Real-world Diagnostic Value of Integrating Oral and Ocular Dryness Testing in Suspected Sjögren’s Disease

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Law, Eman Seyal, Jesse Akaa, David O’Dea, Thao Nguyen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7011813/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Sjögren’s disease is an autoimmune condition requiring a systemic evaluation that integrates serologic, histopathologic, and glandular assessments for diagnosis. Current 2016 ACR/EULAR classification criteria includes anti-Ro serology, labial salivary gland biopsy (LSGB), and measures of oral/ocular dryness. However, oral/ocular dryness evaluations are rarely performed by rheumatologists during routine clinical care. Thus, the real-world diagnostic value of contemporaneous oral/ocular dryness testing remains poorly understood. Objective : To evaluate the incremental value of contemporaneous testing of oral/ocular dryness (Schirmer’s test and unstimulated whole salivary flow) in meeting classification criteria for subjects evaluated with suspected Sjögren’s disease. Methods : 73 subjects referred for suspected Sjögren’s disease were evaluated. Correlations between LSGB results and dryness tests, as well as LSGB results and anti-Ro serology, were evaluated. 31 subjects completed testing of oral/ocular dryness (Schirmer’s test and unstimulated whole salivary flow), anti-Ro serology, and LSGB. Diagnostic pathways were analyzed to assess the contributions of non-invasive tests (serologies and oral/ocular dryness tests) and invasive testing (LSGB) in meeting the threshold for classification criteria. Results : A significant association ( p -value = 0.0263) was observed between LSGB positivity and positive Schirmer’s testing. No significant association was observed between LSGB positivity and anti-Ro positivity, or between LSGB positivity and low unstimulated whole salivary flow. Among those classified, 81% (30/37) met classification independently of LSGB results. Of those who completed testing, 22 met classification criteria for Sjögren’s disease, among whom 68% (15/22) fulfilled criteria independently of LSGB results. Of these 15 subjects, 8 (53%) had negative LSGB with a focus score < 1. While a positive LSGB was mandatory to confirm classification for seronegative subjects, only 11.8% (2/17) of anti-Ro-positive subjects required LSGB for classification. Conclusion : Objective oral/ocular dryness testing, though rarely performed in routine rheumatologic care, is a valuable complement to serology and biopsy in diagnosing Sjögren’s disease. While LSGB is essential for confirming classification in anti-Ro-negative subjects, it adds only modest value to meeting classification criteria in anti-Ro-positive subjects relative to contemporaneous glandular dryness testing. These findings support integrating objective dryness measures into routine diagnostic workflows to reduce reliance on invasive biopsies and improve diagnostic accuracy, especially in seropositive populations. Rheumatology Sjögren’s disease dry eye dry mouth anti-Ro serology labial salivary gland biopsy Schirmer’s test unstimulated whole salivary flow sicca Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Sjögren’s disease (SjD) is a systemic autoimmune condition causing inflammation and destruction of exocrine glands, including the salivary and lacrimal glands, resulting in the development of xerostomia and xerophthalmia in patients. SjD also commonly results in extraglandular systemic manifestations, including pulmonary, renal, neurological, or musculoskeletal involvement. 1 Given its significant heterogeneity in manifestation and disease activity, diagnosing SjD remains clinically challenging, and the time elapsed between symptom development and diagnosis can span several years. 2 , 3 The 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for Sjögren’s disease were developed to standardize subject inclusion for research and clinical trials. These criteria incorporate anti-Ro serology, LSGB, and objective assessments of ocular dryness, such as Schirmer’s test (ST) or ocular staining, as well as oral dryness evaluated through unstimulated whole salivary flow (UWSF) rate. 4 However, objective assessments of ocular/oral dryness are seldom utilized in routine rheumatology practice, where clinicians often rely on subjective symptom reporting or defer glandular dryness evaluations due to time constraints or lack of familiarity with standardized protocols. This highlights a critical translational gap: while the ACR/EULAR criteria emphasize rigorous, quantifiable measures for research validity, their real-world adoption remains limited, potentially hindering accurate diagnosis and patient stratification in everyday clinical care. In fact, a 2017 population-based analysis revealed that in a cohort of 106 SjD subjects, while 97 (91.5%) subjects had undergone anti-Ro serologic testing, only 9 (8.5%) underwent ST and 1 (0.95%) underwent UWSF for assessment of objective ocular and oral dryness, respectively. 5 A 2023 study reports that despite its convenience, ST was performed in only 28% (20/72) of subjects, and UWSF was not performed at all. 6 Both studies report a reduction in the number of subjects meeting the threshold for classification criteria, not due to negative test results, but because objective dryness testing was often not performed. 