The Potential Utility of Salivary and Tear Proteomics to Discriminate Sjögren’s Disease from Non-Sjögren’s Sicca

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Please add more references to paper.

Comments for author File: Comments.pdf

Author Response

Summary of Changes:
We have carefully addressed the reviewers' comments and made substantial revisions to improve the manuscript's comprehensiveness and utility for future researchers. The major changes include an expanded discussion on the limitations of current studies, acknowledgment of the role of the Sjogren's International Collaborative Clinical Alliance (SICCA), a comprehensive analysis of the
potential of Cathepsin S (CatS) activity monitoring for staging and classifying the disease and CatS inhibition as a potential novel therapeutic. The changes made have been highlighted in yellow.

Response to Specific Reviewer Comments:

Role of Sjogren's International Collaborative Clinical Alliance (SICCA):

We have included a dedicated section in the “Classification criteria for SjD” subsection of our report, highlighting the pivotal role played by SICCA in collecting and providing samples from well-validated Sjogren's patients. Additionally, we emphasized the importance of the biorepository and data bank in subsequent studies, and the collaborations contribution to the ACR/EULAR criterion.

Shortcomings in Biomarker Research:

We have incorporated a more thorough analysis of various studies examined that we felt were not fully critiqued before- with a particular focus on highlighting the limitations that exist in the field of biomarker research. This includes addressing the issue of studies being primarily in the discovery phase, the lack of validation studies for discovered markers, and the impact of methodological differences and patient heterogeneity on the variability of reported biomarkers. Additionally, we emphasized the importance of considering sample sizes in biomarker studies.

Inclusion of cathepsin S as a biomarker and novel therapeutic:

We have revised the literature review section to include an extensive examination of relevant published reports, specifically highlighting the work on cathepsin S as a potential biomarker for Sjogren's disease. In reviewing the work done on CatS, we highlighted the literature’s progression from the use of animal models to more recent human trials using CatS inhibitors. Additionally, the utility of CatS inhibitors was explored, while emphasizing the need for further research. We believe that these revisions have strengthened the manuscript, providing a more thorough discussion and addressing the reviewers' insightful comments.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have successfully collected published information on saliva and tear proteins that can potentially be used to distinguish primary Sjögren's disease from non-Sjögren's sicca.  This is a nice review written in a clear manner.

The review focuses on how proteomic results can be used to discriminate (in particular primary) Sjögren's disease (pSS) from non-Sjögren's (nonSS) sicca using saliva and tear samples.  The authors present and discuss the various proteomic methods that are used and also list differentially expressed proteins identified that could be of relevance.  

I consider the topic very relevant in the field.  If we could find an easier solution for diagnosing Sjögren's disease than the existing one(s), that would be very helpful for both the patient and the clinician.  In addition, if we can use saliva and tear samples to follow nonSS patients over time to check if they are in the process of developing pSS that would be most useful.  When the patient finally gets a pSS diagnosis, she or he has most likely had the ailment for many years.  Also, identifying potential biomarker proteins in saliva and tears could help us in our search for the causes of this disease.

This review was very easy to follow, thus giving the reader updated information on the subject.  In addition, the angle where the authors have a focus on pSS vs nonSS and not just pSS vs. healthy controls is very interesting.

I don't have any suggestions for improvements regarding the methodology. To the best of my knowledge, I believe the conclusions are consistent with the evidence and that the authors properly addressed the main question posed. I believe the references are appropriate. My only comment here is that if the authors included a figure that summed up their findings, that would have been nice.

Author Response

We appreciate the kind words of the reviewer.