Reviewer's report
Title:Abdominal Attacks and Treatment in Hereditary Angioedema with
C1-Inhibitor Deficiency
Version:2Date:5 March 2014
Reviewer: Marco Cicardi
Reviewer's report:
The manuscript provides a large amount of detailed data on abdominal attacks in
patients with HAE. There is a huge literature on HAE symptoms, but exclusively
or mostly based on retrospective analysis of data going back several years. The
data of this manuscript were collected within the clinical studies performed for the
development of kalbitor and despite some differences in the study designs; the
information is of high quality and based on objective measurements. Reports
based on specific analysis of subgroups of data derived from the clinical trials
provide new important knowledge. Abdominal attacks have many specific
problems, which are of particular interest for gastroenterologists frequently not
aware of the existence of this condition. Drive attention to these unusual
situations could improve clinical practice. The data in the manuscript are well
organized and described. Shortening the results section leaving part of the data
in tables and figures could improve readability. The part of the discussion that
deals with the diagnosis could be improved as detailed in the specific remarks.
Specific remarks
Discussing the diagnosis the authors state, “once it is suspected it can be
confirmed by laboratory tests” and then they discuss C4. It is not clear to me if
they refer to diagnosis of HAE in a previously not diagnosed patient arriving with
abdominal pain, or if they refer to the reduction of C4 as sign of an ongoing
attack for a patient who already has the diagnosis. Both problems are difficult to
deal for physicians. It is true that C4 identifies HAE, but it is not a test performed
in emergency. On the other hand, C4 reduces during attacks, but its level does
not identify presence or absence of the angioedema. The LevPharma trial tried to
use this parameter to mark the presence of an angioedema attack, but then they
were not able to use it and eventually had to have an external expert judging on
the presence of the symptoms. So far, no reliable marker can define abdominal
angioedema and criteria remain on clinical judgment and efficacy of specific
treatments. I suggest reviewing the paragraph and highlighting these points
The authors properly refer to side effects of long-term prophylaxis with
androgens. To be correct they should also report the paper from Gandhi, which is
based on data from an FDA register of reported side effect. This register listed 10
severe cases of thrombosis related to Cinryze over a period of 3 years of use of
this drug. These drawbacks of Cinryze need to be reported when dealing with its
use in HAE.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
no competing interest
Reviewer's report
Title:Abdominal Attacks and Treatment in Hereditary Angioedema with
C1-Inhibitor Deficiency
Version:2Date:5 March 2014
Reviewer: Marco Cicardi
Reviewer's report:
The manuscript provides a large amount of detailed data on abdominal attacks in
patients with HAE. There is a huge literature on HAE symptoms, but exclusively
or mostly based on retrospective analysis of data going back several years. The
data of this manuscript were collected within the clinical studies performed for the
development of kalbitor and despite some differences in the study designs; the
information is of high quality and based on objective measurements. Reports
based on specific analysis of subgroups of data derived from the clinical trials
provide new important knowledge. Abdominal attacks have many specific
problems, which are of particular interest for gastroenterologists frequently not
aware of the existence of this condition. Drive attention to these unusual
situations could improve clinical practice. The data in the manuscript are well
organized and described. Shortening the results section leaving part of the data
in tables and figures could improve readability. The part of the discussion that
deals with the diagnosis could be improved as detailed in the specific remarks.
Specific remarks
Discussing the diagnosis the authors state, “once it is suspected it can be
confirmed by laboratory tests” and then they discuss C4. It is not clear to me if
they refer to diagnosis of HAE in a previously not diagnosed patient arriving with
abdominal pain, or if they refer to the reduction of C4 as sign of an ongoing
attack for a patient who already has the diagnosis. Both problems are difficult to
deal for physicians. It is true that C4 identifies HAE, but it is not a test performed
in emergency. On the other hand, C4 reduces during attacks, but its level does
not identify presence or absence of the angioedema. The LevPharma trial tried to
use this parameter to mark the presence of an angioedema attack, but then they
were not able to use it and eventually had to have an external expert judging on
the presence of the symptoms. So far, no reliable marker can define abdominal
angioedema and criteria remain on clinical judgment and efficacy of specific
treatments. I suggest reviewing the paragraph and highlighting these points
The authors properly refer to side effects of long-term prophylaxis with
androgens. To be correct they should also report the paper from Gandhi, which is
based on data from an FDA register of reported side effect. This register listed 10
severe cases of thrombosis related to Cinryze over a period of 3 years of use of
this drug. These drawbacks of Cinryze need to be reported when dealing with its
use in HAE.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
no competing interest
Please review this paper.
user
Reviewer's report
Title:Abdominal Attacks and Treatment in Hereditary Angioedema with
C1-Inhibitor Deficiency
Version:2Date:5 March 2014
Reviewer: Marco Cicardi
Reviewer's report:
The manuscript provides a large amount of detailed data on abdominal attacks in
patients with HAE. There is a huge literature on HAE symptoms, but exclusively
or mostly based on retrospective analysis of data going back several years. The
data of this manuscript were collected within the clinical studies performed for the
development of kalbitor and despite some differences in the study designs; the
information is of high quality and based on objective measurements. Reports
based on specific analysis of subgroups of data derived from the clinical trials
provide new important knowledge. Abdominal attacks have many specific
problems, which are of particular interest for gastroenterologists frequently not
aware of the existence of this condition. Drive attention to these unusual
situations could improve clinical practice. The data in the manuscript are well
organized and described. Shortening the results section leaving part of the data
in tables and figures could improve readability. The part of the discussion that
deals with the diagnosis could be improved as detailed in the specific remarks.
Specific remarks
Discussing the diagnosis the authors state, “once it is suspected it can be
confirmed by laboratory tests” and then they discuss C4. It is not clear to me if
they refer to diagnosis of HAE in a previously not diagnosed patient arriving with
abdominal pain, or if they refer to the reduction of C4 as sign of an ongoing
attack for a patient who already has the diagnosis. Both problems are difficult to
deal for physicians. It is true that C4 identifies HAE, but it is not a test performed
in emergency. On the other hand, C4 reduces during attacks, but its level does
not identify presence or absence of the angioedema. The LevPharma trial tried to
use this parameter to mark the presence of an angioedema attack, but then they
were not able to use it and eventually had to have an external expert judging on
the presence of the symptoms. So far, no reliable marker can define abdominal
angioedema and criteria remain on clinical judgment and efficacy of specific
treatments. I suggest reviewing the paragraph and highlighting these points
The authors properly refer to side effects of long-term prophylaxis with
androgens. To be correct they should also report the paper from Gandhi, which is
based on data from an FDA register of reported side effect. This register listed 10
severe cases of thrombosis related to Cinryze over a period of 3 years of use of
this drug. These drawbacks of Cinryze need to be reported when dealing with its
use in HAE.
Level of interest: An article of importance in its field
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
no competing interest
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