Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus

Liza Das; Ashu Rastogi; Edward B. Jude; Mahesh Prakash; Pinaki Dutta; Anil Bhansali

doi:10.1371/journal.pone.0259224

Peer Review History

Original SubmissionMay 11, 2021
29 Jun 2021 Decision Letter - Rayaz A Malik, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-21-15543 Long-Term Foot Outcomes Following Differential Abatement of Inflammation and Osteoclastogenesis for Active Charcot Neuroarthropathy PLOS ONE Dear Dr. Rastogi, 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. I believe there are data which are novel and that need to be further analysed and separated from previously published data in Diabetes Care. Please submit your revised manuscript by Aug 12 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. 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, Rayaz A Malik, MBChB, PhD Academic Editor PLOS ONE Additional Editor Comments: I believe there is merit in publishing some aspects of your study. However, the major concern raised by reviewer 2 is the overlap with data already published recently by this group in Diabetes Care. Saying that I think there are limited interventional trial data in studies of the treatment of Charcot and there are data here which could be better presented in a revision addressing the concerns of both reviewers and removing the overlap with the previously published data (Diabetes Care Volume 42, December 2019 e185) focusing on the novel aspects. 1. Additional information on the long-term outcomes of the Charcot foot after a 3 year-follow up (which is new) needs to be emphasized and detail provided on the methodology and data collection. 2. Data on bone mineral content measured at initiation after 6 months of study therapy requires a more detailed analysis and the association with the rate of reduction of BMC and the rate of change of bone turnover markers and interaction with markers of inflammation assessed. 3. Figure 5 illustrates some of the possible drivers of increased osteoclastic activity in the Charcot foot which could be attributed to the direct effect of methylprednisolone on osteoclasts (J Bone Miner Res. 2010 Oct;25(10):2184-92. doi: 10.1002/jbmr.113.). 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 https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. We noted in your submission details that a portion of your manuscript may have been presented or published elsewhere. [Yes, The data for inflammatory markers and bone turnover markers at 6 months) were published as interim analysis as Diab Care 2019 Dec;42(12):e185-e186. doi: 10.2337/dc19-1659. The present mansucripts pertains to bone mineral content and long term outcomes of Charcot foot and teh prior data is presented as figures which are not published elsewhere.] Please clarify whether this [conference proceeding or publication] was peer-reviewed and formally published. If this work was previously peer-reviewed and published, in the cover letter please provide the reason that this work does not constitute dual publication and should be included in the current manuscript. 3. Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute. Please either amend your manuscript to change the affiliation or corresponding author, or email us at plosone@plos.org with a request to remove this option. [Note: HTML markup is below. Please do not edit.] 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: Partly ******** 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 ****** 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 ****** 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: Nice RCT assessing the effect of MT, a biphosphonate and placebo for the treatment of Charcot foot disease. Surrogate and clinical endpoint were assessed at the same time. The study is well written. However, it does not add much to the literature since findings are already reported in meta-analysis and similar studies. However, it would have been interesting if they added anti-TNF alpha in one of the arms. Major comments: 1- The follow-up is unclear. How often If the follow-up is regular, why not to assess the difference using a Kaplan-Meiyer curve which consists of time-to-first event (remission). If any HR is significant, it could be adjusted using baseline characteristics and diabetes parameters using a cox regression model. 2- How was "remission" assessed? Minor comments: 1- Add number of patients, age and sex in the abstract. Reviewer #2: Dear authors, The aim of the study is to explore the effect of anti-inflammatory or anti-resorptive agents for remission of active CN foot on bone mineral on content (BMC) of the active Charcot foot as well as the effect of these therapies on the consequent long-term outcomes of foot deformities, fractures and amputation in people with Charcot foot. The results of the efficacy of methylprednisolone and zoledronate versus placebo in the management of the Charcot foot have been already published by the same group and it is disappointing to see that this manuscript contains a lot of already published data, although presented in a slightly different context. The paper offers some good points for discussion and figure 5 illustrates some of the possible drivers of increased osteoclastic activity in the Charcot foot. One aspect that could be added is the direct effect of methylprednisolone on osteoclasts (J Bone Miner Res. 2010 Oct;25(10):2184-92. doi: 10.1002/jbmr.113.), which has not been considered when designing this therapy. Glucocorticoids maintain osteoclasts in a prolonged continuous resorption mode, therefore the reported longer duration of casting in patients treated with this agent is not surprising, (despite the effect of steroids to inhibit TNF-alpha primed osteoclastogenesis). The submitted manuscript to a great extent overlaps with data from a recent intervention trial, which is already published by the same group (Diabetes Care Volume 42, December 2019 e185). The additional information on the long-term outcomes of the Charcot foot after a 3 year-follow up (which is new) does not stand out and is almost left to the end of the result section lacking a lot of detail in methodology and data collection. A further new aspect of the current submission is the data on bone mineral content measured at initiation after 6 months of study therapy. This could be potentially of interest. However, it requires a more detailed analysis and perhaps association should have been sought between the rate of reduction of BMC and the rate of change of bone turnover markers and the interaction with markers of inflammation. These new observations might be of interest to be submitted as a commentary or short report. However, the way the current manuscript is presented, these new additions are almost absorbed by the data of the actual (already published) clinical trial. Thus, in my opinion, this manuscript does not contain sufficient new data for a further research paper. ****** 6. 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 #1: No 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. https://doi.org/10.1371/journal.pone.0259224.r001
