Example of Letter to Editor to Epilepsia

7/28/2019 Example of Letter to Editor to Epilepsia

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Example of letter to editor

.

Faculty of Medicine, Khon Kaen University

Khon Kaen 40002, Thailand

Tel / Fax 66-43-.

Email: ..

25 July 2009

Simon D. Shorvon,

Institute of Neurology, University College LondonLondon, WC1N 3BG, United Kingdom

Subject : Manuscript submission

Dear Prof. Shorvon,

I would like to submit the manuscript entitled " Relationship between HLA-

B*1502 and carbamazepineinduced severe cutaneous adverse reactions in a Thai

population". The issue of ethnicity has recently been raised for the association between

CBZ-induced SJS/TEN and HLA-B*1502 in which the strong association was found

only in Han Chinese but not in Japanese and Caucasian populations. To our knowledge,

our data reported herein is the first large cohort study in other Asian ethnic that

demonstrated the strong association between CBZ-induced SJS/TEN and HLA-B*1502.The sensitivity and specificity ofHLA-B*1502 for predicting SJS/TEN caused by CBZ

found in the preset study was very high which suggests that theHLA-B*1502 is a useful

pharmacogenetic marker to identify Thai individuals who may at risk for these

potentially life-threatening cutaneous reactions.

I warrant that this manuscript has been read by all co-authors and I have

submitted this manuscript on behalf of all the authors with their full consent. The

authors declare no conflicts of interest. I would be very appreciated if you could

consider our manuscript for publication in your journal.

Sincerely Yours,

(Dr.)


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Letter from the Editor after submission

From: [email protected] PASS WORD wichittra123

To:

CC:

Subject: Epilepsia - Manuscript EPI-00539-2009.R1

Body: Dear Dr. :

This is a computer generated message.

Thank you very much for submitting your revised manuscript to Epilepsia.

Your manuscript entitled, Association between HLA-B*1502 and

carbamazepineinduced severe cutaneous adverse drug reactions in a Thai

population has been successfully uploaded to Manuscript Central.

Please make note of your manuscript number: EPI-00539-2009.R1. We

will direct all future communications to you, the corresponding author, via

e-mail.

We attempt to complete the review process as fast as possible, andEpilepsia is making strenuous efforts to ensure as short a turn-around time

as is compatible with a high quality peer review process. Manuscript

processing is entirely dependent on the timeliness of our reviewer

feedback. It typically takes one week to assign reviewers and another 2-3

weeks to obtain reviews. If a reviewer does not return his/her comments

within four weeks, another reviewer may be invited. Reminders are sent to

tardy reviewers, but Im sure you can understand that the requested

deadline cannot be enforced.

Revised manuscripts are sent to the original reviewers unless the revisions

are minor, in which case the Editor will usually make a final decision on

the manuscript him/herself.

Date Sent: 16-Sep-2009
mailto:[email protected]:[email protected]:[email protected]


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Example of comment from Editor

06-Sep-2009

EPI-00539-2009Association between HLA-B*1502 and carbamazepineinduced severe cutaneous

adverse reactions in a Thai population

Dear Dr. .:

Your manuscript has been reviewed, and our reviewers have indicated that the paper

should be considered for publication only with significant revisions. The reviewers

found merit in your paper but also expressed significant concerns (see comments

below). In particular, one reviewer suggested that the manuscript be shortened to the

Brief Communication format and we agree with this suggestion. If you can

satisfactorily address these concerns, we will again consider the manuscript. Please

understand that publication after revision is not guaranteed. A decision on acceptance

will be made only after your revised manuscript has been re-reviewed.

Thank you for your interest in publishing your work in Epilepsia, and for submitting

your manuscript to this journal. We look forward to receiving your revised paper.

Sincerely,

Renzo Guerrini, Editor

________________________________________

Reviewers' Comments to Author (if applicable):

Reviewer: 1

Comments to the authors

This article shows that HLA-B*1502 is as strongly associated with CBZ-induced

SJS/TEN in Thai population as in Han Chinese population. Since relationships between

idiosyncratic adverse reaction and HLA-type are dependent on ethnicity, the result of

this large scale case-control study on SJS/TEN in Thai population is worth publishing

with minor revision.

Minor comments

1. Table 2

The SBT of No.2 patient may be read 1502/3909 instead of 502/3909.

