Ultrasonographic characteristics of major salivary glands in anti-centromere antibody-positive primary Sjögren’s syndrome

Hong Ki Min; Se-Hee Kim; Youngjae Park; Kyung-Ann Lee; Seung-Ki Kwok; Sang-Heon Lee; Hae-Rim Kim

doi:10.1371/journal.pone.0259519

Peer Review History

Original SubmissionJune 9, 2021
26 Jul 2021 Decision Letter - Masataka Kuwana, Editor PONE-D-21-19041 Ultrasonographic Characteristics of Major Salivary Glands in Anti-centromere Antibody-positive Primary Sjögren’s Syndrome PLOS ONE Dear Dr. Kim, 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 study, but also pointed out a number of criticisms, which are relevant and critical. All comments made by reviewers must be adequately answered in the revised version. Please submit your revised manuscript by Sep 09 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. 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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: No Reviewer #3: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: 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 Reviewer #3: 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 Reviewer #2: Yes Reviewer #3: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is an interesting article on US characteristics in major salivary gland in patients with ACA+primary Sjoegren's syndrome. ACA+pSS is considered as a subgroup in SS, but differences in the pathogenesis are still unknown. In this study, authors found some characteristic US findings in ACA+pSS. As authors stated in limitation, number of patients in ACA+group is not many and it may be difficult to judge if these findings are definitive or not. ACA+SS is relatively few in all pSS and moreover may be heterogeneous in the various characteristics. US findings usually largely depends on the disease stage. I am not sure whether this kind of characteristics can be caused from existence of a certain type of antibody. If authors want to emphasize current conclusion, more definitive data would be required. Significance of US characteristics should be more discussed. Reviewer #2: The authors investigated the salivary gland ultrasonography (SGUS) findings in primary Sjögren’s syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compared these with those in ACA-negative pSS patients. They conclude that ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component. I think the lower SGUS score in the ACA-positive patients might be due to the significantly older age and lower USFR of this group. To show the possible contribution of ACA to the phenotype of SS, SGUS findings should be compared between age and severity matched groups. What does the difference in hypoechoic area component mean? It should be discussed. As ultrasound is frequently considered the most operator-dependent imaging technique, intra-rater and inter-rater reliability is an important concern. Results of intra- and inter-reader reliability studies should be reported. Scanning procedure and ultrasound equipment should be written in more detail. Reviewer #3: In this manuscript, the authors presented the difference of salivary gland ultrasonography (SGUS) findings between anti-centromere antibody (ACA)-positive and negative primary Sjögren’s syndrome (pSS) patients. The total SGUS score was less severe in ACA-positive pSS patients, and this difference was emphasized in the hypoechoic area component of the SGUS scoring system. In multivariate regression analysis, being positive for unstimulated salivary flow rate (USFR), anti-Ro/SSA, and rheumatoid factor (RF) showed significant association with the SGUS score. Although these findings might be clinically important and meaningful, the authors should address following points. 1) The authors described, ‘Degrees of xerophthalmia and xerostomia, measured by the Schirmer I test and USFR, were comparable between the two groups’. However, in Table1, USFR was significantly lower in ACA-positive pSS patients than in ACA-negative pSS patients. 2) In Table1, the pathological findings of labial salivary glands biopsy should be compared. 3) In Table2, other 3 components of SGUS score, such as echogenicity, homogeneity, and clearness of salivary gland borders should be added. 4) The reason or possible mechanism why hypoechoic area was decreased in ACA-positive pSS patients should be discussed. ****** 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. 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0259519.r001
Revision 1
16 Sep 2021 Author Response Reviewer #1: This is an interesting article on US characteristics in major salivary gland in patients with ACA+primary Sjoegren's syndrome. ACA+pSS is considered as a subgroup in SS, but differences in the pathogenesis are still unknown. In this study, authors found some characteristic US findings in ACA+pSS. As authors stated in limitation, number of patients in ACA+group is not many and it may be difficult to judge if these findings are definitive or not. ACA+SS is relatively few in all pSS and moreover may be heterogeneous in the various characteristics. US findings usually largely depends on the disease stage. I am not sure whether this kind of characteristics can be caused from existence of a certain type of antibody. If authors want to emphasize current conclusion, more definitive data would be required. Significance of US characteristics should be more discussed. Answer : We agree with the referee’s comment. In previous studies, ACA-positive pSS showed several differences with ACA-negative pSS (older age, high prevalence of Raynaud phenomenon, lower prevalence of hypergammaglobulinemia and leukopenia). In present study, some baseline characteristics (age, and USFR) differ between ACA-positive and ACA-negative groups. We selected age- and USFR- matched ACA-negative group, then compared SGUS findings of ACA-positive and age-/USFR- matched ACA-negative