clarified as the data available appears to describe 
the 160 patients finally selected.  
 
- Supplemental table 1: British group A has a range of 2.1 -10.6. In the methodology, it is 
stated that patients 5 -10 year s old were included in Group A. I'm a bit confused that the 
range goes down to 2.1? Is this from the unselected cohort? Shouldn't the "A" cohorts 
remain between 5 -10 years old at diagnosis?  
 
- -Supplemental table 1: I would highly suggest that patients be ph enotyped using the Paris 
classification. It clarifies disease location better. Plus, it is an internationally agreed upon 
classification scheme. It allows easy comparison of this data with other datasets. Also, the 
table may look a bit more organized.  
 
- Supplemental table 1: There is a discrepancy in gender break down that requires an 
explanation by the authors. There is a higher percentage of females in the Italian cohort 
than in the British cohort. This is different than most of the literature that state s that there 
is a higher percentage of males the younger the diagnosis age.  
 
- The definition for escalation of medical therapy is missing. Would introducing enteral 
nutrition be considered escalation? Would an increase in dose for weight gain be 
consider ed escalation? Would change in therapy for personal choices be considered 
escalation?  
 
- Page 10 line 34: I would remove the word tendency. There appears to be statistical 
significance, and a high one in some cases. I use the word tendency more for p valu es 
approaching significance.  
 
- Page 10, line 45: For EIMs, I applaud the attempt at looking at Extra intestinal 
manifestations (EIM). But, inter -observer reliability has been shown to be not very strong 
for EIMs. This was shown in Dassopoulos et al (IBD V ol 13 No 8, August 2007). The 
kappa for large joint arthritis is 0.25, while small joint arthritis is 0.13. The crude inter -
rater variability was 80.1% with a wide range from 46.7 to 100 % agreement for small 
joint arthritis, while large joint had 76.2% (5 3.3-96.7). Due to this, it is difficult to 
compare two different groups potentially phenotyped by two different reviewers and this 
should be at least mentioned in the discussion.  
 
- Page 11 Line 32 -48: This paragraph is a bit difficult to follow and it is unclear what 
specifically is the difference being highlighted in the analysis. It appears that more 
patients in Group A received thiopurines in the first three months compared to group B. 
I'm not sure why there is a further breakdown when the groups overal l are different. It 
may suffice to say that this trend was not driven by one site and was seen in both. It 
becomes difficult to follow and appears repetitive.  
 
- Page 12 Paragraph starting at line 6: The data for the second half of the statement is not 
available within the supplementary data (at least from what I could find). From what is 
available to me at this time, there is no data presented for IFX use at diagnosis.  
 
- Page 13 line 44: I agree with the comment here, but an analysis based upon those 
differences between the two countries may be highlighting the differences between the 
two with regards to treatment pathways used at the institution. To extend this conclusion 
to a difference between the age groups due to which country they come from is diff icult 
and possibly confounded.   
 
- Page 13, line 48 -57. It is stated that for the analysis, there was weighting of the analysis 
to take into account the effect of the country. I believe this is the first time that this is 
mentioned in the manuscript. It's  unclear how this was ascertained or performed and 
should be explained as the weighting changes the multivariate analysis greatly.  
 
- -Page 14, line 37: I found this quite interesting. If there was a difference between the two 
groups in top down vs bottom u p therapy, can the clinical outcomes be compared? I 
understand that this would be difficult to do, but this would be very interesting to see 
whether there is any difference in the method or approach to treatment when it comes to 
outcomes.  
 
- Page 14, line 39: Is the difference between the two units (UK and Italy) in the rates of 
Infliximab usage due to differences in access to biological therapy? This should be 
commented upon.  
 
- Page 15: line 21: I have to disagree with this comment, speci fically with the word 
"impossible". There are situations where a recognized phenotype presents with severe 
disease that predicts poor outcome. Acute severe UC with severe hypoalbuminemia and 
toxic megacolon and extensive Crohn's with perianal disease, EIMs , fever and low 
hemoglobin for example are cases where the disease course is considered to be more 
likely to be complicated and hence naturally leads to a push to use aggressive therapy 
earlier. I would suggest saying that it is difficult or that it isn't clear rather than using the 
word impossible.  
 
- Figure 1B: The analysis between Brit Group A and B is missing.  
 
- Figure 1: Would it be possible to include a figure for infliximab usage? The data should 
be available to do so.  
 
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 spe cify 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.  
 
No 
 
Are you able to assess any statistics in the manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
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, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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 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 inc luded 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: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Abdul Elkadri  
Reviewer’s report:  
The authors review the experiences and clinical phenotypes of Early Onset Inflammatory Bowel 
Disease in two large IBD centers in Europe: one in the UK and the other in Italy. They have 
looked at the differences between two different age groups in an attempt to answer the question: 
"Is earlier onset Inflammatory Bowel Disease more severe than children presenting at an older 
age?". To do so, they have b roken up their cohort into two groups: those age 5 -10, and those 
aged 11 -16. They used various outcomes and phenotypes and compared the two groups to each 
other to attempt to answer the question.  
 
In general, the manuscript tackles an important question a nd attempts to gather mainly 
descriptive data with analysis between each about a rare phenotype by combining two cohorts. 
This introduces some differences which may represent differences in the medical health care 
systems and access to medications, or diff erences in medical practice. Regardless, the authors 
come to the conclusion that there is no measurable difference between the patients presenting 
with inflammatory bowel disease between the age of 5 -10 and the patients presenting between 11 
and 16.  
 
I had hoped to read about treatment outcomes, and this topic was not covered; though it appears 
the data may be available. It is unclear whether the ethnic breakdown of each of the two groups 
is comparable as well. The supplemental tables convey a great deal o f data and should be 
considered to be included in the main manuscript in a modified form.  
 