5 , 6 Given this significant underutilization of ocular/oral dryness testing, its clinical value in the diagnosis and evaluation of SjD, especially in comparison to that of LSGB, remains poorly understood. This prompted us to analyze the various diagnostic pathways of subjects in our cohort to assess the contributions of non-invasive tests (serologies and ocular/oral dryness testing) and invasive testing (eg. LSGB) in meeting the threshold for the 2016 ACR/EULAR classification criteria. Our objective of this study was to investigate the incremental value of performing non-invasive ocular/oral dryness testing in meeting classification criteria for subjects evaluated with suspected Sjögren’s disease. 2 Materials and Methods 2.1 Study Participants Human subjects research was approved by the Institutional Review Board of Mass General Brigham (MGB). Written informed consent was obtained from all subjects for the collection of clinical data prior to enrollment in the research study. Between December 2023 to January 2025, 73 subjects presented to the Sjögren’s Disease rheumatology clinic at Massachusetts General Hospital for evaluation who provided their consent to partake in the study. Subjects underwent anti-Ro serology testing, LSGB, ST, and/or UWSF rate testing. 2.2 SjD Classification Criteria SjD status was defined using the 2016 ACR/EULAR classification criteria. Subjects were evaluated for four criteria components: anti-Ro antibody positivity and LSGB with focus score (FS) ≥1 foci/mm 2 , each scoring three points, as well as unanesthetized ST ≤5 mm/5 min and UWSF rate ≤0.1mL/min, each scoring one point. Ocular staining scores, scoring one point if positive, were not investigated in our study as we aimed to study contemporaneous dryness testing which can be performed within routine rheumatology clinic visits. Subjects presenting with clinical symptoms suggestive of SjD that had undergone sufficient or complete testing such that they scored ≥4 points (i.e. had at least positive serology and histopathology, positive serology and one abnormal dryness test, or positive histopathology and one abnormal dryness test) met classification criteria. Similarly, subjects that had undergone sufficient or complete testing such that they could not score ≥4 points (i.e. at least negative serology and histopathology, negative serology and normal ST and UWSF, or negative histopathology and normal ST and UWSF) did not meet SjD classification criteria. Classification status was not determined for any remaining subjects with insufficient testing. 2.3 Ocular/Oral Dryness Assessments To perform unanesthetized ST, a Schirmer's strip was gently inserted at the junction of the middle and outer third of the lower eyelid of the subject, ensuring it did not touch the cornea. The subject was then instructed to close their eyes gently for the duration of the test. After 5 minutes, the strips were removed, and the amount of wetting was recorded. A positive ST is considered ≤5 mm/5 min in at least one eye. To perform UWSF rate testing, the subject was asked to swallow any residual saliva in their mouth prior to starting and to not speak or make significant facial movements during the test. Saliva was collected into a pre-weighed sterile container as it pooled in the floor of the subject’s mouth. After 5 minutes, the collection was halted, the subject was permitted to swallow, and the collected saliva was weighed to calculate the flow rate in mL/min. A positive UWSF is considered ≤0.1mL/min. 2.4 Clinical and Serologic Assessments We obtained the following clinical and serologic data of our subjects either at the time of evaluation or through review of the medical charts: age, anti-Ro positivity, LSGB FS, antinuclear antibody (ANA) titer, white blood cells (WBC), hemoglobin (HGB), platelets (PLT), absolute neutrophils, absolute lymphocytes, sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin G (IgG), complement 3 (C3), complement 4 (C4), rheumatoid factor (RF), and free kappa light chain to free lambda light chain ratio (free K:L). 2.5 Statistical Analysis We analyzed contemporaneous glandular dryness testing in our cohort utilizing descriptive and correlative statistics. For categorical data, we performed Chi-squared or Fisher’s exact tests to determine significance in associations between variables. We analyzed the correlation between quantitative LSGB focus scores and contemporaneous dryness test (ST and UWSF) results using Spearman’s correlation. We established p-value <0.05 to be statistically significant (*p<0.05, **<0.01, ***p<0.001, ****p<0.0001). Statistical analyses were performed using Prism 10.4.0 (GraphPad Software, La Jolla, CA). Diagnostic pathways of subjects with completed serologic, histopathologic, and glandular dryness testing were visualized via a Sankey plot by organizing test data into source-target pairs with corresponding flow magnitudes. The plot was generated using SankeyMATIC software, with nodes representing outcomes of classification criteria components and link thickness made proportional to the number of subjects in each category. 