groups (supplementary Table 1). These were also similar with original SGUS comparison between ACA-positive and ACA-negative groups. We also added the significance of SGUS in discussion section (line 237-250). Reviewer #2: The authors investigated the salivary gland ultrasonography (SGUS) findings in primary Sjögren’s syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compared these with those in ACA-negative pSS patients. They conclude that ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component. I think the lower SGUS score in the ACA-positive patients might be due to the significantly older age and lower USFR of this group. To show the possible contribution of ACA to the phenotype of SS, SGUS findings should be compared between age and severity matched groups. Answer : As reviewer’s comment, we compared the SGUS score of ACA positive pSS with age- and USFR- matched ACA negative pSS group. The main results (lower SGUS score, lower hypoechoic area score of ACA positive pSS) were similar with original results. These were supplied as supplementary Table 1. What does the difference in hypoechoic area component mean? It should be discussed. Answer : Although SGUS is useful tool for pSS diagnosis, however, little is known about the impact of hypoechoic area (SGUS score) in pSS prognosis. In one study, the hypoechoic area score significantly progressed in pSS patients ("Ultrasonographic Changes of Major Salivary Glands in Primary Sjögren's Syndrome." J Clin Med 2020; 9(3)). We added these on discussion section (line 242-243). As ultrasound is frequently considered the most operator-dependent imaging technique, intra-rater and inter-rater reliability is an important concern. Results of intra- and inter-reader reliability studies should be reported. Answer : We added intra- and inter-reader reliability on result section (line 198-200) Scanning procedure and ultrasound equipment should be written in more detail. Answer : We added detailed information of US scanning procedure and equipment (line 114-120, 142-145) Reviewer #3: In this manuscript, the authors presented the difference of salivary gland ultrasonography (SGUS) findings between anti-centromere antibody (ACA)-positive and negative primary Sjögren’s syndrome (pSS) patients. The total SGUS score was less severe in ACA-positive pSS patients, and this difference was emphasized in the hypoechoic area component of the SGUS scoring system. In multivariate regression analysis, being positive for unstimulated salivary flow rate (USFR), anti-Ro/SSA, and rheumatoid factor (RF) showed significant association with the SGUS score. Although these findings might be clinically important and meaningful, the authors should address following points. 1) The authors described, ‘Degrees of xerophthalmia and xerostomia, measured by the Schirmer I test and USFR, were comparable between the two groups’. However, in Table1, USFR was significantly lower in ACA-positive pSS patients than in ACA-negative pSS patients. Answer : We revised the sentence (line 182-184). 2) In Table1, the pathological findings of labial salivary glands biopsy should be compared. Answer : We agree that minor salivary gland biopsy is important in pSS diagnosis. However, most of the enrolled pSS patients in present study did not performed minor salivary gland biopsy. As biopsy is invasive procedure, in our rheumatology clinics, only ambiguous patients (highly suspicious for pSS, but not fulfilled the classification criteria for pSS) were consulted for minor salivary gland biopsy. 3) In Table2, other 3 components of SGUS score, such as echogenicity, homogeneity, and clearness of salivary gland borders should be added. Answer : We added information of echogenicity / homogeneity / clearness of salivary gland borders in Table 2. 4) The reason or possible mechanism why hypoechoic area was decreased in ACA-positive pSS patients should be discussed. Answer : Although SGUS is useful tool for pSS diagnosis, however, little is known about the role of hypoechoic area (SGUS score) in pSS. In addition, we originally expected that hyperechoic band may be increased in ACA-positive group, because ACA is usually found in systemic sclerosis which cause systemic fibrous change in various organs. We wrote this on discussion section (278-288). Suggesting possible mechanism at this stage may be cause overestimation of present study. We only found that the hypoechoic area score significantly progressed in pSS patients ("Ultrasonographic Changes of Major Salivary Glands in Primary Sjögren's Syndrome." J Clin Med 2020; 9(3)). We added these on discussion section (line 242-243). Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0259519.r002
21 Oct 2021 Decision Letter - Masataka Kuwana, Editor Ultrasonographic Characteristics of Major Salivary Glands in Anti-centromere Antibody-positive Primary Sjögren’s Syndrome PONE-D-21-19041R1 Dear Dr. Min, 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 Reviewer #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: 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 #3: 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 #3: 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: All comments have been addressed with new analysis and description. I do not have further comment on this article. Reviewer #3: Authors have successfully revised the manuscript according to reviewers’ comments. I have no further comments. ****** 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 #3: No https://doi.org/10.1371/journal.pone.0259519.r003
Formally Accepted
25 Oct 2021 Acceptance Letter - Masataka Kuwana, Editor PONE-D-21-19041R1 Ultrasonographic Characteristics of Major Salivary Glands in Anti-centromere Antibody-positive Primary Sjögren’s Syndrome Dear Dr. Min: 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.0259519.r004

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