PONE-D-20-30296

Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: A nationwide longitudinal cohort study

PLOS ONE

Dear Dr. Sohn,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The topic is very interesting, and the manuscript is well written, but several major factors should be acknowledged before considering this article to be published:

- METHODS:

a) Clear inclusion and exclusion criteria should be written to understand both populations.

b) In terms of specific stroke risk, basic data from this condition should be provided, to understand if certain covariates could affect mortality and functional outcomes: severity of stroke cases (according to NIHSS), etiology of ischemic stroke (according to ASCOD, TOAST or any other classification criteria), type of acute therapy (IV thrombolysis, thrombectomy, both, or usual medical care), admission to stroke unit, general or rheumatology ward. Please clarifiy if this data is available, as I understand you adquire data from the NHID.

c) Clear definition on each risk factor should be added (i.e. hypertension)

RESULTS

a) P values are missing, on each one of the tables (HR). When adding statistical analysis for association, you should provide this values. 

b) Kaplan Meier Curve should be corrected: Log-rank p value should be included, On the X axis, the authors should clarify if they are using person-year or years. Number at risk table should be included for each group, below X axis on each point of the analysis.

c) When including data from severity, type of stroke, and acute therapy I suggest to run again your analysis, to evaluate if the previous findings still remain in terms of covariates.

Please submit your revised manuscript by Jan 15 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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2. Please include the date(s) on which you accessed the databases or records to obtain the data used in your study.

3. Thank you for submitting your revised manuscript and for improving the text overlap instances. There are still a few instances of text overlap with the following publications that need to be addressed:

https://www.jocn-journal.com/article/S0967-5868(20)31310-2/fulltext

https://ard.bmj.com/content/72/4/541

Please revise the manuscript to rephrase the duplicated text, cite your sources, and provide details as to how the current manuscript advances on previous work. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

We will carefully review your manuscript upon resubmission, so please ensure that your revision is thorough

4. We noticed you have some minor occurrence of overlapping text with the following previous publications, which needs to be addressed:

https://www.jocn-journal.com/article/S0967-5868(20)31310-2/fulltext

https://link.springer.com/article/10.1007/s00701-018-3499-7

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Editor:

- METHODS:

a) Clear inclusion and exclusion criteria should be written to understand both populations.

b) In terms of specific stroke risk, basic data from this condition should be provided, to understand if certain covariates could affect mortality and functional outcomes: severity of stroke cases (according to NIHSS), etiology of ischemic stroke (according to ASCOD, TOAST or any other classification criteria), type of acute therapy (IV thrombolysis, thrombectomy, both, or usual medical care), admission to stroke unit, general or rheumatology ward. Please clarifiy if this data is available, as I understand you adquire data from the NHID.

c) Clear definition on each risk factor should be added (i.e. hypertension)

RESULTS

a) P values are missing, on each one of the tables (HR). When adding statistical analysis for association, you should provide this values. 

b) Kaplan Meier Curve should be corrected: Log-rank p value should be included, On the X axis, the authors should clarify if they are using person-year or years. Number at risk table should be included for each group, below X axis on each point of the analysis.

c) When including data from severity, type of stroke, and acute therapy I suggest to run again your analysis, to evaluate if the previous findings still remain in terms of covariates.

d) Finally, the previous changes should be considered in terms of the Discussion section, if significant changes are found.

Reviewer #1: In the introduction part you have to explain better the definition of rheumatoid arthritis in which it doesn’t describe the dysfunction produced by it.

It is important the mention the definition of seropositive rheumatoid arthritis and what kind of antibodies were used to classify the population.

In the study design and subjects would be better if you explain what kind of DMARD was prescribed (biological or synthetic)

Reviewer #2: This work approaches ischemic stroke in RA patients, a relevant complication considering the increased cardiovascular risk. It describes the incidence of ischemic stroke in Korean RA patients, obtaining data from a national database. Although it draws some interesting conclusions regarding stroke incidence and its associations, there are important aspects to be addressed.

Major points

1. I consider the most concerning point is that there are contradictory statements regarding the main objective of the study (incidence of stroke in RA patients). In lines 136 and 137, the statement is: “The incidence of ischemic stroke was lower in the seropositive RA group (2.31%, 64 patients) than in the control group (3.70%, 512 patients)”; whereas in lines 142 and 143, it is: “The incidence of ischemic stroke was significantly higher in the seropositive RA group than in the control group (p =0.014, Fig 2).” Did the authors mean “cumulative incidence” in the second statement? If they were referring to person-years, they must clarify and include that information in the text, and not only in the figure.