3 Results Among all subjects with complete serologic, histopathologic, and oral/ocular dryness assessments, 22 met the 2016 ACR/EULAR SjD classification criteria threshold while 9 did not. Among all subjects with incomplete assessments which were sufficient to determine classification status, 17 met classification criteria while 6 did not. Our contemporaneous dryness assessments provided us the opportunity to categorize subjects who met SjD classification criteria as FS-independent or FS-dependent. We defined FS-independent subjects as those who obtained the minimum of 4 points to meet the threshold for ACR/EULAR SjD classification criteria regardless of LSGB FS result. FS-independent subjects must be anti-Ro-positive (three points) with at least one positive oral/ocular dryness test (one to two points). Conversely, FS-dependent subjects require a LSGB FS ≥1 (three points) and are either seropositive (three points) with negative oral/ocular dryness testing or are seronegative with at least one positive oral/ocular dryness test (one to two points). Among the 22 subjects who met SjD classification criteria with comprehensive testing, we identified 15 to be FS-independent. Among the 17 subjects who met SjD classification criteria without comprehensive testing, we identified 15 to be FS-independent (Figure 1). Among all subjects evaluated that did and did not meet the threshold for classification criteria, we analyzed the percentage of subjects with abnormal serologic results. We found significant associations between meeting classification criteria and exhibiting positive anti-Ro antibodies ( p -value < 0.0001), positive LSGB FS ( p -value = 0.0003), positive ST ( p -value = 0.0030), elevated IgG ( p -value = 0.0342), positive RF ( p -value = 0.0003), and elevated free K:L ( p -value = 0.0016), respectively (Table 1). We tested for the presence of any association between positive LSGB and abnormalities in other components of the classification criteria; namely anti-Ro serology, ST, and UWSF. We observed a statistically significant association between LSGB FS positivity and ST positivity ( p- value = 0.0263). Among subjects with a positive LSGB FS, 50% (9/18) had positive ST, whereas among subjects with a negative LSGB FS, 15.8% (3/19) had positive ST. We did not observe a statistically significant association between LSGB FS positivity and either anti-Ro positivity ( p -value = 0.0897) or UWSF rate positivity ( p -value = 0.6693) (Figure 2). Given the significant association between abnormal LSGB and ST, we then examined whether a correlation existed between the degree of inflammation observed in the LSGB FS and the degree of objective ocular and oral dryness observed in ST and UWSF. We observed that a higher FS correlates with lower ST ( p -value = 0.0023), but, interestingly, we did not observe a significant correlation between LSGB FS and UWSF ( p -value = 0.0712) (Figure 3). A total of 30/37 (81%) subjects who met SjD classification criteria were FS-independent. We observed significant associations between being FS-independent and having anti-Ro antibodies (by definition) ( p -value < 0.0001), positive ST ( p- value = 0.0298), and elevated IgG ( p -value = 0.0213) (Table 2). We next decided to specifically analyze the 22 subjects that met SjD classification and underwent complete serologic, histopathologic, and oral/ocular dryness assessments to understand the incremental value of ST and UWSF in meeting classification criteria. Among those that met classification, 15/22 (68.2%) subjects were FS-independent and 7/22 subjects (31.8%) were FS-dependent. Among the 15 FS-independent subjects who met classification criteria, all (100%) were anti-Ro-positive (by definition), only 7/15 (46.7%) had positive LSGB, 8/15 (53.3%) had positive ST, and 12/15 (80%) had positive UWSF rates. Among the 7 FS-dependent subjects who met criteria, only 2/7 (28.6%) were anti-Ro-positive, all subjects (100%) had positive LSGB results (by definition), 1/7 (14.3%) had positive ST, and 5/7 (71.4%) had positive UWSF rates. Remarkably, anti-Ro seropositivity paired with oral/ocular dryness testing sufficed for classification in most seropositive cases as only 2/17 (11.8%) seropositive SjD cases were FS-dependent (Figure 4). We visualized serologic, histopathologic, and oral/ocular dryness testing results in a Sankey plot, highlighting FS-independent pathways according to ST positivity or negativity. We observed that 6/8 (75%) FS-independent subjects with positive ST had positive FS (blue pathway), and 6/7 (86%) FS-independent subjects with negative ST had a negative FS (purple pathway) (Figure 5a). Thus, 12/15 (80%) FS-independent subjects exhibited concordance between LSGB and ST results, while only 1/7 (14.3%) FS-dependent subject exhibited concordance. We did not observe such a pattern with UWSF (Figure 5b). 4 Discussion The clinical heterogeneity of SjD, encompassing both glandular and extraglandular manifestations, complicates diagnosis, particularly in patients with atypical presentations. While multidisciplinary evaluation is often necessary—especially in seronegative cases requiring histopathologic confirmation via LSGB)—our data demonstrate that LSGB provides only modest incremental diagnostic value in seropositive SjD. Most seropositive patients met classification criteria through objective oral/ocular dryness measures, independent of LSGB results. This underscores the utility of integrating these non-invasive tests into routine workflows to reduce biopsy dependence. A key limitation of LSGB lies in its technical variability, which complicates interpretation. Challenges include inconsistent glandular sampling, ambiguous reporting of non-specific chronic sialadenitis, and discrepancies in FS calculation due to ductal atrophy, fibrosis, or inter-observer variability. 