Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis

Jumpei Temmoku; Masayuki Miyata; Eiji Suzuki; Yuya Sumichika; Kenji Saito; Shuhei Yoshida; Haruki Matsumoto; Yuya Fujita; Naoki Matsuoka; Tomoyuki Asano; Shuzo Sato; Hiroshi Watanabe; Kiyoshi Migita

doi:10.1371/journal.pone.0274775

Peer Review History

Original SubmissionJune 17, 2022
14 Jul 2022 Decision Letter - Masataka Kuwana, Editor PONE-D-22-17384Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritisPLOS ONE Dear Dr. Migita, 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. Our reviewers found some interests in this manuscript, but also pointed out a number of critical issues that require improvement or even amendment. I ask the authors to fully respond to all comments made by the reviewers in the revised manuscript. Please submit your revised manuscript by Aug 28 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. 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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: No ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: I Don't Know 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: The authors compared the efficacy and safety between abatacept (ABT) and tocilizumab (TCZ) in elderly patients with rheumatoid arthritis (RA). The focusing point of this study is important and interesting in the era of ageing society. The authors concluded that drug retention rates were equivalent between ABT and TCZ, but the rates of discontinuation due to adverse event (AE) seemed to be lower with ABT than TCZ in elderly patients with RA. However, this study contains several serious concerns. major 1. The authors should make a strict distinction between the terms of “Elderly-onset RA” and “Elderly RA”. These two terms refer to different population of RA (i.e the former refers to RA diagnosed at age of 65 or older, and the latter refers to patients who are currently 65 years or older regardless of the age of RA onset.) and which population should be targeted depends on the aim of the study, however, the authors use these terms confusingly. Therefore, the authors should review the design of the study and definition of patients depending on the aim of this study and revise the manuscript. 2. The authors showed all AEs leading to the discontinuation of ABT or TCZ in Table 2, but some AEs (ILD, liver dysfunction, renal dysfunction, cardiovascular disease, hypothyroidism) are generally unlikely to be associated with ABT or TCZ administration. Thus, it is questionable whether those AEs are due to these drug administrations and discontinuation of ABT or TCZ were necessary. Thus, the author should add explanations about detailed situation of each AE. 3. The authors highlighted the risk of ILD in the TCZ group, but it is not well verified or described. First, it is necessary to describe whether the ILDs were new occurrences after the initiation of TCZ or exacerbations of already diagnosed. Also, effect of MTX should be considered. 4. Regarding efficacy, the authors only showed achieving rate of low disease activity according to CDAI and DAS28-CRP at 24 weeks. When I read the method (P7L2-5), it seems that this did not include remission. It is desirable to analyze it including remission to evaluate effectiveness of the treatments. The authors should also show the longitudinal changes of score of CDAI and DAS28-CRP, proportion of the category of each disease activity (remission, low-, moderate-, high-disease activity), each component of composite measures, if possible. 5. Please describe summary of rate of reasons for drug discontinuation in ”Drug overall retention rates” section in P11. 6. AEs should be listed as a whole AE and then divided into AEs that led to drug discontinuation and AEs that did not. 7. The author excluded patients with no history of csDMARDs in Figure 1. What is the reason for excluding these patients? 8. The authors should add more detail clinical characteristics at the time of initiation of ABT or TCZ in Table 1. Each component of composited measures (SJC, TJC, PtGA, PGA), concomitant use of csDMARDs other than MTX, proportion of chronic kidney disease (eGFR<60), dose of glucocorticoid, types of used bDMARDs should be added. 9. Table 1 showed 12 patients with ABT group and 25 patients with TCZ group have ever used prior bDMARDs use. Is that mean are all prior bDMARDs TNF inhibitors? If not, it is necessary to describe the person who used both ABT and TCZ during the period. Minor 1. Please correct abbreviations in the manuscript and figures. Abbreviations should be defined at first mention and used consistently thereafter, but it has not complied with frequently (ex. Adverse event (AE), low disease activity (LDA), abatacept (ABT, ABA) etc.). 2. “In the matched analysis,・・・・(P2L12, in abstract)” is not appropriate sentence because it may mislead that background were adjusted by using Propensity score matching etc. 3. In P8-9, check and correct the results for the rate of glucocorticoid use, as the results are opposite in the text and in Table 1. 