PONE-D-21-21631Effects of intra-articular Platelet-Rich Plasma (PRP) injections on osteoarthritis in the thumb basal joint and scaphoidtrapeziotrapezoidal joint.PLOS ONE

Dear Dr. Wilcke,

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Reviewers' comments:

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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: Partly

Reviewer #2: Partly

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

Reviewer #1: No

Reviewer #2: I Don't Know

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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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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)

Reviewer #1: This is a relatively short and simple analysis of available data to answer whether PRP injections improve osteoarthritis in the thumb basal joint and scaphoidtrapeziotrapezoidal joint. The organization is clear and the short paper is well written. I submit the findings may be potentially useful but it is a one-arm study which is also much more open to bias and misleading conclusions. A main question I have is whether there is enough substantial material for a publication given the paper is relatively much shorter than others I have refereed in the journal and the data is very simply analyzed.

I focus on the statistical aspects for the study. Overall, I find the analysis relatively simple which can be particularly problematic when the sample size is small. Some particular concerns are

a) There was mention about excluding patients from the study because they had incomplete data. It is not clear what exclusion rule was used whether the missingness had something to do with the disease progression or the pain the patient is suffering. Are data missing at random or completely missing at random or otherwise? Statistical methods will then have to specially used for different types of missingness;

b) There are statistical tests that are more reliable for analysis small sample data that are more reliable; permutation tests may be better alternatives. Similarly, Shapiro-Wilk’s test results on whether the data are normally distributed can also be questionable for small data set;

and

c) There were demographic data or covariates on the patients but there was no discussion if some of them play a role in explaining the findings the authors obtained.

Reviewer #2: Well written and pleasant to read paper.

Introduction:

- How is it relevant to only focus on the short-term effects of this treatment? I'm not sure it is, but please explain. As CMC1 OA is a chronic condition (we will all get osteoarthritis of the thumb if we live long enough), we should focus on treatments that have long-term benefits. Most likely a "quick fix" with an injection or surgical intervention is not the solution.

- Please change "conservative treatment" to "non-operative treatment".

Methods:

- The 3-4 weeks interval between the injections: please explain how you chose this time interval.

- Symptom intensity of CMC1 OA is strongly related to the influence of psychosocial aspects; patients with greater symptoms of catastrophic thinking and depression have greater pain intensity. In many multivariable analysis, these are the strongest contributors to several outcomes including pain (see papers of Becker et al., Wilkens et al., or Prof. Ring). At least, this must be mentioned as it could lead to a potential bias in the findings of the current paper.

- How did you estimate an SD of 2 points for NRS pain?

- What where the inclusion criteria or selection criteria for patients to receive a PRP injection?

Results & Discussion:

- Please write out "thirty-three" and other numbers that are at the beginning of a sentence.

- Line 111-112: these results don't exceed the MCID. Although there is some variety among studies about the MCID for pain scores (NRS/VAS), most agree that an improvement of 1 point is not enough to reach an MCID in outcome (Danoff 2018, Lee 2003). Even the study referred to in this manuscript (Salaffi et al.) supports the use of a "much better" improvement on pain relief as a clinically important outcome: and that is 2 points. I think the authors must revise this point and their conclusion. They found a significant but not a clinically important difference in pain improvement. This is in line with the other study findings that shows no difference in PROMs. And it does not support the (costly) use of PRP for patients with CMC1 OA seeking specialty care.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-21-21631R1Effects of intra-articular Platelet-Rich Plasma (PRP) injections on osteoarthritis in the thumb basal joint and scaphoidtrapeziotrapezoidal joint.PLOS ONE

Dear Dr. Wilcke,

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 Jan 20 2022 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,

Gabriel de Araújo, M.D., 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

Reviewer #3: (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

Reviewer #3: No

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

Reviewer #2: Yes

Reviewer #3: No

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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

Reviewer #3: 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 #2: Yes

Reviewer #3: Yes

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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: I would recommend to accept this paper. However, one more suggestion:

* The conclusion of this paper is that PRP injections do not lead to pain relief, decrease of physical limitations or improvement of strength. The last paragraph of the discussion however, seems like a plea for the harmless use of PRP injections. Please look at this again. And delete the last sentence: "Although this study has methodological flaws, and it is important to test PRP in randomized placebo-controlled studies, our study results suggest that PRP injections have no effect on pain intensity, physical limitations, or thumb strength among patients with osteoarthritis in the thumb basal joint or STT-joint."

Reviewer #3: Thank you for the opportunity to review this paper.

The present paper is a 29-patient retrospective case series on the use of PRP in the treatment of thumb basal joint and STT joint OA. The authors observed a significant but small effect in terms of pain relief for osteoarthritis in the thumb basal joint or STT-joint.

The paper is in general well written and easy to follow. However, it has several methodological issues.

I credit the authors for prospective data collection. However, I cannot see why the authors did not define clear study objective/question and a study protocol a priori in order to collect a prospective case series. This leads to several shortcomings.

Perhaps the biggest concern is the lack of explicit inclusion and/or exclusion criteria which leads to major heterogeneity between participants: Both thumb basal joint and STT arthrosis (in my opinion, these conditions may be related to different biomechanical changes), age 34-86, posttraumatic or primary arthrosis (?), the duration of symptoms before treatment, pre-treatment pain intensity (no borders for inclusion/exclusion), associated conditions that might affect the result (e.g. small joint arthritis in general, thumb MCP arthritis), previous trauma or surgery of the hand/wrist and treatment of contralateral TMC/STT joint arthritis (successful non-operative/operative treatment of contralateral TMC/STT might affect patients expectations).