7 These issues are particularly problematic in late-stage SjD, where fibrotic or atrophied glands may yield falsely low FS values, risking misclassification. In contrast, contemporaneous ST and UWSF—central to the 2016 ACR/EULAR criteria—provide standardized, functional assessments of dryness that circumvent these histopathologic pitfalls. While classification criteria are not synonymous with clinical diagnosis, 8 they offer a structured framework to address diagnostic complexity in SjD. For instance, objective dryness may not be evident in SjD in earlier stages of disease, though may be able to still capture subclinical dysfunction. 9 Objective dryness metrics not only quantify disease severity but also bridge the well-documented discordance between subjective symptoms and objective findings. 10 For instance, our cohort included patients with profound ocular damage who lacked subjective dryness complaints, echoing prior reports of asymptomatic disease. Furthermore, 53% of FS-independent subjects in our study would have failed classification criteria without ST or UWSF testing, highlighting the indispensability of these tests in seropositive patients with equivocal or negative biopsies. Notably, ST exhibited stronger correlations with LSGB positivity that were not evident with UWSF. The inverse relationship between ST values and FS, along with 80% concordance between positive ST and LSGB, suggests ST may serve as a surrogate biomarker for LSGB in select cases. Conversely, the fact that low UWSF did not have an association with abnormal FS aligns with mixed findings in prior studies, 11-13 suggesting its diagnostic performance may require refinement. Nevertheless, UWSF remains valuable for objectively capturing oral dryness severity. Our methodology preserved LSGB accessibility for eligible patients but prioritized evaluating the added diagnostic utility of dryness testing. Only 11.8% of seropositive subjects required LSGB for classification, reinforcing that most seropositive SjD cases can be diagnosed without biopsy when ST and UWSF are utilized. Despite barriers such as the non-billable status of dryness testing in the U.S.—a likely contributor to its underuse—our findings advocate for its integration into clinical practice. These tests provide timely, actionable insights that enhance diagnostic accuracy while reducing reliance on invasive biopsies, particularly in seropositive populations. This analysis has several limitations. First, the study’s relatively small cohort size may restrict the generalizability of findings, particularly given the heterogeneity inherent to SjD phenotypes. Second, the absence of ocular staining scores—a component of the ACR/EULAR criteria—likely influenced the observed reliance on ST and UWSF rates as surrogate dryness measures. This omission precludes definitive conclusions about whether a fully non-invasive diagnostic pathway (e.g., serology, ocular staining, UWSF, and ST) could complement LSGB in borderline cases. For example, the 2/17 anti-Ro-positive subjects who required LSGB for classification despite negative ST/UWSF results might still meet criteria non-invasively if ocular staining data were available, underscoring the need for standardized multimodal dryness assessments. Prospective studies with larger cohorts should prioritize integrating ocular staining scores to validate the robustness of non-invasive classification pathways. Additionally, longitudinal evaluation of oral/ocular dryness metrics could clarify their temporal stability and prognostic utility, particularly in seropositive patients with fluctuating symptom severity. 5 Conclusion Given the underutilization of dryness testing in real-world rheumatologic evaluations for suspected SjD, we aimed to assess the added value of non-invasive ocular and oral dryness tests relative to invasive LSGB. Our findings show that approximately 81% of subjects meeting SjD classification criteria did so based solely on non-invasive testing (anti-Ro positivity and ST and/or UWSF). A significant correlation was observed between abnormal ST and LSGB FS ≥ 1, as well as among FS-independent subjects, though this pattern was not evident with LSGB and anti-Ro serology or UWSF. These results suggest that contemporaneous dryness testing should be integrated into routine rheumatologic care, as many suspected SjD cases meet classification criteria independent of LSGB histopathology. Abbreviations SjD Sjögren’s Disease ST Schirmer’s testing UWSF Unstimulated whole salivary flow LSGB Labial salivary gland biopsy FS Focus score ACR/EULAR American College of Rheumatology/European League Against Rheumatism ANA Antinuclear Antibody WBC White blood cells HGB Hemoglobin PLT Platelets ESR Sedimentation rate CRP C-reactive protein IgG Immunoglobulin G C3 Complement 3 C4 Complement 4 RF Rheumatoid Factor Free K:L Free kappa light chain to free lambda light chain ratio Declarations Conflict of Interest BML has provided consultancy or expert advice in the area of Sjögren’s disease to Novartis and has undertaken clinical trials for Horizon. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions ES: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Data Curation, Writing — Original Draft, Writing — Review and Editing, Visualization. JA: Investigation, Data Curation, Writing — Review and Editing. DO: Investigation, Data Curation, Writing — Review and Editing. TN: Investigation, Data Curation, Writing — Review and Editing. RWR: Investigation, Resources, Writing — Review and Editing. BML: Conceptualization, Methodology, Validation, Formal Analysis, Investigation, Resources, Data Curation, Writing — Original Draft, Writing — Review and Editing, Visualization, Supervision, Project Administration, Funding Acquisition. Funding This work was supported by the National Institutes of Health (5T32HL116275-12). References Mariette, X. and Criswell, L.A. 