I congratulate the authors on describing this difficult to describe population.  
 
My comments are the following:  
 
- Page 5 line 27: I don't believe that the reference used here supports the statement in this 
sentence. The paper referenced is the paper by Glocker et al describing an IL10 
deficiency patient. The paper used the age cutoff of 12 months to select a compari son 
group when looking for IL10 and IL10R defects. A better reference might be the Paris 
modification of the Montreal classification by Levine et al, among others using an older 
age group for comparison. Furthermore, The Paris modification of the Montreal 
classification uses age 10 as the cutoff between early onset and pediatric onset IBD. This 
was selected based upon the available evidence and expert opinion. Commenting on this 
fact may further justify the selection of age=11 used in this cohort, as the cu toff used in 
this manuscript was selected mainly via age distribution of the cohort.  
- Page 5 Methods paragraph: From my read, I believe what was done was an age matched 
cohort in each location with cutoffs based upon the distribution of their cohorts wi th a 
focus on the lowest quartile. 80 were selected from each institution with 40 in each age 
category was used for analysis. It's a bit unclear how the selection from the 287 was 
performed. Was it random? Was the final selected 80 comparable to the 80 fro m the 
unselected population? This hasn't been clarified as the data available appears to describe 
the 160 patients finally selected.  
 
- Supplemental table 1: British group A has a range of 2.1 -10.6. In the methodology, it is 
stated that patients 5 -10 year s old were included in Group A. I'm a bit confused that the 
range goes down to 2.1? Is this from the unselected cohort? Shouldn't the "A" cohorts 
remain between 5 -10 years old at diagnosis?  
 
- -Supplemental table 1: I would highly suggest that patients be ph enotyped using the Paris 
classification. It clarifies disease location better. Plus, it is an internationally agreed upon 
classification scheme. It allows easy comparison of this data with other datasets. Also, the 
table may look a bit more organized.  
 
- Supplemental table 1: There is a discrepancy in gender break down that requires an 
explanation by the authors. There is a higher percentage of females in the Italian cohort 
than in the British cohort. This is different than most of the literature that state s that there 
is a higher percentage of males the younger the diagnosis age.  
 
- The definition for escalation of medical therapy is missing. Would introducing enteral 
nutrition be considered escalation? Would an increase in dose for weight gain be 
consider ed escalation? Would change in therapy for personal choices be considered 
escalation?  
 
- Page 10 line 34: I would remove the word tendency. There appears to be statistical 
significance, and a high one in some cases. I use the word tendency more for p valu es 
approaching significance.  
 
- Page 10, line 45: For EIMs, I applaud the attempt at looking at Extra intestinal 
manifestations (EIM). But, inter -observer reliability has been shown to be not very strong 
for EIMs. This was shown in Dassopoulos et al (IBD V ol 13 No 8, August 2007). The 
kappa for large joint arthritis is 0.25, while small joint arthritis is 0.13. The crude inter -
rater variability was 80.1% with a wide range from 46.7 to 100 % agreement for small 
joint arthritis, while large joint had 76.2% (5 3.3-96.7). Due to this, it is difficult to 
compare two different groups potentially phenotyped by two different reviewers and this 
should be at least mentioned in the discussion.  
 
- Page 11 Line 32 -48: This paragraph is a bit difficult to follow and it is unclear what 
specifically is the difference being highlighted in the analysis. It appears that more 
patients in Group A received thiopurines in the first three months compared to group B. 
I'm not sure why there is a further breakdown when the groups overal l are different. It 
may suffice to say that this trend was not driven by one site and was seen in both. It 
becomes difficult to follow and appears repetitive.  
 
- Page 12 Paragraph starting at line 6: The data for the second half of the statement is not 
available within the supplementary data (at least from what I could find). From what is 
available to me at this time, there is no data presented for IFX use at diagnosis.  
 
- Page 13 line 44: I agree with the comment here, but an analysis based upon those 
differences between the two countries may be highlighting the differences between the 
two with regards to treatment pathways used at the institution. To extend this conclusion 
to a difference between the age groups due to which country they come from is diff icult 
and possibly confounded.   
 
- Page 13, line 48 -57. It is stated that for the analysis, there was weighting of the analysis 
to take into account the effect of the country. I believe this is the first time that this is 
mentioned in the manuscript. It's  unclear how this was ascertained or performed and 
should be explained as the weighting changes the multivariate analysis greatly.  
 
- -Page 14, line 37: I found this quite interesting. If there was a difference between the two 
groups in top down vs bottom u p therapy, can the clinical outcomes be compared? I 
understand that this would be difficult to do, but this would be very interesting to see 
whether there is any difference in the method or approach to treatment when it comes to 
outcomes.  
 
- Page 14, line 39: Is the difference between the two units (UK and Italy) in the rates of 
Infliximab usage due to differences in access to biological therapy? This should be 
commented upon.  
 
- Page 15: line 21: I have to disagree with this comment, speci fically with the word 
"impossible". There are situations where a recognized phenotype presents with severe 
disease that predicts poor outcome. Acute severe UC with severe hypoalbuminemia and 
toxic megacolon and extensive Crohn's with perianal disease, EIMs , fever and low 
hemoglobin for example are cases where the disease course is considered to be more 
likely to be complicated and hence naturally leads to a push to use aggressive therapy 
earlier. I would suggest saying that it is difficult or that it isn't clear rather than using the 
word impossible.  
 
- Figure 1B: The analysis between Brit Group A and B is missing.  
 
- Figure 1: Would it be possible to include a figure for infliximab usage? The data should 
be available to do so.  
 
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 spe cify 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.  
 
No 
 
Are you able to assess any statistics in the manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
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, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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 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 inc luded 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