While the authors have assessed the severity of the arthritic changes - in my opinion it is as important to assess the joint congruency as the thumb basal joint might be clinically stable, instable or chronically subluxated - which might affect the outcome of the injection as the biomechanical basis of the disease might be different.

Another concern lies in the preparation of PRP - how rich is platelet-rich? No laboratory testing is made to control for the quality of the agent. Moreover, how do the authors believe that the quantity (0,5-2ml) of PRP affects the outcome? How was the interval between treatments decided? The regulatory aspects of the use of PRP for TMC and STT OA should also be declared.

The enrollment lasted from sep 2018 to sep 2019. Was it a consecutive series? Was the enrollment based on patient preference? How many patients declined? Were there any exclusion criteria?

Post-treatment regimen? The authors state that “The patients could resume work and daily activities immediately after the injection as tolerated.” - did the patients use a splint? Was there any hand exercise regimen? The authors report that two patients were prescribed pain medication at first injection, whereas 20 did not use any pain medication. Seven patients used pain medication for “unrelated reasons” All of these might significantly affect the outcome as the post-treatment protocol was not defined.

In the statistics paragraph the authors have presented a power calculation. A post-hoc power calculation seems off, why not just look at 95% CI? Why not repeated measures analysis of variance?

The results are very brief and mainly presented without numbers (percentage, SD, IQR, 95% CI) or significance levels. Lines 111-114 are not results per se but patient characteristics (a methodological concern). The minimally clinically important difference for pain presented in power calculation is 2 points (2 SD). However, the authors interpret a 1-point decrease in NRS a “substantial improvement”. How is this clinically relevant? The patients reported the pain to be “slightly better” - which could represent treatment bias and reflect the expectations of the patients. Patient acceptable symptom state (PASS) would better reflect the clinical outcome as PASS is the highest symptom level at which patients consider themselves well.

Moreover, the authors report that 15 patients requested a new PRP injection, and two patients wished for a corticosteroid injection at the follow-up 4 months after the first injection. Thus, at least 58% of the patients were probably not happy with the treatment. Was surgery an option? What about the 42%, what happened then? I would be interested if the treatment reduces the number of surgeries in the long-term. As the authors point out in the introduction - successful conservative treatment that delays or reduces the need for surgery is of great value. However, the present paper does not give any clinically relevant information on the matter as the results are very short term.

The subject of the present manuscript is very welcome as an increasing interest in biologic agents - as nonoperative treatment modalities or to augment surgical procedures - has been observed in recent years. However, the methodological shortcomings of the present paper make it hard to support the publication of this paper.

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Reviewer #2: No

Reviewer #3: 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.]

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Effects of intra-articular Platelet-Rich Plasma (PRP) injections on osteoarthritis in the thumb basal joint and scaphoidtrapeziotrapezoidal joint.

PONE-D-21-21631R2

Dear Dr. Wilcke,

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,

Gabriel de Araújo, M.D., MSc

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The manuscript is well written and value. Besides that, I agree that all reviewers comments would improve the scientific quality of you study. For this reason, I am sending the reviewers suggestions for your appreciation.

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 #4: (No Response)

Reviewer #5: (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 #4: Partly

Reviewer #5: Yes

**********

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

Reviewer #4: Yes

Reviewer #5: 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 #4: Yes

Reviewer #5: 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 #4: Yes

Reviewer #5: Yes

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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 #4: Thank you for the possibility to review this manuscript. As the authors report, there are few studies of the effect of PRP on osteoarthritis in the hand. This could be interesting work. However, some minor issues should be addressed.

The results section could be further explored by the authors.

The data described in lines 87 to 98 could be presented in a table, including the respective percentage of each characteristic.

Line 95 - The timing of corticosteroid use prior to PRP treatment may affect results. Considering that the majority of patients used corticosteroids (n=20), it is necessary to describe the period of time of use before treatment with PRP.

Table 2, considering the small number of the sample and the variability in the scores, it is important to present the percentage of improvement among the patients. Another strategy is to present the average of the differences between the moments.

Line 112- The authors described that 16 patients (57%) answered “yes” to the question whether they experienced a positive effect from the injections. It is necessary to explore who these patients are. Are there characteristics associated with this response (age, sex...)?

The subject of the present study is interesting and “polemical”, since there is little evidence on the subject. The subject of the present study is interesting and controversial, since there is little evidence on the subject. However, considering the limitations of the study (sample number and retrospective data), a detailed description of the results is necessary.

Reviewer #5: The Authors present a retrospective analysis about PRP injection for CMC-I or STT osteoarthritis.

The topic is interesting and relevant for the clinicians. The manuscript is well written and easy to read. The corrected version already take into account the previous comments.

The only two remaining problems that cannot bee changed are:

- the real composition of the injected PRP. It was obtained with a commercial kit and there is no way to check what was injected. In my opinion the technique is well described and could b reproduced easily.

- the amount injected. It is often difficult to inject a significant amount in the CMC-I and STT due to the small joint space and the arthritic changes and it is possible that the efficacy is dose-dependent. In the knee, a joint with a much larger intrarticular volume, the positive effect could be demonstrated. Future studies should address this issue.

Despite these two points I recommend to accept the paper.

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Reviewer #4: No

Reviewer #5: No