PONE-D-25-06222Postoperative joint pain is associated with long-term all-cause mortality after total joint arthroplastyPLOS ONE

Dear Dr. Zhai,

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Academic Editor

PLOS ONE

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Additional Editor Comments:

The reviewers have made comments to improve the manuscript, in particular statistical analysis, interpretation of the results, and implication of study findings.

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Reviewers' comments:

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Comments to the Author

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

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Reviewer #1: Partly

Reviewer #2: Partly

Reviewer #3: No

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: I Don't Know

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: 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)

Reviewer #1: The manuscript “Postoperative joint pain is associated with long-term all-cause mortality after total joint Arthroplasty” examined the effect of post-operative pain on mortality among patients undergoing TJR. Specific comments and clarifications are below:

1. Abstract (lines 14-16): “… their postoperative joint pain at least one-year after TJA…” Was WOMAC collected at several time points after surgery? Please clarify.

2. Methods, Page 5: Please include the exact duration of the follow-up period (e.g., last date, average # of years of follow-up) and the number of post-operative measurements.

3. Page 5, lines 79-80: Please clarify what post-operative time point was used for the analysis.

4. Page 6: I think that the label ‘sustained pain’ is misleading as it is based on a one-time pain reporting based on a question asking for pain in the past 48 hours.

Furthermore, I think that post-operative pain status is not the best variable to accomplish the study objectives, as it does not account for the level of pre-operative pain. I think a variable looking at changes in pain pre- and post- operatively is more appropriate for the study question. Please comment on the choice of the pain variables used.

5. Page 7: Given that comorbidity data was available, I wonder why the models did not control for comorbidities. Please, clarify

6. Results, Page 7: Given the significant attrition (33%), please expand on the sources of loss to follow-up. For example, how many did not have mortality data and why (e.g., unable to link?), how many did not complete WOMAC? Additionally, how the sample of patients include and excluded differ in terms of basic demographic variables collected. Please include this information in the discussion of the study limitations.

7. Table 1 (knee): the data for age and sex appears to be scrambled.

8. Table 4: Are these estimates from Kaplan-Meier or Cox models?

9. Supplementary Table 1: I suggest including the prevalence of comorbidities. I don’t think that p-values without the prevalence are useful.

Reviewer #2: Authors present retrospective, secondary analysis of data derived from the Newfoundland Osteoarthritis Study regarding correlation between WOMAC pain scores (classified as ‘sustained pain,’ ‘pain while active,’ and ‘pain at rest) and long-term (11-year) mortality with the idea that post-arthroplasty pain is understudied outside of directly assessing surgical outcomes and that this is an important area of study as chronic pain may have important consequences on health outcomes and mortality. Authors set the stage by reviewing the rising use of arthroplasty surgery as well as previously published work discussing mortality and post-operative pain following hip and knee arthroplasty. After analysis (Kaplan-Meier survival analysis, multivariable Cox proportional hazards regression) the authors conclude that “patient-reported postoperative joint pain, particularly pain while active, could be a valuable predictor of long-term all-cause mortality in TJA patients” and further recommend that this pain be addressed in patients who experience it.

The authors (2 from the division of Genetics & Genomics, 1 from the department of internal medicine, 1 from the department of surgery) having educational training in epidemiology and clinical experience caring for this patient population appear to have the appropriate training to undertake this study.

While successful arthroplasty surgery and the prevention of post-operative pain/mortality are important topics, there are several considerations to be addressed in this manuscript before it will add clearly and positively to the literature.

1. Statistical analysis. Do the authors control for any of the comorbidities listed in the primary analysis? It does not appear that this was the case. It would be important to control for comorbidities (coronary artery disease, chronic obstructive pulmonary disease, peripheral arterial disease, diabetes) which are likely stronger predictors of mortality post-operative mortality in the post-operative setting than pain. It would also be important to control for these comorbidities as some of them may be associated with pain with activity (i.e., CAD, PAD). The authors mention 37 comorbidities being examined with Chi-squared or Fisher’s exact test – however many of these comorbidities are not relevant predictors of mortality. Olsen et al. offer a more concise and relevant list of comorbidities in the citation below.