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Arthur, Shen, H., Cook, R.J., Bailey, D., R. John McComb, Rutka, J.A., Slomovic, A.R. and Caffery, B. (2011). Whole stimulated salivary flow: Correlation with the pathology of inflammation and damage in minor salivary gland biopsy specimens from patients with primary Sjögren’s syndrome but not patients with sicca. Arthritis & Rheumatism , 63(7), pp.2014–2020. doi:https://doi.org/10.1002/art.30295. Tables Table 1. Demographic, clinical, and serologic data of subjects. Meet Classification Criteria N=39 n/N (%) Do Not Meet Classification Criteria N=15 n/N (%) p -value Mean Age 57 54 Female 38/39 (97.4) 15/15 (100) 1.0000 ANA ≥ 1:320 18/33 (56.3) 6/15 (40) 0.3502 † Positive Anti-Ro 34/39 (87.2) 1/15 (6.7) <0.0001**** LSGB FS ≥ 1 18/26 (69.2) 0/9 (0) 0.0003*** ST ≤ 5mm/5 min 20/38 (52.6) 1/14 (7.1) 0.0030** † UWSF ≤ 0.1 mL/min 25/31 (80.6) 7/12 (58.3) 0.2407 WBC < 4.5 K/uL 11/38 (28.9) 3/14 (21.4) 0.7325 HGB < 12.0 g/dL 15/38 (39.5) 4/14 (28.6) 0.4690 † PLT < 150 K/uL 5/38 (13.2) 2/14 (14.4) 1.0000 Absolute Neutrophils <1.8 K/uL 3/38 (7.9) 2/14 (14.4) 0.6024 Absolute Lymphocytes 19 mm/h 11/29 (37.9) 4/15 (26.7) 0.5204 Positive CRP > 8.0 mg/L 11/33 (33.3) 4/15 (26.7) 0.6442 † Total IgG > 1295 mg/dL 16/35 (45.7) 1/12 (8.3) 0.0342* C3 < 81 mg/dL 1/33 (3) 2/15 (13.3) 0.2266 C4 14 IU/mL 18/33 (54.5) 0/15 (0) 0.0003*** † Free K:L > 1.7 16/34 (47) 0/14 (0) 0.0016** Percentages of subjects with abnormal results are categorized based on meeting or not meeting the threshold for ACR/EULAR SjD classification criteria. Unless indicated (†: Chi-squared test), P -values listed were calculated by Fisher’s test. Significant p -values comparing percentages are labeled as follows: *p<0.05, p**<0.01, ***p<0.001, ****p<0.0001. ANA: antinuclear antibody, WBC: white blood cells, HGB: hemoglobin, PLT: platelets, ESR: sedimentation rate, CRP: C-reactive protein, IgG: immunoglobulin G, C3: complement 3, C4: complement 4, RF: rheumatoid factor, Free K:L: free kappa light chain to free lambda light chain ratio Table 2. Demographic, clinical, and serologic data of FS-independent and FS-dependent subjects that meet SjD classification. FS-Independent N=30 n/total (%) FS-Dependent N=7 n/total (%) p -value Mean Age 58 56 Female 30/30 (100) 6/7 (85.7) 0.1892 ANA ≥ 1:320 14/24 (58.3) 3/7 (42.9) 0.6705 Positive Anti-Ro 30/30 (100) 2/7 (28.6) <0.0001**** LSGB FS ≥ 1 9/17 (52.9) 7/7 (100) 0.0538 ST ≤ 5mm/5 min 19/29 (73.1) 1/7 (14.3) 0.0298* UWSF ≤ 0.1 mL/min 20/24 (83.3) 5/7 (71.4) 0.5959 WBC < 4.5 K/uL 8/29 (27.6) 2/7 (28.6) 1.0000 HGB < 12.0 g/dL 12/29 (41.4) 1/7 (14.3) 0.2092 PLT < 150 K/uL 4/29 (13.8) 1/7 (14.3) 1.0000 Absolute Neutrophils <1.8 K/uL 3/29 (10.3) 0/7 (0) 1.0000 Absolute Lymphocytes 19 mm/h 9/22 (40.9) 2/6 (33.3) 1.0000 Positive CRP > 8.0 mg/L 9/25 (36) 2/7 (28.6) 1.0000 Total IgG > 1295 mg/dL 15/27 (55.5) 0/6 (0) 0.0213* C3 < 81 mg/dL 1/24 (4.2) 0/7 (0) 1.0000 C4 14 IU/mL 14/24 (58.3) 3/7 (42.9) 0.6705 Free K:L > 1.7 5/26 (19.2) 0/6 (0) 0.5546 Percentages of subjects with abnormal results are listed. P -values listed were calculated by Fisher’s test; significant p -values comparing percentages are labeled as follows: *p<0.05, p**<0.01, ***p<0.001, ****p<0.0001. ANA: antinuclear antibody, WBC: white blood cells, HGB: hemoglobin, PLT: platelets, ESR: sedimentation rate, CRP: C-reactive protein, IgG: immunoglobulin G, C3: complement 3, C4: complement 4, RF: rheumatoid factor, Free K:L: free kappa light chain to free lambda light chain ratio Additional Declarations The authors declare potential competing interests as follows: BML has provided consultancy or expert advice in the area of Sjögren’s disease to Novartis and has undertaken clinical trials for Horizon. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7011813","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":478559575,"identity":"30a379f4-5644-4d70-9d91-f3330ace3aca","order_by":0,"name":"Brandon M. Law","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7klEQVRIiWNgGAWjYBACA3Yg8QHM5IEKHWBgkMCrhZmBgXEGWAMpWph5SNJizsz8TNp2h429PQPvwc+VbXb5fAeYD97mwaPFspnNTDr3TFpiDwNfsuTZtmTLmQfYkq3xaTE4zGB2O7ftcALQYQaSDWeYDQwO8JhJ49fC/u22Zdthe6AW458NZ+qBWvi/EdDCY3abse0wYw8Dj5lkQ8VhkC1seLVYNvOU/+wF+QWo17Kh4riB5GE2Y8s5eLSYs7dvNvgJDDH29h7jmw0G1QZ8x5sf3niDRwsYMDYACWYYjxm3QjQto2AUjIJRMApwAQCJRUTTtS4IFwAAAABJRU5ErkJggg==","orcid":"","institution":"Massachusetts General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Brandon","middleName":"M.","lastName":"Law","suffix":""},{"id":478559576,"identity":"cca6fe0d-e1b6-400b-b488-ae36aaafbf88","order_by":1,"name":"Eman Seyal","email":"","orcid":"","institution":"Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Eman","middleName":"","lastName":"Seyal","suffix":""},{"id":478559577,"identity":"7cd07999-0cdd-4570-8239-e289d2be8e41","order_by":2,"name":"Jesse Akaa","email":"","orcid":"","institution":"Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jesse","middleName":"","lastName":"Akaa","suffix":""},{"id":478559578,"identity":"cd44564b-4867-4139-a397-668b8c585af1","order_by":3,"name":"David O’Dea","email":"","orcid":"","institution":"Massachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"O’Dea","suffix":""},{"id":478559579,"identity":"cf7d626a-1c76-4737-81af-8222ee3de97d","order_by":4,"name":"Thao