Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease

Masaichi Kato; Ken Sugimoto; Kentaro Ikeya; Ryosuke Takano; Ai Matsuura; Takahiro Miyazu; Natsuki Ishida; Satoshi Tamura; Shinya Tani; Mihoko Yamade; Yasushi Hamaya; Moriya Iwaizumi; Satoshi Osawa; Takahisa Furuta; Hiroyuki Hanai

doi:10.1371/journal.pone.0254548

Peer Review History

Original SubmissionApril 21, 2021
24 May 2021 Decision Letter - Emiko Mizoguchi, Editor PONE-D-21-13113 Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease PLOS ONE Dear Professor Ken Sugimoto: 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. Your manuscript was assessed by two expert reviewers in this field, and substantive issues have been raised as listed below: Regarding the criticisms from both reviewers, you must fully address the issues in the revised results and discussion sections. In particular, a separated analysis between UC and CD (e.g., UC alone, CD alone) seems to be critical, as mentioned by Reviewer 1. In addition, you need to carefully mention the severity of UC as well as CD in the revised manuscript, as suggested by Reviewer 2. Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. Please submit your revised manuscript by Jun 21 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. 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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, Emiko Mizoguchi, M.D., Ph.D. Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 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 In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records/samples used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records/samples were accessed; c) the source of the medical records/samples analyzed in this work (e.g. hospital, institution or medical center name). 3. We note that you obtained consents from participants to take part in your retrospective study. In the Ethics Statement on the online submission form and the manuscript Methods , please clarify the context in which consent was obtained, and specify whether patients provided: 1) Consent to use their medical records/samples in research 2) Consent to undergo the procedure 3) Consent to take part in the study reported in this manuscript. If the ethics committee waived the need for additional informed consent, please state this. Thank you for your attention to these requests." 4. Please include the following information regarding your study design in your Methods: 1) Whether the use of adalimumab described in your study was implemented as standard-of-care at your hospital. 2) Whether assignment of patients to adalimumab was made at the discretion of the treating physician or for the purposes of research." 5. Please note that PLOS does not permit references to 'data not shown.' Authors should provide the relevant data within the manuscript, the Supporting Information files, or in a public repository. If the data are not a core part of the research study being presented, we ask that authors remove any references to these data. 6. Thank you for stating the following financial disclosure: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. At this time, please address the following queries: a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution. b) State what role the funders took in the study. 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In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 8. 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. 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: Although this is a retrospective, observational study, it reveals the interesting results that non-trough ADA levels may predict the outcomes of IBD patients. The research is presented in an intelligible fashion. Several points should be clarified. All through the study: This type of studies has been usually conducted for a separated disease, such as UC alone, or CD alone, not for combined IBD like this study. Please describe the advantages and disadvantages of this method. Line 275: I would like to know the reasons why AAA did not correlate with treatment continuity in this study, which is quite different from most prior reports. Due to AAA levels? combined evaluation of UC and CD? Please describe. Reviewer #2: Kato et al. examined the correlation between anti-ADA antibody level and ADA continuity or endoscopic remission in UC and CD patients. Moreover, the authors examined the correlation between ADA level and ADA continuity or endoscopic remission. They found that a higher serum ADA level, including non-trough level, was associated with both higher ADA continuity and endoscopic remission rate, but level of AAA did not. Thus, they concluded that ADA level, including trough level and non-trough level, is useful for predicting clinical outcome of UC and CD patients treated with ADA. There are some concerns about this study. 1. The authors evaluated the ADA level, including trough and non-trough. In each result, they should show the timing of measuring the ADA concentration (average, mean, etc.). 2. In Diamond study, combination of ADA and immunomodulator more effective on mucosal improvement that ADA monotherapy. They should show the endoscopic remission rate or endoscopic improvement rate in ADA monotherapy therapy and in ADA and IM combination therapy. 3. In general, the ADA continuity is associated with the improvement of clinical symptoms. Therefore, the ADA level may be associated with the improvement of clinical symptoms. They should show the correlation between the ADA level and the improvement of clinical symptoms. Moreover, they should show the correlation between the positive or negative of AAA and the improvement of clinical symptoms. 4. The timing of evaluation of AAA level is missing. 5. The severity of UC and CD patients in this study is missing. ****** 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.0254548.r001
Revision 1