Olsen F, Hård Af Segerstad M, Nellgård B, Houltz E, Ricksten SE. The role of bone cement for the development of intraoperative hypotension and hypoxia and its impact on mortality in hemiarthroplasty for femoral neck fractures. Acta Orthop. 2020 Jun;91(3):293-298. doi: 10.1080/17453674.2020.1745510. Epub 2020 Apr 2. PMID: 32237931; PMCID: PMC8023921.

2. Selection and interpretation of PROM (WOMAC). The authors bin patients into four groups (‘sustained pain’ versus ‘pain while active’ versus ‘pain at rest’ and controls). Is there any basis for using this approach previously in the literature? The authors citation for utilizing this approach references one of their previous studies which correlated metabolic biomarkers with ‘sustained’ pain. This previous work does not adequately prove that parsing apart the WOMAC measure in this way is valid. How specifically were patients binned? If a patient answered a 1 on both activity (walking, going up/down stairs) questions and a 1 on only a single rest (pain at night, pain while sitting) question were they still binned as a “pain while active” patient? What about the contralateral scenario?

3. Discussion/interpretation of results. The conclusion that ‘Efforts should be taken to address such pain in these patients, especially in those with preexisting cardiac/circulatory conditions and/or neoplasms to potentially reduce increased mortality’ highlights the disconnect between the studies methodology, conclusions, and the literature. This study’s findings are too preliminary to make a recommendation such as this. Further, the recommendation is disconnected form the clinical literature as arthroplasty surgeons are always trying to treat their patient’s pain – so they are already doing this. The introduction presents a more compelling interpretation of the goals for the data: ‘It is important to identify indicators for mortality to better inform patients, enhance patient care algorithms, and monitor surgical care systems.’ The discussion could also be made more concise.

Other Specifics:

-70: Is there a citation that can be included that can link to the study protocol or provide more detail on the index study. It is outside the scope of this specific article but readers should be able to easily access what the goal of the original study is, what the inclusion/exclusion criteria were, etc.

-79: Is there a citation that can be included which provides data on the validity of the WOMAC?

-117-118: Not ideal loss to follow-up.

-97-99 + page 16 ‘postoperative joint pain and COD’ section: cause of death data was only available for 10% of the original sample.

Reviewer #3: I thank the authors and the editorial team for the opportunity to review their work on the association of joint pain one year postoperatively and mortality. I think I do understand how this study came to be conceptually, but have difficulties to understand the conclusions drawn from the results. Foremost: What would your biological explanation be for the established association? Would mortality go down if we would give patients more pain killers? Why did your model not include comorbidity even though you had access to this important information? In summary, I am afraid that I do not consider that this study adds to the literature in a meaningful way.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes:  Anders Brüggemann, MD, PhD

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Attachments

Attachment

Submitted filename: PONE-D-25-06222_comments to authors.docx

PONE-D-25-06222R1Postoperative joint pain is associated with long-term all-cause mortality after total joint arthroplastyPLOS ONE

Dear Dr. Zhai,

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 Aug 01 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.

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: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols .

We look forward to receiving your revised manuscript.

Kind regards,

Yuanyuan Wang, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

The authors have addressed the reviewers' comments appropriately. One reviewer requested a minor revision by adding a limitation.

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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 #1: All comments have been addressed

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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 #1: Yes

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

Reviewer #1: 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 #1: Yes

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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 #1: 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 #1: I thank the authors for addressing my comments thoroughly. My only remaining comment, though, is that I suggest adding a sentence to the limitations section pointing out that the analysis did not account for pre-operative level of pain.

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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

**********

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Postoperative joint pain is associated with long-term all-cause mortality after total joint arthroplasty

PONE-D-25-06222R2

Dear Dr. Zhai,

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,

Yuanyuan Wang, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The authors have addressed all the reviewers' comments.

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