Nguyen","email":"","orcid":"","institution":"Massachusetts General HospitalMassachusetts General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Thao","middleName":"","lastName":"Nguyen","suffix":""},{"id":478559580,"identity":"a71de30e-2750-492e-aa72-2ad57f366778","order_by":5,"name":"Rahmatullah W. Rahmati","email":"","orcid":"","institution":"Massachusetts Eye \u0026 Ear","correspondingAuthor":false,"prefix":"","firstName":"Rahmatullah","middleName":"W.","lastName":"Rahmati","suffix":""}],"badges":[],"createdAt":"2025-06-30 14:52:02","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7011813/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7011813/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85942243,"identity":"291bfa4a-39a6-4b73-a761-8519f4f7f8b9","added_by":"auto","created_at":"2025-07-03 11:54:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":55381,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/9448c0d100242d7a04066971.png"},{"id":85942244,"identity":"79d4b7d7-da0a-412a-9567-ddd33fc535ef","added_by":"auto","created_at":"2025-07-03 11:54:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41195,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/94853fbb25a67bae9137e78b.png"},{"id":85942247,"identity":"db0b590c-3393-41ec-84c0-295828f1a6b9","added_by":"auto","created_at":"2025-07-03 11:54:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":50168,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/037ca5edb9ca67235b0cf809.png"},{"id":85942253,"identity":"70b430a9-dcd2-4cd8-8cc1-d304d5c0fd2c","added_by":"auto","created_at":"2025-07-03 11:54:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":44197,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/a8f99535742dbc858fe53fe6.png"},{"id":85942250,"identity":"e0246a41-4eb7-425f-96d1-17caa640dd29","added_by":"auto","created_at":"2025-07-03 11:54:03","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":110203,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig5.png","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/322c4cb98cffecbe91f1b4f4.png"},{"id":85943432,"identity":"b1c64e85-9bc1-4257-ad46-15e6b97f54aa","added_by":"auto","created_at":"2025-07-03 12:10:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":982010,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7011813/v1/b6c75f6d-ee4e-402f-8e9b-70abdb9460c2.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: BML has provided consultancy or expert advice in the area of Sjögren’s disease to Novartis and has undertaken clinical trials for Horizon. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest","formattedTitle":"\u003cp\u003eReal-world Diagnostic Value of Integrating Oral and Ocular Dryness Testing in Suspected Sjögren’s Disease\u003c/p\u003e","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eSj\u0026ouml;gren\u0026rsquo;s disease (SjD) is a systemic autoimmune condition causing inflammation and destruction of exocrine glands, including the salivary and lacrimal glands, resulting in the development of xerostomia and xerophthalmia in patients. SjD also commonly results in extraglandular systemic manifestations, including pulmonary, renal, neurological, or musculoskeletal involvement.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Given its significant heterogeneity in manifestation and disease activity, diagnosing SjD remains clinically challenging, and the time elapsed between symptom development and diagnosis can span several years.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe 2016 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for Sj\u0026ouml;gren\u0026rsquo;s disease were developed to standardize subject inclusion for research and clinical trials. These criteria incorporate anti-Ro serology, LSGB, and objective assessments of ocular dryness, such as Schirmer\u0026rsquo;s test (ST) or ocular staining, as well as oral dryness evaluated through unstimulated whole salivary flow (UWSF) rate.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e However, objective assessments of ocular/oral dryness are seldom utilized in routine rheumatology practice, where clinicians often rely on subjective symptom reporting or defer glandular dryness evaluations due to time constraints or lack of familiarity with standardized protocols. This highlights a critical translational gap: while the ACR/EULAR criteria emphasize rigorous, quantifiable measures for research validity, their real-world adoption remains limited, potentially hindering accurate diagnosis and patient stratification in everyday clinical care. In fact, a 2017 population-based analysis revealed that in a cohort of 106 SjD subjects, while 97 (91.5%) subjects had undergone anti-Ro serologic testing, only 9 (8.5%) underwent ST and 1 (0.95%) underwent UWSF for assessment of objective ocular and oral dryness, respectively.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e A 2023 study reports that despite its convenience, ST was performed in only 28% (20/72) of subjects, and UWSF was not performed at all.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Both studies report a reduction in the number of subjects meeting the threshold for classification criteria, not due to negative test results, but because objective dryness testing was often not performed.