18 Jun 2021 Author Response June 12, 2021 Subject: Revised Manuscript (PONE-D-21-13113) “Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease” Dear Prof. Emiko Mizoguchi: Thank you for providing us with the opportunity to revise our manuscript (PONE-D-21-13113) as well as for the reviewers’ helpful suggestions and comments. We have addressed the concerns, comments, and questions raised by reviewers 1 and 2 and present our detailed point-by-point responses below. Revisions in the manuscript are indicated in red. We hope that these revisions have improved the quality of our manuscript and have made it suitable for publication. We have uploaded the marked and unmarked copies of our manuscript, as requested. Response to Reviewers We are very grateful to the reviewers for investing their time and effort into reviewing our research. We answered each reviewers’ comment below. Reviewer #1: Although this is a retrospective, observational study, it reveals the interesting results that non-trough ADA levels may predict the outcomes of IBD patients. The research is presented in an intelligible fashion. Several points should be clarified. All through the study: This type of studies has been usually conducted for a separated disease, such as UC alone, or CD alone, not for combined IBD like this study. Please describe the advantages and disadvantages of this method. Authors’ response: We appreciate the reviewer's advice. In this study, the number of cases with UC or CD alone was small, so that we evaluated them as a combined IBD in all studies. The advantage of this method is that it increases the number of cases and improves statistical reliability. The downside is that we cannot show differences in the results between UC and CD. We also analyzed cases with UC or CD alone. In the CD cases, the ADA continuation rate was significantly higher in the high drug level group than in the low drug level group (p = 0.003), but in the UC cases, there was no significant difference between the two groups (p = 0.190). However, the absence of significant differences with respect to the UC cases may have been due to the low case number (19) as compared to that for the CD cases (33). We have added these results to the Results section (Page 11, Line 21) and added Supplementary Figure 1 A-B. Line 275: I would like to know the reasons why AAA did not correlate with treatment continuity in this study, which is quite different from most prior reports. Due to AAA levels? combined evaluation of UC and CD? Please describe. Authors’ response: We appreciate the reviewer's advice. The reasons why AAA levels were not related to treatment continuity include: 1. The sample size of our study was smaller than that of the Diamond study. 2. It is unclear whether AAA in this study is a neutralizing or a non-neutralizing antibody. Non-neutralizing antibodies may not affect the pharmacological action of anti-TNFα antibodies. In the assay of the Immundiagnostik AG (IDK monitor®) used in this study, it was difficult to distinguish neutralizing from non-neutralizing antibodies. Reviewer #2: Kato et al. examined the correlation between anti-ADA antibody level and ADA continuity or endoscopic remission in UC and CD patients. Moreover, the authors examined the correlation between ADA level and ADA continuity or endoscopic remission. They found that a higher serum ADA level, including non-trough level, was associated with both higher ADA continuity and endoscopic remission rate, but level of AAA did not. Thus, they concluded that ADA level, including trough level and non-trough level, is useful for predicting clinical outcome of UC and CD patients treated with ADA. Authors’ response: We are grateful to the reviewer for evaluating this study. We have reviewed and revised the manuscript according to the reviewer’s comments as follows. There are some concerns about this study. 1. The authors evaluated the ADA level, including trough and non-trough. In each result, they should show the timing of measuring the ADA concentration (average, mean, etc.). Authors’ response: We appreciate the reviewer’s precise advice. The timing of the ADA concentration measurement was 11 days after ADA administration (median, IQR 4-14). This important point in our research was added to the Results section (Page 12, Line 14). 2. In Diamond study, combination of ADA and immunomodulator more effective on mucosal improvement that ADA monotherapy. They should show the endoscopic remission rate or endoscopic improvement rate in ADA monotherapy therapy and in ADA and IM combination therapy. Authors’ response: We appreciate the reviewer's advice. In our study, contrary to the results of the Diamond study, there was no significant difference in the rate of mucosal healing between the ADA monotherapy group and the ADA and IM combination therapy group (p = 0.34, χ2 test). We added this result to the Discussion section (Page 16, Line 6). 3. In general, the ADA continuity is associated with the improvement of clinical symptoms. Therefore, the ADA level may be associated with the improvement of clinical symptoms. They should show the correlation between the ADA level and the improvement of clinical symptoms. Moreover, they should show the correlation between the positive or negative of AAA and the improvement of clinical symptoms. Authors’ response: Unfortunately, this was a retrospective study and lacked records of clinical evaluations, such as CAI and CDAI. It was, thus, not possible to correlate the ADA concentration and positive or negative AAA with clinical symptoms. We described this issue as a limitation in the Discussion section (Page 16, Line 20). We are very sorry that we cannot amend the manuscript based on the reviewer’s good suggestions. 4. The timing of evaluation of AAA level is missing. Authors’ response: We appreciate the reviewer's advice. In all cases, the AAA level was evaluated at the same timing as the ADA concentration measurement. We added this information to the Methods section (Page 6, Line 19). 5. The severity of UC and CD patients in this study is missing. Authors’ response: We appreciate the reviewer’s suggestions. As mentioned earlier, this study lacked records for clinical evaluations such as CAI and CDAI. The endoscopic severity of 44 cases evaluated endoscopically was MES 2 for UC (median, IQR 0-3) and SES-CD 9 for CD (median, IQR 0-25). We described the endoscopic severity in the Results section (Page 12, Line 14). We are most grateful to the reviewers' suggestions that helped to provide a more consistent and sounder interpretation of our results. Attachments Attachment Submitted filename: Response to Reviewers for PLOS ONE.docx https://doi.org/10.1371/journal.pone.0254548.r002
29 Jun 2021 Decision Letter - Emiko Mizoguchi, Editor Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease PONE-D-21-13113R1 Dear Professor Ken Sugimoto, 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, Emiko Mizoguchi, M.D., Ph.D. 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: (No Response) 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: No Reviewer #2: No https://doi.org/10.1371/journal.pone.0254548.r003
Formally Accepted
1 Jul 2021 Acceptance Letter - Emiko Mizoguchi, Editor PONE-D-21-13113R1 Therapeutic monitoring of adalimumab at non-trough levels in patients with inflammatory bowel disease Dear Dr. Sugimoto: 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 Dr. Emiko Mizoguchi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0254548.r004

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