The impact of biologic agents on cardiovascular risk factors in patients with rheumatoid arthritis: A meta analysis

Xiaodong Jia; Zheming Yang; Jiayin Li; Zhu Mei; Lihui Jia; Chenghui Yan

doi:10.1371/journal.pone.0306513

Peer Review History

Original SubmissionSeptember 22, 2023
11 Jan 2024 Decision Letter - Antoine Fakhry AbdelMassih, Editor PONE-D-23-30031The impact of biologic agents on cardiovascular risk factors in patients with rheumatoid arthritis: A Meta analysisPLOS ONE Dear Dr. Yan, 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. ============================== Dear authors, please revise the manuscript in light of my comments and those of reviewer 1. ============================== Please submit your revised manuscript by Feb 25 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. 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I invite the authors to justify this discrepancy and to edit the manuscript by removing non-biologic therapies. or by adding the full spectrum of medications used in RA. [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: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 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: No ****** 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 ****** 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: 1- The question of research should be made clear using the PICO model. 2- The study designs must be mentioned in the inclusion criteria. 3- Metanalyses and systematic reviews should be registered, and the registration number needs to be used as reference during the submission process. 4- Causes of heterogeneity aren’t clearly explained. 5- There are some drug names that are not correctly written. 6- Why is leflunomide and mycophenolate mentioned in the search strategy since they are considered conventional synthetic non biologic DMARDs, and if the authors wanted to address additionally conventional synthetic DMARDS where are the other DMARDs including methotrexate and hydroxychloroquine…..etc. 7- The dates for studies included “from …..till” wasn’t mentioned in the search strategy. 8- Combining studies with different treatment strategies like studies using biologics monotherapy versus biologics with conventional DMARDs makes the meta-analysis will yield heterogenous data. ****** 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 ******** [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.0306513.r001
Revision 1
23 Feb 2024 Author Response 1-The question of research should be made clear using the PICO model. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. We have clarified the research question using the PICO model on page 2, lines 25-26, as indicated with red markers. (Objective: This study aims to assess the effects of biologic therapy on cardiovascular risk factors in patients with rheumatoid arthritis (RA) and determine its clinical efficacy). Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 2- The study designs must be mentioned in the inclusion criteria. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have now explicitly mentioned the study designs in the inclusion criteria. We acknowledge that this is an important piece of information that will help readers better understand the scope and methodology of our research. We have mentioned the study designs in the included criteria on page 5, lines 108-109, as indicated with red markers. (All included studies consisted of randomized controlled trials as well as retrospective or prospective observational studies). We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further enhance the accuracy and completeness of our paper. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 3-Meta analyses and systematic reviews should be registered, and the registration number needs to be used as reference during the submission process. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have registered our meta-analyses and systematic reviews. We have obtained a registration number, which we will now reference during the submission process to ensure transparency and adherence to best practices. We have registered the meta-analyses and systematic reviews, and the registration number has been used as a reference during the submission process. The information can be found on page 3, lines 48-49 (Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/, CRD42024504911), and page 4, lines 85 (The review proposal was registered with PROSPERO: CRD42024504911.), as indicated with red marker. We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further strengthen the quality and reliability of our paper. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 4-Causes of heterogeneity aren’t clearly explained. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have provided a clearer explanation of the causes of heterogeneity in our study. We acknowledge that understanding and addressing sources of heterogeneity are crucial for interpreting the results accurately. We have clearly explained the causes of heterogeneity in all results through sensitivity and subgroup analysis, as show on page 11, lines 183-186 ( Following the exclusion of the study conducted by Novikova et al. (2016), the impact of biologic-based treatment on total cholesterol levels was no longer statistically significant (MD = 0.02, 95% CI: [-0.02, 0.18], p = 0.79). Furthermore, the heterogeneity decreased substantially from 81% to 1% (SFigure 1)) and lines 188-201(different treatment approaches; In the subgroup analysis of different drug treatments, no heterogeneity was detected, and the combined effect size suggested a tendency towards a reduction in total cholesterol levels among patients receiving biologics in combination with disease-modifying antirheumatic drugs (DMARDs). However, this observed trend did not reach statistical significance (SFigure 2)), with a red marker. We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further enhance the clarity and robustness of our findings. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 5-There are some drug names that are not correctly written. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have carefully reviewed the drug names mentioned in our manuscript and rectified any incorrect spellings or errors. We understand the importance of accurately identifying and referencing the drugs used in our study. In our revised version, we have ensured that all drug names are correctly written and have verified their accuracy through appropriate sources, such as official drug databases and reputable references. We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further enhance the accuracy and reliability of our paper. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 6-Why is leflunomide and mycophenolate mentioned in the search strategy since they are considered conventional synthetic non biologic DMARDs, and if the authors wanted to address additionally conventional synthetic DMARDS where are the other DMARDs including methotrexate and hydroxychloroquine…..etc. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have carefully reviewed the mention of leflunomide and mycophenolate in the search strategy. We acknowledge that these medications are conventional synthetic non-biologic DMARDs and might not align with the scope of our study. In our revised version, we have removed the mention of leflunomide and mycophenolate from the search strategy as they do not directly align with our objectives. We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further enhance the accuracy and relevance of our study. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 7-The dates for studies included “from …..till” wasn’t mentioned in the search strategy. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. Based on your recommendation, we have included the specific dates for the study inclusion period in the search strategy. We acknowledge the importance of clearly indicating the time frame during which studies were considered for inclusion. We have added the dates for studies in the search strategy on page 5, lines 90 ,as indicated with red marker (The search was conducted until May 2023). We sincerely appreciate your guidance and suggestions, and we believe that these modifications will further enhance the clarity and comprehensiveness of our study. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. 8- Combining studies with different treatment strategies like studies using biologics monotherapy versus biologics with conventional DMARDs makes the meta-analysis will yield heterogenous data. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have carefully considered the issue raised. You are correct in pointing out that combining studies with different treatment strategies, such as biologics monotherapy versus biologics with conventional DMARDs, may introduce heterogeneity into the meta-analysis. We acknowledge the potential impact of this heterogeneity on the pooled data. In our revised version, we have taken your suggestion into account and conducted a subgroup analysis to address the heterogeneity arising from different treatment strategies. This approach allows us to assess the effects of these distinct treatment approaches separately, providing a more comprehensive understanding of the results. We have added the subgroup analysis comparing biologics monotherapy versus biologics with conventional DMARDs in the results section on page 11, lines 197-201 (In the subgroup analysis of different drug treatments, no heterogeneity was detected, and the combined effect size suggested a tendency towards a reduction in total cholesterol levels among patients receiving biologics in combination with disease-modifying antirheumatic drugs (DMARDs). However, this observed trend did not reach statistical significance (SFigure 2)), page 12, lines 220-222 (When stratified by different treatment approaches, biologic treatment of RA was found to effectively reduce triglyceride levels when using biologics monotherapy (MD = -0.16, 95% CI [-0.28, -0.04], P = 0.01) (Figure 6)), and page 13, lines 232-233(The subgroup analyses based on different treatment methods and treatment duration did not reveal statistically significant findings (Figure 7-8)), as indicated with red markers. We sincerely appreciate your guidance and suggestions, and we believe that the inclusion of subgroup analysis will improve the robustness and accuracy of our meta-analysis. Should there be any other areas that require improvement, please do not hesitate to let us know. We would be more than happy to make further modifications to the manuscript. Thank you once again for your time and professional insights. Attachments Attachment Submitted filename: Response to Reviewers&#39.docx https://doi.org/10.1371/journal.pone.0306513.r002
15 May 2024 Decision Letter - Antoine Fakhry AbdelMassih, Editor PONE-D-23-30031R1The impact of biologic agents on cardiovascular risk factors in patients with rheumatoid arthritis: A Meta analysisPLOS ONE Dear Dr. Yan, 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. ============================== The last comments by Reviewer 2, are rather limitations than points to improve. Please mention them in a limitation section at the end of your manuscript. ============================== Please submit your revised manuscript by Jun 29 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, Antoine Fakhry AbdelMassih 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. [Note: HTML markup is below. Please do not edit.] 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: My opinion: 1. Comprehensive Assessment of Cardiovascular Risk: it is crucial to consider a wide range of cardiovascular risk factors beyond lipid levels, such as the use of aspirin, statins, antihypertensive drugs, smoking status, presence of diabetes,familiarity and obesity. These factors play a significant role in determining overall cardiovascular risk in patients with rheumatoid arthritis (RA). 2.Disease Severity and Cardiovascular Risk: the differences in intima-media thickness (IMT) between patients on biologic therapy and control groups could be influenced by the baseline disease severity and overall cardiovascular risk profile of the patients. Patients not on biologic therapy may have a milder disease activity, leading to potentially lower cardiovascular risk compared to those on biologic agents. This confounding factor should be carefully considered and addressed in the analysis. 3.Inflammatory Influence: chronic inflammation in RA can lead to alterations in lipid metabolism, including changes in lipid levels that may not align with the expected cardiovascular risk profile. Biologic therapy targeting inflammation may improve lipid profiles but may not always translate to a reduced cardiovascular risk due to the complex interplay between inflammation and lipid metabolism (lipid paradox).. 4..Long-Term Observations: Evaluating the impact of biologic therapy on cardiovascular risk factors over a longer period is essential to capture any potential changes or trends that may not be evident in a short-term study. Longitudinal studies can provide a more comprehensive understanding of the effects of biologic agents on cardiovascular health in RA patients. The lipid paradox highlights the importance of considering long-term cardiovascular risk assessment beyond lipid levels alone. While improvements in lipid profiles with biologic therapy are beneficial, the overall impact on cardiovascular outcomes may be influenced by a combination of traditional and non-traditional risk factors. ****** 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 #2: Yes: Giuseppe Germano ******** [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.0306513.r003
Revision 2
19 May 2024 Author Response 1-Comprehensive Assessment of Cardiovascular Risk: it is crucial to consider a wide range of cardiovascular risk factors beyond lipid levels, such as the use of aspirin, statins, antihypertensive drugs, smoking status, presence of diabetes,familiarity and obesity. These factors play a significant role in determining overall cardiovascular risk in patients with rheumatoid arthritis (RA). Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. We have revised the limitations section in the manuscript and expanded our discussion on broader cardiovascular risk factors that should be considered in addition to lipid levels. Specifically, we have addressed the importance of assessing cardiovascular risk factors such as the use of aspirin, statins, antihypertensive drugs, smoking status, presence of diabetes, familiarity, and obesity in patients with rheumatoid arthritis (RA). We emphasize that these factors play a significant role in determining the overall cardiovascular risk in this patient population. By incorporating these factors into our analysis, we can gain a more comprehensive understanding of the relationship between rheumatoid arthritis and cardiovascular disease. In the newly added limitation section, we have highlighted the need for future studies to comprehensively assess these factors in order to provide a more accurate assessment of cardiovascular risk in patients with RA. This will enhance our understanding of the complex interplay between rheumatoid arthritis and cardiovascular disease and help inform clinical decision-making. Here is an updated version: “One of the primary limitations of our study is that although we focus on lipid levels as cardiovascular risk factors in RA, it is important to note that there are other significant risk factors that should be taken into account. Factors such as the use of aspirin, statins, antihypertensive drugs, smoking status, presence of diabetes, familiarity, and obesity play a substantial role in determining the overall cardiovascular risk in these patients. Future studies should aim to comprehensively assess these factors to provide a more accurate evaluation of cardiovascular risk in RA.” You may also refer to the manuscript (page 16, line 309-315) for more details, which have been highlighted in red. Once again, we thank you for your insightful comments, which have greatly improved the quality of our paper. We remain committed to further enhancing our research and addressing any additional concerns you may have. Thank you for considering our response. 2- Disease Severity and Cardiovascular Risk: the differences in intima-media thickness (IMT) between patients on biologic therapy and control groups could be influenced by the baseline disease severity and overall cardiovascular risk profile of the patients. Patients not on biologic therapy may have a milder disease activity, leading to potentially lower cardiovascular risk compared to those on biologic agents. This confounding factor should be carefully considered and addressed in the analysis. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. We have revised the limitations section in the manuscript to address the concern you raised regarding the potential influence of disease severity and overall cardiovascular risk profile on the differences in intima-media thickness (IMT) observed between patients on biologic therapy and the control groups. We acknowledge that patients not on biologic therapy may have a milder disease activity, which could potentially result in a lower cardiovascular risk compared to those on biologic agents. This confounding factor is indeed an important consideration and needs to be carefully addressed in our analysis. In the limitation section, we emphasize the need for future studies to account for and analyze the baseline disease severity and overall cardiovascular risk profiles of patients. By doing so, we can provide a more comprehensive understanding of the relationship between biologic therapy, disease severity, and cardiovascular risk. This will help mitigate the potential confounding effects and enhance the accuracy of our findings. Here is an updated version: “Furthermore, the observed differences in intima-media thickness (IMT) between patients on biologic therapy and control groups may be influenced by the baseline disease severity and overall cardiovascular risk profile of the patients. Patients not receiving biologic therapy might have milder disease activity, potentially leading to a lower cardiovascular risk compared to those on biologic agents. This confounding factor should be carefully considered and addressed in future analyses to ensure an accurate assessment of the impact of biologic therapy on cardiovascular risk.” You may also refer to the manuscript (page 16-17, line 315-322) for more details, which have been highlighted in red. Once again, we thank you for your insightful comments, which have greatly improved the quality of our paper. We remain committed to further enhancing our research and addressing any additional concerns you may have. Thank you for considering our response. 3-Inflammatory Influence: chronic inflammation in RA can lead to alterations in lipid metabolism, including changes in lipid levels that may not align with the expected cardiovascular risk profile. Biologic therapy targeting inflammation may improve lipid profiles but may not always translate to a reduced cardiovascular risk due to the complex interplay between inflammation and lipid metabolism (lipid paradox). Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments.We have revised the limitations section in the manuscript to address the concern you raised regarding the inflammatory influence in rheumatoid arthritis and its impact on lipid metabolism. We acknowledge that chronic inflammation in RA can lead to alterations in lipid levels, which may not align with the expected cardiovascular risk profile. While biologic therapy targeting inflammation can potentially improve lipid profiles, it may not always translate to a reduced cardiovascular risk due to the complex interplay between inflammation and lipid metabolism, commonly known as the "lipid paradox." In the limitation section, we discuss the need to consider the influence of chronic inflammation on lipid metabolism and its implications for assessing cardiovascular risk in RA patients. We emphasize that although biologic therapy may positively impact lipid profiles, the overall cardiovascular risk reduction may be affected by factors related to the underlying inflammatory processes. We highlight the importance of further research to better understand this intricate relationship between inflammation, lipid metabolism, and cardiovascular risk in RA. Here is an updated version: “ It is also worth noting that chronic inflammation associated with RA can lead to alterations in lipid metabolism, resulting in changes in lipid levels that may not align with the expected cardiovascular risk profile. While biologic therapy targeting inflammation may improve lipid profiles, the complex interplay between inflammation and lipid metabolism, known as the "lipid paradox," may limit the translation of improved lipid profiles into reduced cardiovascular risk. Future studies should further investigate this interrelationship to better understand how inflammation affects lipid metabolism and its implications for assessing cardiovascular risk in RA.” You may also refer to the manuscript (page 17, line 322-329) for more details, which have been highlighted in red. Once again, we thank you for your insightful comments, which have greatly improved the quality of our paper. We remain committed to further enhancing our research and addressing any additional concerns you may have. Thank you for considering our response. 4-Long-Term Observations: Evaluating the impact of biologic therapy on cardiovascular risk factors over a longer period is essential to capture any potential changes or trends that may not be evident in a short-term study. Longitudinal studies can provide a more comprehensive understanding of the effects of biologic agents on cardiovascular health in RA patients. The lipid paradox highlights the importance of considering long-term cardiovascular risk assessment beyond lipid levels alone. While improvements in lipid profiles with biologic therapy are beneficial, the overall impact on cardiovascular outcomes may be influenced by a combination of traditional and non-traditional risk factors. Response to Reviewer: Thank you for your valuable feedback on our paper. We highly appreciate your suggestions and have made the necessary revisions in response to your comments. We have revised the limitations section in the manuscript to address the importance of long-term observations in evaluating the impact of biologic therapy on cardiovascular risk factors in patients with rheumatoid arthritis. We acknowledge that assessing these effects over a longer period is crucial to capture any potential changes or trends that may not be evident in short-term studies. Longitudinal studies can provide a more comprehensive understanding of the effects of biologic agents on cardiovascular health in RA patients. Furthermore, we discuss the significance of considering long-term cardiovascular risk assessment beyond lipid levels alone, as highlighted by you. We recognize the lipid paradox, which emphasizes the need to evaluate the overall impact of biologic therapy on cardiovascular outcomes considering a combination of both traditional and non-traditional risk factors. While improvements in lipid profiles resulting from biologic therapy are beneficial, other factors may influence the overall cardiovascular outcomes in RA patients. In the limitation section, we emphasize the necessity of conducting longitudinal studies to assess the long-term impact of biologic therapy on cardiovascular risk factors in RA. By considering a broader range of risk factors and incorporating data from extended observation periods, we can gain a more comprehensive understanding of the complex relationship between biologic therapy, cardiovascular risk factors, and outcomes in RA patients. Here is an updated version: “Lastly, the short-term nature of our study limits our ability to capture any potential long-term changes or trends related to the effects of biologic therapy on cardiovascular risk factors in RA patients. Longitudinal studies are essential for obtaining a more comprehensive understanding of the long-term impact of biologic agents on cardiovascular health in this population. Additionally, incorporating a broader range of traditional and non-traditional risk factors is crucial for a more holistic evaluation of cardiovascular outcomes in RA patients.” You may also refer to the manuscript (page 17, line 329-335) for more details, which have been highlighted in red. Once again, we thank you for your insightful comments, which have greatly improved the quality of our paper. We remain committed to further enhancing our research and addressing any additional concerns you may have. Thank you for considering our response. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0306513.r004
20 Jun 2024 Decision Letter - Antoine Fakhry AbdelMassih, Editor The impact of biologic agents on cardiovascular risk factors in patients with rheumatoid arthritis: A Meta analysis PONE-D-23-30031R2 Dear Dr. Yan, 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, Antoine Fakhry AbdelMassih 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 #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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #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 #2: Yes: Giuseppe Germanò ******** https://doi.org/10.1371/journal.pone.0306513.r005
Formally Accepted
20 Jul 2024 Acceptance Letter - Antoine Fakhry AbdelMassih, Editor PONE-D-23-30031R2 PLOS ONE Dear Dr. Yan, 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 Antoine Fakhry AbdelMassih Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0306513.r006

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