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Given this significant underutilization of ocular/oral dryness testing, its clinical value in the diagnosis and evaluation of SjD, especially in comparison to that of LSGB, remains poorly understood. This prompted us to analyze the various diagnostic pathways of subjects in our cohort to assess the contributions of non-invasive tests (serologies and ocular/oral dryness testing) and invasive testing (eg. LSGB) in meeting the threshold for the 2016 ACR/EULAR classification criteria. Our objective of this study was to investigate the incremental value of performing non-invasive ocular/oral dryness testing in meeting classification criteria for subjects evaluated with suspected Sj\u0026ouml;gren\u0026rsquo;s disease.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003ch2\u003e\u003cem\u003e2.1 Study Participants\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eHuman subjects research was approved by the Institutional Review Board of Mass General Brigham (MGB). Written informed consent was obtained from all subjects for the collection of clinical data prior to enrollment in the research study. Between December 2023 to January 2025, 73 subjects presented to the Sj\u0026ouml;gren\u0026rsquo;s Disease rheumatology clinic at Massachusetts General Hospital for evaluation who provided their consent to partake in the study. Subjects underwent anti-Ro serology testing, LSGB, ST, and/or UWSF rate testing.\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e2.2 SjD Classification Criteria\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eSjD status was defined using the 2016 ACR/EULAR classification criteria.\u003csup\u003e\u0026nbsp;\u003c/sup\u003eSubjects were evaluated for four criteria components: anti-Ro antibody positivity and LSGB with focus score (FS) \u0026ge;1 foci/mm\u003csup\u003e2\u003c/sup\u003e, each scoring three points, as well as unanesthetized ST \u0026le;5 mm/5 min and UWSF rate \u0026le;0.1mL/min, each scoring one point. Ocular staining scores, scoring one point if positive, were not investigated in our study as we aimed to study contemporaneous dryness testing which can be performed within routine rheumatology clinic visits. Subjects presenting with clinical symptoms suggestive of SjD that had undergone sufficient or complete testing such that they scored \u0026ge;4 points (i.e. had at least positive serology and histopathology, positive serology and one abnormal dryness test, or positive histopathology and one abnormal dryness test) met classification criteria. Similarly, subjects that had undergone sufficient or complete testing such that they could not score \u0026ge;4 points (i.e. at least negative serology and histopathology, negative serology and normal ST and UWSF, or negative histopathology and normal ST and UWSF) did not meet SjD classification criteria. Classification status was not determined for any remaining subjects with insufficient testing.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e2.3 Ocular/Oral Dryness Assessments\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eTo perform unanesthetized ST, a Schirmer\u0026apos;s strip was gently inserted at the junction of the middle and outer third of the lower eyelid of the subject, ensuring it did not touch the cornea. The subject was then instructed to close their eyes gently for the duration of the test. After 5 minutes, the strips were removed, and the amount of wetting was recorded. A positive ST is considered \u0026le;5 mm/5 min in at least one eye. To perform UWSF rate testing, the subject was asked to swallow any residual saliva in their mouth prior to starting and to not speak or make significant facial movements during the test. Saliva was collected into a pre-weighed sterile container as it pooled in the floor of the subject\u0026rsquo;s mouth. After 5 minutes, the collection was halted, the subject was permitted to swallow, and the collected saliva was weighed to calculate the flow rate in mL/min. A positive UWSF is considered \u0026le;0.1mL/min.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e2.4 Clinical and Serologic Assessments\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eWe obtained the following clinical and serologic data of our subjects either at the time of evaluation or through review of the medical charts: age, anti-Ro positivity, LSGB FS, antinuclear antibody (ANA) titer, white blood cells (WBC), hemoglobin (HGB), platelets (PLT), absolute neutrophils, absolute lymphocytes, sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin G (IgG), complement 3 (C3), complement 4 (C4), rheumatoid factor (RF), and free kappa light chain to free lambda light chain ratio (free K:L).\u003c/p\u003e\n\u003ch2\u003e\u003cem\u003e2.5 Statistical Analysis\u0026nbsp;\u003c/em\u003e\u003c/h2\u003e\n\u003cp\u003eWe analyzed contemporaneous glandular dryness testing in our cohort utilizing descriptive and correlative statistics. For categorical data, we performed Chi-squared or Fisher\u0026rsquo;s exact tests to determine significance in associations between variables. We analyzed the correlation between quantitative LSGB focus scores and contemporaneous dryness test (ST and UWSF) results using Spearman\u0026rsquo;s correlation. We established p-value \u0026lt;0.05 to be statistically significant (*p\u0026lt;0.05, **\u0026lt;0.01, ***p\u0026lt;0.001, ****p\u0026lt;0.0001). Statistical analyses were performed using Prism 10.4.0 (GraphPad Software, La Jolla, CA). Diagnostic pathways of subjects with completed serologic, histopathologic, and glandular dryness testing were visualized via a Sankey plot by organizing test data into source-target pairs with corresponding flow magnitudes. The plot was generated using SankeyMATIC software, with nodes representing outcomes of classification criteria components and link thickness made proportional to the number of subjects in each category.