2. The authors performed not a cohort study but a case-control study.

3. Grammatical errors in Discussion part

Line 15, p13: Who did not carried HLA-B*1502

Line 30, p14: who may at risk for these


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Reviewer: 2


Comments:

1.This study is primarily verifying the genetic association information in a differentpopulation, and lacks of novelty/investigation. As the absence of impact to this field,

revision to Brief Communication is suggested.

2.The title needs revision.

3.The authors described two methods for determining HLA-B genotype, i.e., sequence-

specific primers for real-time PCR (a commercial kit) and sequence-based typing

(SBT). The information for the commercial kit was not clear in the manuscript, and the

authors should provide more detailed information regarding the kit, such as reference

paper, oligonucleotide sequence, discrimination of the ~1000 known HLA-B alleles,

false positive rate, false negative rate, sensitivity/specificity of the kit. By comparison,SBT is a well established method, and it could offer clear and accurate HLA genotype

data. These two methods are redundant, in which the commercial kit could not provide

genotype data, thus it is not so relevant in this study.

4.The authors did not clearly describe the ethnic genetic background of their study

subjects. In the method, the patients were described to be native Thais or Thai-Chinese,

however, the results part reported the patients were native Thai. A clear assessment of

the genetic background is very important for a genetic association study. It is important

to see whether the association is only replicated in Chinese, or in both the Thais, and

Chinese.

5.The genetic background of enrolled study subjects will influence how to choose a

suitable reference population for studying the allele frequency association. The ethnic

genetic background of the enrolled subjects should be further stratified.

6.The HLA-B*1502 allele/phenotype frequency data of different populations provided

in the manuscript is inconsistent, incorrect and confusing.

7.The authors enrolled a large cohort of carbamazepine-SJS patients. It is a pity they

did not provide the incidence data of this disease.

8.The authors mentioned 27 patients received concomitant drugs in addition to

carbamazepine. They did not provide supportive, assessable method for determining

carbamazepine being the most likely culprit drug.

9.The table 2 is out of order.


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10.The table 3 provides association information between HLA-B alleles and CBZ-SJS.

It is incomplete.

11.There were many typos and the manuscript needs English editing. For example, the

method section of SBT is sequence-based, not sequence base.


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Example of response to editor after received the comment from reviwers

..Faculty of Medicine, Khon Kaen University

Khon Kaen 40002, Thailand

Tel / Fax.

Email: .

16 September 2009

The Editor,

Epilepsia,

Subject : Manuscript resubmission

Dear The Editor,

Thank you very much for accepting our manuscript (EPI-00539-2009) to be

published in your journal. We have revised our manuscript according to the

reviewerscomments. We have also shorten our manuscript to the Brief Communication

format as you suggestion. One of the reviewer suggested us to change the title of our

manuscript so we decide to change from Relationship between HLA-B*1502 and

carbamazepineinduced severe cutaneous adverse reactions in a Thai population to

Association between HLA-B*1502 and carbamazepineinduced severe cutaneous

adverse drug reactions in a Thai population. We also response to all comments from

reviewers point by point.

We would be very appreciated if you could consider our manuscript to be

published in your journal.

Sincerely Yours,

(Dr..)


7/13

Response to Reviewerscomments

Reviewer: 1


This article shows that HLA-B*1502 is as strongly associated with CBZ-induced

SJS/TEN in Thai population as in Han Chinese population. Since relationships between

idiosyncratic adverse reaction and HLA-type are dependent on ethnicity, the result of

this large scale case-control study on SJS/TEN in Thai population is worth publishing

with minor revision.

Minor comments

1. Table 2

The SBT of No.2 patient may be read 1502/3909 instead of 502/3909.

2. The authors performed not a cohort study but a case-control study.

3. Grammatical errors in Discussion part

Line 15, p13: Who did not carried HLA-B*1502

Line 30, p14: who may at risk for these

Response: Thank you very much for suggestions and point out some typing errors in

the manuscript. We have corrected those typing errors already.

Reviewer: 2


Comments:

1. This study is primarily verifying the genetic association information in a different

population, and lacks of novelty/investigation. As the absence of impact to this field,

revision to Brief Communication is suggested.