4. In Table 3, the number of MTX users in the AE group is incorrect. Reviewer #2: This study compared efficacy and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis and showed comparable efficacy between both agents. On the other hand, the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA. Major comments The reviewer has a concern with the inclusion criteria. #1 This study enrolled elderly (age ≥65 years) patients, irrespective of onset age with a mean of 7 years. Onset age is one of the important factors to determine clinical features including therapeutic responses. The reviewer is afraid that the authors confuse clinical features of elderly RA patients with those of elderly onset RA (EORA) patients. For example, the author described “Elderly patients with RA seem to have a characteristic pattern with a more acute onset, systemic involvement, and worse functional outcomes” (P19, L14-15), but this report compared EORA patients with young onset RA patients. The reviewer suggests analyzing the data by stratifying onset age or focusing those in patients having onset age over 60 years old. #2 This study applied the 1987 ACR classification, but not 2010 ACR/EULAR, in spite of the study duration from 2014 to 2021. The reviewer is afraid that the inclusion criteria missed some of elderly onset RA patients. The reviewer suggests adding the data when the patients are enrolled based on the 2010 ACR/EULAR criteria. Minor comments #3 The reviewer suggests showing the administration routes and the standard dose of ABT and TCZ, because the standard dose of TCZ is different among countries. In addition, the interval of subcutaneous injection with TCZ can be shortened to one week. The reviewer is also interested in how often the interval is shortened because of the insufficient efficacy. #4 Table 1 shows 25.5% of patients treated with ABT and 31.3% of those with TCZ have received prior bDMARD The reviewer is afraid it is hard to interpret the data in patients who had a switch from ABT to TCZ or TCZ to ABT. To avoid the complexity, the reviewer suggests showing the data in patients who received ABT or TCZ as the first bDMARD. #5 spelling error “the ACPA possibilities” (P17, L15) => positivity ****** 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: Yes: Mitsuhiro Takeno ******** [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/. 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Revision 1
28 Aug 2022 Author Response Reviewer #1: The authors compared the efficacy and safety between abatacept (ABT) and tocilizumab (TCZ) in elderly patients with rheumatoid arthritis (RA). The focusing point of this study is important and interesting in the era of ageing society. The authors concluded that drug retention rates were equivalent between ABT and TCZ, but the rates of discontinuation due to adverse event (AE) seemed to be lower with ABT than TCZ in elderly patients with RA. However, this study contains several serious concerns. major 1. The authors should make a strict distinction between the terms of “ Elderly-onset RA” and “Elderly RA”. These two terms refer to different population of RA (i.e the former refers to RA diagnosed at age of 65 or older, and the latter refers to patients who are currently 65 years or older regardless of the age of RA onset.) and which population should be targeted depends on the aim of the study, however, the authors use these terms confusingly. Therefore, the authors should reviewthe design of the study and definition of patients depending on the aim of this study and revise the manuscript. We appreciate your critical comments. According to your important comments, we discriminate “Elderly RA” and EORA and corrected these descriptions in the revived manuscript. We also performed the same analysis using the selected elderly-onset RA patients as requested by Reviewer #2. We presented these new data in the revised manuscript. 2. The authors showed all AEs leading to the discontinuation of ABT or TCZ in Table 2, but some AEs (ILD, liver dysfunction, renal dysfunction, cardiovascular disease, hypothyroidism) are generally unlikely to be associated with ABT or TCZ administration. Thus, it is questionable whether those AEs are due to these drug administrations and discontinuation of ABT or TCZ were necessary. Thus, the author should add explanations about detailed situation of each AE. We appreciate your critical comments. According to your important comments, we described the detailed situations concerting the discontinuation of TCZ or ABT due to AEs in the revised manuscript. 3. The authors highlighted the risk of ILD in the TCZ group, but it is not well verified or described. First, it is necessary to describe whether the ILDs were new occurrences after the initiation of TCZ or exacerbations of already diagnosed. Also, effect of MTX should be considered. We appreciate your critical comments. According your comments, we described the detailed information concerning the occurrence of ILD and the effects of MTX in TCZ group in the revised manuscript. 4. Regarding efficacy, the authors only showed achieving rate of low disease activity according to CDAI and DAS28-CRP at 24 weeks. When I read the method (P7L2-5), it seems that this did not include remission. It is desirable to analyze it including remission to evaluate effectiveness of the treatments. The authors should also show the longitudinal changes of score of CDAI and DAS28-CRP, proportion of the category of each disease activity (remission, low-, moderate-, high-disease activity), each component of composite measures, if possible. We appreciate your critical comments. According to your precise comments, we presented these important data in the new Figure in the revised manuscript. 5. Please describe summary of rate of reasons for drug discontinuation in ”Drug overall retention rates” section in P11. According to your important comments, we described the rates of reasons for drug discontinuation in this section of the revised manuscript. 6. AEs should be listed as a whole AE and then divided into AEs that led to drug discontinuation and AEs that did not. According to your important comments, we listed whole AEs dividing into AEs leading to or not-leading to drug discontinuation in the revised Table 2. 7. The author excluded patients with no history of csDMARDs in Figure 1. What is the reason for excluding these patients? We appreciate your important comments. These patients were excluded from the analysis due to the following reasons: Since the pre-existing serious complications (progressing ILD, renal insufficiency, hematological disorders, advanced disability), which limit the use of MTX and may affect the clinical course in these patents. 