Revision 1
1 Oct 2021 Author Response Sir, We sincerely thank you and the reviewers for their time in reviewing the manuscript and providing valuable comments and suggestions. We have modified the manuscript accordingly and the changes in the revised manuscript are highlighted BLUE. Also, please find below the point-by-point reply to the reviewers’ comments. Reviewer #1: Nice RCT assessing the effect of MT, a biphosphonate and placebo for the treatment of Charcot foot disease. Surrogate and clinical endpoint were assessed at the same time. The study is well written. However, it does not add much to the literature since findings are already reported in meta-analysis and similar studies. However, it would have been interesting if they added anti-TNF alpha in one of the arms. Reply: We sincerely thank you for your appreciation and the suggestions. We agree that TNF alpha (Etanercept) could have been added in one of the arms. Etanercept use was not planned (not available in our country at the time of study initiation). However, we will consider future studies with etanercept. Major comments: 1- The follow-up is unclear. How often If the follow-up is regular, why not to assess the difference using a Kaplan-Meier curve which consists of time-to-first event (remission). If any HR is significant, it could be adjusted using baseline characteristics and diabetes parameters using a cox regression model. Reply: The follow up details following remission of active Charcot is provided in the revised manuscript (patients were recalled fortnightly). We performed Kaplan-Meier analysis for the time to remission and subsequently analysed predictors of remission by Cox regression model. The details are presented in the revised manuscript (Results section). 2- How was "remission" assessed? Reply: Remission criteria for active charcot are mentioned in the method section of revised manuscript. Minor comments: 1- Add number of patients, age and sex in the abstract. Reply: Thanks for the suggestion. The number of patients, age and sex are added in the revised abstract. Reviewer #2: Dear authors, The aim of the study is to explore the effect of anti-inflammatory or anti-resorptive agents for remission of active CN foot on bone mineral on content (BMC) of the active Charcot foot as well as the effect of these therapies on the consequent long-term outcomes of foot deformities, fractures and amputation in people with Charcot foot. The results of the efficacy of methylprednisolone and zoledronate versus placebo in the management of the Charcot foot have been already published by the same group and it is disappointing to see that this manuscript contains a lot of already published data, although presented in a slightly different context. The paper offers some good points for discussion and figure 5 illustrates some of the possible drivers of increased osteoclastic activity in the Charcot foot. One aspect that could be added is the direct effect of methylprednisolone on osteoclasts (J Bone Miner Res. 2010 Oct;25(10):2184-92. doi: 10.1002/jbmr.113.), which has not been considered when designing this therapy. Glucocorticoids maintain osteoclasts in a prolonged continuous resorption mode, therefore the reported longer duration of casting in patients treated with this agent is not surprising, (despite the effect of steroids to inhibit TNF-alpha primed osteoclastogenesis). Reply: We thank you for the suggestion. We agree regarding the direct effect of steroids on osteoclasts. However, premise of the study was that the inciting event of inflammation and inflammatory cytokine mediated activation of RANKL could be curbed with steroids so as to have earlier remission. The effect of BMC with steroids was an expected outcome on short term that is the decrease in BMD of foot bone. The same is discussed in the revised manuscript. The submitted manuscript to a great extent overlaps with data from a recent intervention trial, which is already published by the same group (Diabetes Care Volume 42, December 2019 e185). The additional information on the long-term outcomes of the Charcot foot after a 3 year-follow up (which is new) does not stand out and is almost left to the end of the result section lacking a lot of detail in methodology and data collection. Reply: We accept that the present study describes the acute charcot remission with the three therapies, that is curtailed in the revised manuscript as suggested in view of prior publication. However, the revised manuscript also entails the long-term outcomes after initial intervention and the Kaplan Meier analysis and predictors of remission. The method, result and discussion section is modified accordingly. A further new aspect of the current submission is the data on bone mineral content measured at initiation after 6 months of study therapy. This could be potentially of interest. However, it requires a more detailed analysis and perhaps association should have been sought between the rate of reduction of BMC and the rate of change of bone turnover markers and the interaction with markers of inflammation. These new observations might be of interest to be submitted as a commentary or short report. However, the way the current manuscript is presented, these new additions are almost absorbed by the data of the actual (already published) clinical trial. Reply: We thank you for the suggestions. We have done a corelation analysis between change in BMC and the changes in the inflammatory markers and BTMs. The same are presented in the result section of revised manuscript. We hope that the revised manuscript may be considered for publication. Sincerely, Ashu Rastogi Deptt. of Endocrinology PGIMER, Chandigarh INDIA Attachments Attachment Submitted filename: Reply PLOS One Aug 2.docx https://doi.org/10.1371/journal.pone.0259224.r002
18 Oct 2021 Decision Letter - Rayaz A Malik, Editor Long-Term Foot Outcomes Following Differential Abatement of Inflammation and Osteoclastogenesis for Active Charcot Neuroarthropathy in Diabetes Mellitus PONE-D-21-15543R1 Dear Dr. Jude, 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, Rayaz A Malik, MBChB, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for addressing the concerns of the reviewers and revising the manuscript appropriately. Reviewers' comments: https://doi.org/10.1371/journal.pone.0259224.r003
Formally Accepted
27 Oct 2021 Acceptance Letter - Rayaz A Malik, Editor PONE-D-21-15543R1 Long-Term Foot Outcomes Following Differential Abatement of Inflammation and Osteoclastogenesis for Active Charcot Neuroarthropathy in Diabetes Mellitus Dear Dr. Jude: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Rayaz A Malik Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0259224.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .