Dear Dr. Wang,

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.

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ACADEMIC EDITOR: 

Title and abstract

- The abstract should include the total number of patients.

Introduction

- You may highlight the epidemiology of RA, including its prevalence and female-to-male ratio.DOI: 10.1177/03000605231204477

- You may draw attention to the RA patient's annual healthcare costs. DOI: 10.3389/fmed.2023.1221393

- The gaps in knowledge and rationale for the study need to be mentioned.

Patients and methods

- Please outline this section following the STROBE guidelines.

- Describe the setting, locations, exposure, follow-up, and data collection

-  How were the patients selected (e.g., consecutively, randomly, or selectively)?

- You need to state in the Methods section that you have followed STROBE guidelines: ‘The reporting of this study conforms to STROBE. (Insert new reference number)

Results

- Abbreviations should be explained as subtitles below the Figures / Tables

Discussion

- A comparison of your results and the relevant previous studies should be made.

- How can future research build on these observations? What are the key experiments that must be done? 

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Please submit your revised manuscript by Jul 17 2025 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,

Wesam Gouda, MD,PhD

Academic Editor

PLOS ONE

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2. Thank you for stating in your Funding Statement:

“This study was supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2022YFC2504600, 2022YFC3601800), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-005, 2022-I2M-1-004, 2023-I2M-2-005), The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-PT320-002, 2019-PT330-004), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-013), The Special Science Research for Health Development in Capital (No.2024-1G-2082)

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

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USGS EROS (Earth Resources Observatory and Science (EROS) Center) (public domain): http://eros.usgs.gov/#

Natural Earth (public domain): http://www.naturalearthdata.com/

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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?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: This manuscript addresses an important topic, providing valuable insights into the economic burden of rheumatoid arthritis (RA). The study design and methodological rigor are commendable, and the detailed cost analysis is a notable strength. However, some areas require further refinement to enhance clarity and impact.

Study Design and Methods: The recruitment flowchart is helpful, but the criteria for excluding "unqualified questionnaire quality" (n=22) need clarification. Additionally, the rationale for selecting the Gradient Boosting Machine (GBM) method over other approaches should be elaborated.

Data Presentation: The cost distribution chart is effective, but the discussion on medication expenses could explore potential cost-containment strategies, such as the role of generics or insurance reforms. Consider condensing the frequency tables into supplementary materials for improved readability.

Ethical and Research Transparency: Describe in detail, if applicable, IRB approval, funding, and detailed information about data availability. Include a data availability statement to foster reproducibility.

Interpretation and Recommendations: Even though the study has identified a significant cost component, the discussion should be further extended to cover policy implications in particular, which may include indirect cost reduction strategies such as telemedicine or workplace accommodations. Future research ideas could include extending this framework to other conditions.

In summary, this manuscript is a strong contribution to understanding the economic burden of RA. Addressing the above points will improve the study's clarity, robustness, and practical implications.

Reviewer #2: Reviewer Comments (Minor Revisions):

The manuscript presents a well-designed cross-sectional cost-of-illness study using data from a large national RA registry. The application of inverse probability weighting (IPW) via generalized boosted modeling and the use of bootstrap methods for cost estimation are appropriate and robust. The findings offer valuable insight into the economic burden of RA in China and identify key cost drivers that have clinical and policy relevance.

However, I would suggest two minor revisions to improve the clarity and interpretability of the study:

1. Survey Response Rate and Generalizability: The response rate of approximately 7% (1,293 of 18,507 eligible patients) raises potential concerns about non-response bias. Although IPW adjustment mitigates this to some extent, residual bias from unmeasured confounders (e.g., income, health-seeking behavior) may remain. I recommend briefly expanding the discussion on this limitation and its implications for the generalizability of the findings.

2. Attribution of Costs to RA vs. Comorbidities: It is not entirely clear whether the estimated costs are specific to RA-related healthcare utilization or may include expenditures related to comorbidities. Since RA patients often have overlapping medical conditions, further clarification in the Methods and Discussion sections regarding the attribution of costs would enhance transparency.

These revisions are relatively minor and do not detract from the overall quality of the work. I support publication pending minor revisions.

Reviewer #3: The research entitled "Average Annual Costs of Rheumatoid Arthritis Estimated by Inverse Probability Weighting and Their Predictors: A Cross-Sectional Study Based on the Chinese Registry of Rheumatoid Arthritis (CREDIT) Cohort" explicitly acknowledges a number of caveats and limitations.

1. Cross-Sectional Design: The study employs a cross-sectional approach, indicating that data were gathered at a singular moment in time. This methodological framework constrains the capacity to ascertain causal relationships between predictors, such as disease activity or treatment modalities, and annual expenditures.

2. Data Acquisition and Representational Validity: Data pertaining to outpatient and inpatient expenditures were gathered through online questionnaires, a method that may potentially lead to recall bias or inaccuracies in reporting if patients fail to accurately remember or disclose their expenses.

3. The sample was derived from the CREDIT cohort, and while inverse probability weighting (IPW) was employed to construct a weighted population that mirrors the larger RA patient demographic, there exists a possibility that the sample may not comprehensively represent all RA patients in China, particularly those individuals not included in the registry. The low response rate may still affect representativeness and external validity.

4. Methods of Estimation: Indirect costs were assessed through the human capital approach; however, this method may overlook certain societal expenses, including intangible costs associated with quality of life and unpaid labor. This may lead to an underestimation of the true indirect cost burden in RA.

5. Attribution Challenge in Health Expenditures: The research recognized the challenges associated with differentiating healthcare expenses that can be directly linked to RA from those arising from concurrent comorbid conditions. Consequently, the analysis encompassed all healthcare expenditures reported by patients with RA over the preceding year, which may lead to an overestimation of costs specifically associated with RA.

6. Employing bootstrap methods for cost estimation yields strong confidence intervals; nevertheless, it is contingent upon the premise that the sample is representative and that the resampling effectively reflects the variability within the population.

7. Possible Confounding Variables: Despite the application of multivariate regression and inverse probability weighting to account for confounding factors, there remains the possibility of residual confounding arising from variables that are either unmeasured or inaccurately measured.

8. Generalizability: The research is predicated on data sourced from China, where healthcare systems, cost frameworks, and treatment modalities may exhibit significant variations in comparison to other nations. This disparity potentially constrains the applicability of the findings beyond the specific context of China.

9. Language and Grammar: The manuscript contains several grammatical errors and awkward phrasing.

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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.

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Reviewer #1: Yes:  Kola Adegoke

Reviewer #2: No

Reviewer #3: No

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Average annual costs of Rheumatoid Arthritis estimated by inverse probability weighting and their influence factors: a cross-sectional study based on Chinese Registry of Rheumatoid arthritis (CREDIT) Cohort.

PONE-D-24-53064R1

Dear Dr. Wang,

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.

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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,

Wesam Gouda, MD,PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

The PLOS Data policy

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #2: (No Response)

Reviewer #3: (No Response)

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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: Yes:  Yiduo Sun

Reviewer #3: Yes:  Adel Azzam

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