Clinical impact of ceruloplasmin levels at ANCA-associated vasculitis diagnosis

Louis Camboulive; Frédérique Grandhomme; Nicolas Martin Silva; Kathy Khoy; Delphine Mariotte; Thierry Lobbedez; Anaël Dumont; Alexandre Nguyen; Hubert de Boysson; Achille Aouba; Samuel Deshayes

doi:10.1371/journal.pone.0311678

Peer Review History

Original SubmissionApril 2, 2024
29 Jul 2024 Decision Letter - Masataka Kuwana, Editor PONE-D-24-07849Clinical impact of ceruloplasmin levels at ANCA-associated vasculitis diagnosisPLOS ONE Dear Dr. CAMBOULIVE, 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. Specifically, our reviewers found some interests in this study, but pointed out a number of comments and suggestions that require improvement and amendment. I ask the authors to fully respond to all comments made by reviewers in the revised version. Please submit your revised manuscript by Sep 12 2024 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, Masataka Kuwana, MD, PhD Academic Editor PLOS ONE 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 note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. [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: Yes ******** 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: This retrospective monocentric study conducted at Caen University Hospital aims to evaluate the prognostic impact of serum ceruloplasmin levels at the diagnosis of AAV. The study involved 92 patients with anti-MPO or anti-PR3 antibodies. The results suggest that a low serum level of ceruloplasmin at diagnosis is associated with worse survival in anti-MPO AAV patients but not in anti-PR3 AAV patients. Previous studies have not thoroughly examined the prognostic implications of ceruloplasmin levels in AAV, thus the findings are significant as they highlight a potential biomarker for prognosis in anti-MPO AAV, which could influence treatment decisions and patient management. However, some conrcenrs should be addressed. 1. the authors should discuss more deeply the pathological significance of MPO in AAV and the significance of ceruloplasmin as a defense mechanism against it in the introduction. 2. please consider providing more detailed demographic data to better understand the patient population in the results, such as initial PSL dose, use of immunosuppressive agents etc. 3. the authors should consider addressing the potential confounding factors that might influence ceruloplasmin levels, more thoroughly in the discussion. 4. the authors should consider why only survival is different, whereas there are no differences in the baseline clinical characteristics and the recurrence rates of patients with and without elevated ceruloplasmin levels. Reviewer #2: The authors retrospectively examined the serum levels of ceruloplasmin in 50 patients with anti-MPO antibodies-positive AAV, and demonstrated that the mortality was significantly higher in patients with low serum ceruloplasmin levels as compared to those with high serum levels of ceruloplasmin, albeit no significant differences in relapse rate or renal failure was observed between the two groups. No such difference was observed in patients with anti-PR3 antibodies-positive AAV, Minor points to be addressed. (1) Please specify the race of patients with ANCA-associated vasculitis, since anti-MPO-antibodies are prevalent in GPA in Asian countries including Japan (Rheumatology 50:1916, 2011; J Rheumatol 44: 216, 2017; Arthritis Res Ther 16: R101, 2014 et al). (2) Please determine the cut off levels of serum ceruloplasmin to discriminate the survival by ROC curve analysis. (3) It should be mentioned whether serum levels of ceruloplasmin are determined genetically by polymorphism or not. ****** 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: Yes: Ryu Watanabe 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.0311678.r001
Revision 1
4 Sep 2024 Author Response Dear Reviewer 1, thank you for your valuable feedback. Please find our responses below. - To address this first concern, here is the modification we have brough to the introduction “MPO is a key component of neutrophil granules, capable of producing hypochlorous acid (HClO), which contributes to tissue destruction and inhibits α1 anti-trypsin, a plasma inhibitor of PR3. In ANCA-associated vasculitis, MPO is primarily expressed on the surface of activated neutrophils, where anti-MPO antibodies bind to it, triggering the release of reactive oxygen species. This process leads to the formation of neutrophil extracellular traps (NETs), which have cytotoxic properties that cause inflammation and vascular injury.” We also added the following phrase in the introduction “inadequate inhibition of MPO by low ceruloplasmin levels may contribute to a more severe phenotype in ANCA-associated vasculitis by enhancing oxidative stress and tissue damage through increased MPO activity and interaction with ANCA anti-MPO.” - We have taken your advice into consideration and modified our results accordingly. - Regarding the cofounding confounding factors that might influence ceruloplasmin levels, we have added the following details to the manuscript: “Moreover, serum level of ceruloplasmin can be influenced the following parameters: systemic inflammation, hepatic and renal functions (which are frequently disturbed in ANCA-associated vasculitis). Ceruloplasmin serum levels are more often increased during systemic inflammation and impaired renal function, whereas they are decreased in the case of liver failure.” - We thank you for this highly relevant remark. The low number of deaths in our study makes reliable analysis difficult. The patients who died had not experienced a relapse prior to their death (except for 1 patient), which prevents them from relapsing. We have made some modifications to the manuscript (in the discussion) in regards to your comments. “Based on our study's results, decreased ceruloplasmin levels appear to be a marker of poor prognosis in anti-MPO ANCA-associated vasculitis. Although patients with similar BVAS scores did not show a higher relapse rate, the increased number of deaths might be attributed to infectious causes. However, our sample size is too small to confirm this definitively.” Dear reviewer 2, we thank you for your comments, here are our responses: - In France, we are not allowed to collect the race of the patients. However, the recruitment is taking place in France, where the majority of GPA cases are found, both nationally and in our center. (https://link.springer.com/article/10.1186/s41927-024-00385-8), (https://pubmed.ncbi.nlm.nih.gov/30805643/) - Following your review, we have added the cut off levels of serum ceruloplasmin to discriminate the survival by ROC curve analysis. The ROC curve is added as the S2 Fig. - There do seem to be polymorphisms that influence ceruloplasmin levels, but these were not investigated in our study. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0311678.r002
24 Sep 2024 Decision Letter - Masataka Kuwana, Editor Clinical impact of ceruloplasmin levels at ANCA-associated vasculitis diagnosis PONE-D-24-07849R1 Dear Dr. CAMBOULIVE, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Masataka Kuwana, MD, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): 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 Reviewer #2: All comments have been addressed ******** 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 #1: Yes Reviewer #2: 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: The authors revised the manuscript based on the reviewers' comments. I think the manuscript is now acceptable to this journal. Reviewer #2: (No Response) ****** 7. 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: Yes: Ryu Watanabe Reviewer #2: No ******** https://doi.org/10.1371/journal.pone.0311678.r003
Formally Accepted
29 Sep 2024 Acceptance Letter - Masataka Kuwana, Editor PONE-D-24-07849R1 PLOS ONE Dear Dr. CAMBOULIVE, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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 Prof. Masataka Kuwana Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0311678.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 .