PONE-D-23-07128JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with Rheumatoid Arthritis: A protocol for a prevalent new-user cohort study using the nationwide DANBIO register.PLOS ONE

Dear Dr. Burden,

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors plan to study the prevalence, and incidence, of serious viral infections, VTE and cardiac events in the Danbio registry comparing JAKi with TNF treated patients.

Their methodology is quite sound and they have done a good job in presenting it.

However, and this is important, the reader is unable to judge the representativeness and generalizability of their approach. This is because the Danish health care system approves minimal disease criteria in order to be eligible to receive either a b or tsDMARD. These criteria differ across national health care systems. These European eligibility criteria are typically quite different from country to country and are very different from eligibility criteria in the US.

This is reflected by the very much different prevalence of prescribing both b and tsDMARDs in single national health care systems from country to country.

Therefore, the authors must present plans to supply data on: 1. Eligibility to receive both b and tsDMARDs in the Danish system; 2. Percentage of patients (prevalent and incident described separately) who are prescribed these agents with the overall percentage of patients treated in the health care system used as a denominator; and 3. Describe how the population studied in this selective population might affect the results they report.

That is, if only patients with more severe disease receive these agents in Denmark, while patients with much less (mean and median) standard disease metrics receive these same drugs in other countries then these differences are potentially very relevant and affect the generalizability and representativeness of other populations around the world who access these drugs with different baseline disease activity criteria. National health care systems are able to set their own minimal disease criteria based upon a policy of willingness to pay for different disease activity levels.

Reviewer #2: Thank you for giving me the opportunity to review this article. I have carefully read the article. Although there are important safety data from individual RTCs as well as from pooled analyses on RCTs, real-world data comparing safety of JAKi and TNFi are currently limited. Therefore, the aim of the study serves to provide valuable safety knowledge on JAKi treatment of RA patients.

The article deals with the study design and methodology of the planned prospective cohort study, and overall, the study design has been elaborately made to avoid confounding. However, some part of the description lacks detailed explanation.

I suggest that the followings be explained in more detail.

1. Different abbreviations (DNPR and NPR) were used for the same meaning in the “DATA SOURCE| section.

2. For Figure 1. incorporate the difference between MACE/VTE cohort and viral infection cohort.

3. Figure 1 should come after the paragraph “base cohort”.

4. In figure 2, only prevalent new user of JAKi and his or her potential controls are depicted. Please make it include the incident new users.

5. In figure 2, describing why patient 3 and 4 are not potential controls will help readers to understand the study cohort selectiotn process.

6. In “Base Cohort” section, the sentence “Note that the base cohort entry may be previous to the study period for TNFi users” will be better placed in “Exposure set” section since such discrepancy occurs when matching a TNFi user to a prevalent new user of a JAKi. Figure 2 will help understanding, which is also being placed in “Exposure set” section.

7. There are four levels of study populations: study population, base cohort, exposure sets, and study cohort, which makes the readers confusing. Please add explanations for the purpose of this multi-level populations “upfront” and psecify the role of each population.

8. Do authors distinguish switching between different TNFis? Authors did not specify whether they will censor at switching from one TNFi to a different TNFi, which makes me assume that the authors will treat TNFis as a class. However, in Figure 2, the exposure set condition includes types of TNFi.

9. Please present the PPV of each outcome definition for the DNPR. If there is no PPV made for ICD10 used with DNPR, describe possibility of the misclassification bias.

10. Follow-up and censoring

censoring as a result of change in the exposure status, which will be defined as (i) treatment discontinuation (defined by recorded treatment discontinuation or a gap of >90 days, in which case we assume stop at start/stop of the gap) please rephrase the underline part since it is hard to follow.

11. ascertainment periods for individual covariates are different. Briefly explain on which criteria each of the time period was set.

12. It is not clear whether the matching is fixed ratio (1:4) or variable ratio. Please specify.

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Reviewer #1: No

Reviewer #2: No

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JAK-inhibitors and risk on serious viral infection, venous thromboembolism and cardiac events in patients with Rheumatoid Arthritis: A protocol for a prevalent new-user cohort study using the Danish nationwide DANBIO register.

PONE-D-23-07128R1

Dear Dr. Burden,

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.

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Kind regards,

Ryu Watanabe, M.D., Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors responded adequately to the comments and suggestions raised by the reviewers. I think the manuscript is now acceptable to this journal.