Response: The issue of ethnicity has been raised for the association between CBZ-

induced SJS/TEN andHLA-B*1502 since the strong association was found only in Han

Chinese but not in Japanese and Caucasian populations. The US-FDA has recently

released a warning to health professionals and patients that these severe cutaneous

adverse drug reactions (SCADR) may occur in patients withHLA-B*1502 and has also


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recommended genetic screening for patients of Asian ancestry prior to initiation of

CBZ therapy. WhetherHLA-B*1502 is a valid pharmacogenetic test for CBZ-induced

SJS/TEN in all Asian populations need to be further investigated.

The present study is the first large scale case-control study in Asian ethnic that

has high frequency of HLA-B*1502 other than Han Chinese. The strong association

between this HLA-B allele and CBZ-induced SJS/TEN suggests that an application of

HLA-B*1502 genotyping as a screening tool before prescribing CBZ will help to

prevent CBZ-induced SJS/TEN in Thailand as well as other Southeast Asian countries

which have high prevalence of these SCADR.

As the reviewer and the Editor suggest that our manuscript should be revised to

Brief Communication, we t have to rewrote several parts in the manuscript to suit to the

format of Brief Communication.

2. The title needs revision.

Response: We revised the title from Relationship betweenHLA-B*1502 and

carbamazepineinduced severe cutaneous adverse reactions in a Thai population to

Association betweenHLA-B*1502 and carbamazepineinduced severe cutaneous

adverse drug reactions in a Thai population

3. The authors described two methods for determining HLA-B genotype, i.e., sequence-

specific primers for real-time PCR (a commercial kit) and sequence-based typing

(SBT). The information for the commercial kit was not clear in the manuscript, and the

authors should provide more detailed information regarding the kit, such as reference

paper, oligonucleotide sequence, discrimination of the ~1000 known HLA-B alleles,

false positive rate, false negative rate, sensitivity/specificity of the kit. By comparison,

SBT is a well established method, and it could offer clear and accurate HLA genotype

data. These two methods are redundant, in which the commercial kit could not provide

genotype data, thus it is not so relevant in this study.

Response: The standard method for determination of HLA-B genotypes is

sequence-based typing (SBT). However, this method is impractical in the clinical

setting because the excess cost of the system, reagents and software analysis as well as


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long term turn around time. The simple HLA-B*1502 test may open the door for

clinical applications ofHLA-B*1502 to prevent CBZ-induced SJS/TEN. In the present

study, we determined the presence ofHLA-B*1502 in subjects by using PG1502 DNA

detection kit because we want to evaluate the clinical utility of this test kit compared to

the SBT method. This test kit was approved by Taiwans Department of Health as an

in vitro diagnostic (IVD).

Because this kit is a commercial kit and the manufacturer could not share the

detail of the oligonucleotide sequences that used in their kit with us. However, we add

some detail of this kit such as sensitivity and specificity in the method part (page 6) as :

HLA-B*1502 genotyping

Analysis for the presence of the HLA-B*1502 allele was performed using a

PG1502 DNA detection kit (PharmiGene, Inc., Taipei, Taiwan) that was approved by

Taiwans Department of Health as an in vitro diagnostic (IVD). The kits are real-time

PCR-based with sequencing specific primers directed toward HLA-B*1502 and the

internal control gene. The sensitivity and specificity of this kit for detection of the

HLA-B*1502 allele claimed by the manufacture are ~99% and >95% , respectively.

As the Editor suggested that our manuscript should be revised to Brief

Communication, we therefore have to shorten the material part in the manuscript.

The false positive and false negative of the test also mentioned in the

Discussion part (page 10, 1st paragraph) as

According to manufacturers experience, however, this test may give false

positive results for individuals who carryHLA-B*1513. Although theHLA-B*1513 was

not detected in our patients, its allelic frequency in a general Thai population is about


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1.5% (dbMHC database; http://www. ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi).

Therefore, using this kit in a population with a high frequency ofHLA-B*1513 may

exclude some patients who may not be at risk of CBZ-induced SJS/TEN.

4. The authors did not clearly describe the ethnic genetic background of their study

subjects. In the method, the patients were described to be native Thais or Thai-

Chinese, however, the results part reported the patients were native Thai. A clear

assessment of the genetic background is very important for a genetic association study.

It is important to see whether the association is only replicated in Chinese, or in both

the Thais, and Chinese.

Response: Thank you very much for valuable suggestions. All of our patients in cases

and controls were native Thais. We interviewed all subjects about their ancestry to

make sure whether they are native Thais or not. We agree with the reviewers opinion

that a clear assessment of the genetic background is very important for a genetic

association study and it is important to see whether the association is in our native

Thais or not.

We therefore revise the last paragraph in the Study population section (page 6) to

All case and control patients were interviewed by investigators about the

history of their biological parents and grandparents and they were classified as native

Thai because both of their biological parents and grandparents were born in Thailand.

Subjects were informed both verbally and in writing about the experimental procedures

and the purpose of the study. The study protocol was approved by the institutional

review boards.


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5. The genetic background of enrolled study subjects will influence how to choose a

suitable reference population for studying the allele frequency association. The ethnic

genetic background of the enrolled subjects should be further stratified.

Response: All of our cases and controls were native Thais and recruited from

the same hospitals. In our opinion, we think it is not necessary to further stratified

tthem.

6. The HLA-B*1502 allele/phenotype frequency data of different populations provided

in the manuscript is inconsistent, incorrect and confusing.

Response: Thank you so your comments. We did correct for the confusing data

already. Since there are two different types of frequency, allelic frequency and

phenotype frequency that we used in our previous version, we decided to mention only

the allelic frequency of HLA-B*1502 in this revised version.

We change from The frequency subjects who carriedHLA-B*1502 (phenotype

frequency) observed in the CBZ-tolerant controls (11.90%) was quite similar to that

reported in the general Thai population (12.12%) (data from dbMHC data base;

http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg. cgi). The 3rd paragraph, page 12

of the original version

To In the present study, the HLA-B*1502 allele was found in 37 out of 42 CBZ-

induced SJS/TEN patients (88.10%) as compared to 5 out of 42 (11.90%) CBZ-tolerant

controls. The 6.0% allelic frequency of HLA-B*1502 observed in the CBZ-tolerant

control group was quite similar to the 6.1% that was reported in the general Thai

population (dbMHC database; http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi).

(2nd paragraph, page 9 of this revised manuscript )

7. The authors enrolled a large cohort of carbamazepine-SJS patients. It is a pity they

did not provide the incidence data of this disease.

Response: Most of our SJS/TEN cases were the patients who admitted in our

hospital (Srinagarind Hospital) which is the tertiary care hospital and almost all of the


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cases were referred from other city hospitals nearby. So we could not estimate the

incidence of CBZ-induced SJS because we did not have the actual number of patients

who have been prescribed CBZ in those hospitals. However, the incidence of CBZ-

induced SJS/TEN has been previously reported by Locharernkul et al., 2008 in

Epilepsia and we did mention this incidence in our e result part (page 8) as Thus, by

assuming the prevalence of CBZ-induced SJS/TEN in a Thai population as 0.27% as

previously reported (Locharernkul et al., 2008), the PPV and NPV of the HLA-B*1502

were 1.92% and 99.96%.

8. The authors mentioned 27 patients received concomitant drugs in addition to

carbamazepine. They did not provide supportive, assessable method for determining

carbamazepine being the most likely culprit drug.

Response: We mentioned in the first paragraph of the methods and material

section that In all enrolled cases, CBZ would be identified as the culprit drug for SJS

or TEN if the symptoms occurred within the first 3 months of CBZ exposure and the

symptoms resolved upon withdrawal of this drug and also mentioned in the 2nd

paragraph of the result part that Thirteen patients received only CBZ while 27 patients

received concomitant drugs. However, there were no apparent cutaneous adverse

reactions when these medications were not concomitantly taken with CBZ.

9. The table 2 is out of order.

Response: We have corrected it already.

10.The table 3 provides association information between HLA-B alleles and CBZ-SJS.

It is incomplete.

Response: We have revised Table 3 according to the reviewers comment by selecting

some alleles that presented in > 2 patients either in case or control group. We think it is

not necessary to show all alleles in this table. The title of the Table also changed from

Frequencies of individualHLA-B allele in patients with CBZ-induced SJS/TEN and


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CBZ-tolerant patients to Frequencies of certainHLA-B allele in patients with CBZ-

induced SJS/TEN and CBZ-tolerant patients.

11. There were many typos and the manuscript needs English editing. For example, the

method section of SBT is sequence-based, not sequence base.

Response: We have revised carefully checked for typos and also ask Prof. James Wills

who is an Emeritus Professor at University of Wisconsin-Madison , USA for English

editing of the manuscript for us.

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