8. The authors should add more detail clinical characteristics at the time of initiation of ABT or TCZ in Table 1. Each component of composited measures (SJC, TJC, PtGA, PGA), concomitant use of csDMARDs other than MTX, proportion of chronic kidney disease (eGFR<60), dose of glucocorticoid, types of used bDMARDs should be added. We appreciated your critical comments. According to your comments, we presented this important information in new Table 1 in the revised manuscript. 9. Table 1 showed 12 patients with ABT group and 25 patients with TCZ group have ever used prior bDMARDs use. Is that mean are all prior bDMARDs TNF inhibitors? If not, it is necessary to describe the person who used both ABT and TCZ during the period. We appreciate your important comments. According to your comment, we added these important information in revised Table1. Minor 1. Please correct abbreviations in the manuscript and figures. Abbreviations should be defined at first mention and used consistently thereafter, but it has not complied with frequently (ex. Adverse event (AE), low disease activity (LDA), abatacept (ABT, ABA) etc.). We corrected these abbreviations in the revised manuscript. 2. “In the matched analysis,・・・・(P2L12, in abstract)” is not appropriate sentence because it may mislead that background were adjusted by using Propensity score matching etc. We appreciate your critical comments. We deleted these sentences in the revised manuscript. 3. In P8-9, check and correct the results for the rate of glucocorticoid use, as the results are opposite in the text and in Table 1. We corrected these mistakes in the revised manuscript. 4. In Table 3, the number of MTX users in the AE group is incorrect. We corrected these mistakes in the revised manuscript. Reviewer #2: This study compared efficacy and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis and showed comparable efficacy between both agents. On the other hand, the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA. Major comments The reviewer has a concern with the inclusion criteria. #1 This study enrolled elderly (age ≥65 years) patients, irrespective of onset age with a mean of 7 years. Onset age is one of the important factors to determine clinical features including therapeutic responses. The reviewer is afraid that the authors confuse clinical features of elderly RA patients with those of elderly onset RA (EORA)patients. For example, the author described “Elderly patients with RA seem to have a characteristic pattern with a more acute onset, systemic involvement, and worse functional outcomes” (P19, L14-15), but this report compared EORA patients with young onset RA patients. The reviewer suggests analyzing the data by stratifying onset age or focusing those in patients having onset age over 60 years old. We appreciate your critical comments. According to your important comments, we analyzed the same analysis subjected RA patients with the onset age over 60 years old. We presented these new results in the revised manuscript. #2 This study applied the 1987 ACR classification, but not 2010 ACR/ EULAR, in spite of the study duration from 2014 to 2021. The reviewer is afraid that the inclusion criteria missed some of elderly onset RA patients. The reviewer suggests adding the data when the patients are enrolled based on the 2010 ACR/EULAR criteria. We appreciate your critical comments. According to your comments, we applied the 2010 ACR/EULAR classification criteria, in the revised manuscript. However, we could not expand the number of the elderly RA patients. Minor comments #3 The reviewer suggests showing the administration routes and the standard dose of ABT and TCZ, because the standard dose of TCZ is different among countries. In addition, the interval of subcutaneous injection with TCZ can be shortened to one week. The reviewer is also interested in how often the interval is shortened because of the insufficient efficacy. We appreciate your critical comments. According to your comments, the administration ruts of ABT and TCZ in the revised manuscript. #4 Table 1 shows 25.5% of patients treated with ABT and 31.3% of those with TCZ have received prior Bdmard. The reviewer is afraid it is hard to interpret the data in patients who had a switch from ABT to TCZ or TCZ to ABT. To avoid the complexity, the reviewer suggests showing the data in patients who received ABT or TCZ as the first bDMARD. We appreciated your critical comments. According to your important comments, we added the important information concerning the prior Biologics in the revised Table 1. #5 spelling error “the ACPA possibilities” (P17, L15) => positivity According to your precise comments, we corrected these mistakes in the revised manuscript. Attachments Attachment Submitted filename: Reviewer response new.docx https://doi.org/10.1371/journal.pone.0274775.r002
6 Sep 2022 Decision Letter - Masataka Kuwana, Editor Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis PONE-D-22-17384R1 Dear Dr. Migita, 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, 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors responded appropriately to reviewer's comments. Please correct the abbreviation of abatacept in Figure 7 and 10 (ABA→ABT). ****** 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: Satoshi Takanashi ******** https://doi.org/10.1371/journal.pone.0274775.r003
Formally Accepted
9 Sep 2022 Acceptance Letter - Masataka Kuwana, Editor PONE-D-22-17384R1 Comparing the effectiveness and safety of Abatacept and Tocilizumab in elderly patients with rheumatoid arthritis Dear Dr. Migita: 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 Prof. Masataka Kuwana Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0274775.r004

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