2. Authors should clarify why they included only patients with newly diagnosed RA, and not with prevalent RA. This could lead to bias and to a lower risk of ischemic stroke, since patients with a longer disease duration could have an even higher risk than those who were newly diagnosed in the established time period.

3. Authors should clarify whether the ischemic stroke was diagnosed after RA. Although that seems intuitive, it is not included in the Methods section.

Minor points:

1. Line 85: “Accessed the databases number of this paper is NHIS-2019-2-194.” This statement does not make sense.

2. Line 97: There is a ”27” which seems out of place.

3. Lines 134 and 135: although the authors mention that there were significant differences in the prevalence of diabetes, hypertension, dyslipidemia and stroke, they do not clarify which were more prevalent in the RA patients and which in the control group. Even though that information can be found on Table 3, since there are differences in each condition, I consider it should be added to the text.

4. Line 192: Is it atrial fibrosis or atrial fibrillation? Authors should also clarify why would that explain a higher risk of stroke in RA patients

5. Line 203: What do you mean by “radiation grade”?

6. Because of the nature of the study, we do not know the smoking status of the population. Since smoking is a risk factor for both RA and stroke, this should be discussed as a limitation.

7. The different prevalence of diabetes and dyslipidemia between both groups should be discussed.

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-20-30296R1

Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: A nationwide longitudinal cohort study

PLOS ONE

Dear Dr. Sohn,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors addressed my previous comments correctly. However, there are still some aspects I consider should be corrected:

- There are several grammatical errors throughout the manuscript, they should be corrected.

- Abstract:

The following statement is not clear: “Patients with seropositive rheumatoid arthritis (RA) who were matched in age and sex.”

Authors should state that they studied both RA patients and controls, who were age- and sex-matched.

I consider the abstract conclusion is not accurate. “Due to the high risk of ischemic stroke, close observation is especially necessary in female, hypertension, non-diabetes, and non-dyslipidemia RA subgroups”.

Whereas RA patients who were female, hypertense and without diabetes or hypertension had a higher risk of strike than their non-RA counterparts, it does not mean that they were the group with the highest stroke risk. It should be interpreted that these patients, even without the traditional risk factors for stroke (except for hypertension), had a higher risk which could be potentially attributed to RA.

Introduction

This sentence does not make sense: “Unlike debilitating joint effects, RA is reported to be primarily associated with a decrease in median survival rate”. Please rephrase.

Line 84 and 85: Change “who” for “that” and delete the “]” sign.

Line 95: it should be “citrullinated”

Line 122: Is it hospitalization >1 day?

Results

Are incidence rates in Table 3 correct? In people with RA over 65 years of age, it is 14.33 vs 1.02 in controls, with no significant difference. Also, it is mentioned that patients with RA without diabetes had a higher risk than controls, and the incidence rate shown in the Table is lower on those patients (0.49 vs 0.73)

The p value for hypertension in Table 3 should be in patients with hypertension, not without

I would suggest deleting this statement “The hazard ratio of ischemic stroke among male patients in the seropositive RA group was 1.12 (95% CI, 0.68–1.84)”, since it was not significant and is shown in the Table.

Discussion

The discussion is somewhat difficult to follow; it lacks cohesion and fails to give potential explanations and/or show the relevance of some of the study findings.

As I mentioned in my previous comments, the different prevalence of diabetes and dyslipidemia between both groups should be added to the discussion (not just mentioned in the Results section).

The paragraph in lines 232 to 236 is not clear. The differential outcomes of myocardial infarction and stroke and then the different mechanisms leading to both of them do not appear to be related.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Association between ischemic stroke and seropositive rheumatoid arthritis in Korea: A nationwide longitudinal cohort study

PONE-D-20-30296R2

Dear Dr. Sohn,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Miguel A. Barboza, MD, MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Most of my comments have been correctly addressed and I consider the manuscript has substantially improved. However, as I had already stated, I have one major concern regarding results depicted on Table 3.

According to those results, RA patients without diabetes have a lower incidence rate of stroke than non-diabetic controls (0.49 in RA vs 0.73 in non-RA controls), but the HR suggests RA is a risk factor for stroke in this group of patients (1.47; 1.106-1.952). On the other hand, RA patient with diabetes have a higher incidence rate than patients with diabetes and without RA, but the HR shows RA as a protective factor (although non-significant). Are those incidence rates correct?

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No