\u0026nbsp;\u003c/p\u003e"},{"header":"3 Results","content":"\u003cp\u003eAmong all subjects with complete serologic, histopathologic, and oral/ocular dryness assessments, 22 met the 2016 ACR/EULAR SjD classification criteria threshold while 9 did not. Among all subjects with incomplete assessments which were sufficient to determine classification status, 17 met classification criteria while 6 did not. Our contemporaneous dryness assessments provided us the opportunity to categorize subjects who met SjD classification criteria as FS-independent or FS-dependent. We defined FS-independent subjects as those who obtained the minimum of 4 points to meet the threshold for ACR/EULAR SjD classification criteria regardless of LSGB FS result. FS-independent subjects must be anti-Ro-positive (three points) with at least one positive oral/ocular dryness test (one to two points). Conversely, FS-dependent subjects require a LSGB FS \u0026ge;1 (three points) and are either seropositive (three points) with negative oral/ocular dryness testing or are seronegative with at least one positive oral/ocular dryness test (one to two points). Among the 22 subjects who met SjD classification criteria with comprehensive testing, we identified 15 to be FS-independent. Among the 17 subjects who met SjD classification criteria without comprehensive testing, we identified 15 to be FS-independent (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAmong all subjects evaluated that did and did not meet the threshold for classification criteria, we analyzed the percentage of subjects with abnormal serologic results. We found significant associations between meeting classification criteria and exhibiting positive anti-Ro antibodies (\u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.0001), positive LSGB FS (\u003cem\u003ep\u003c/em\u003e-value = 0.0003), positive ST (\u003cem\u003ep\u003c/em\u003e-value = 0.0030), elevated IgG (\u003cem\u003ep\u003c/em\u003e-value = 0.0342), positive RF (\u003cem\u003ep\u003c/em\u003e-value = 0.0003), and elevated free K:L (\u003cem\u003ep\u003c/em\u003e-value = 0.0016), respectively (Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe tested for the presence of any association between positive LSGB and abnormalities in other components of the classification criteria; namely anti-Ro serology, ST, and UWSF. We observed a statistically significant association between LSGB FS positivity and ST positivity (\u003cem\u003ep-\u003c/em\u003evalue = 0.0263). Among subjects with a positive LSGB FS, 50% (9/18) had positive ST, whereas among subjects with a negative LSGB FS, 15.8% (3/19) had positive ST. We did not observe a statistically significant association between LSGB FS positivity and either anti-Ro positivity (\u003cem\u003ep\u003c/em\u003e-value = 0.0897) or UWSF rate positivity (\u003cem\u003ep\u003c/em\u003e-value = 0.6693) (Figure 2).\u003c/p\u003e\n\u003cp\u003eGiven the significant association between abnormal LSGB and ST, we then examined whether a correlation existed between the degree of inflammation observed in the LSGB FS and the degree of objective ocular and oral dryness observed in ST and UWSF. We observed that a higher FS correlates with lower ST (\u003cem\u003ep\u003c/em\u003e-value = 0.0023), but, interestingly, we did not observe a significant correlation between LSGB FS and UWSF (\u003cem\u003ep\u003c/em\u003e-value = 0.0712) (Figure 3).\u003c/p\u003e\n\u003cp\u003eA total of 30/37 (81%) subjects who met SjD classification criteria were FS-independent. We observed significant associations between being FS-independent and having anti-Ro antibodies (by definition) (\u003cem\u003ep\u003c/em\u003e-value \u0026lt; 0.0001), positive ST (\u003cem\u003ep-\u003c/em\u003evalue = 0.0298), and elevated IgG (\u003cem\u003ep\u003c/em\u003e-value = 0.0213) (Table 2).\u003c/p\u003e\n\u003cp\u003eWe next decided to specifically analyze the 22 subjects that met SjD classification and underwent complete serologic, histopathologic, and oral/ocular dryness assessments to understand the incremental value of ST and UWSF in meeting classification criteria. Among those that met classification, 15/22 (68.2%) subjects were FS-independent and 7/22 subjects (31.8%) were FS-dependent. Among the 15 FS-independent subjects who met classification criteria, all (100%) were anti-Ro-positive (by definition), only 7/15 (46.7%) had positive LSGB, 8/15 (53.3%) had positive ST, and 12/15 (80%) had positive UWSF rates. Among the 7 FS-dependent subjects who met criteria, only 2/7 (28.6%) were anti-Ro-positive, all subjects (100%) had positive LSGB results (by definition), 1/7 (14.3%) had positive ST, and 5/7 (71.4%) had positive UWSF rates. Remarkably, anti-Ro seropositivity paired with oral/ocular dryness testing sufficed for classification in most seropositive cases as only 2/17 (11.8%) seropositive SjD cases were FS-dependent (Figure 4).\u003c/p\u003e\n\u003cp\u003eWe visualized serologic, histopathologic, and oral/ocular dryness testing results in a Sankey plot, highlighting FS-independent pathways according to ST positivity or negativity. We observed that 6/8 (75%) FS-independent subjects with positive ST had positive FS (blue pathway), and 6/7 (86%) FS-independent subjects with negative ST had a negative FS (purple pathway) (Figure 5a). Thus, 12/15 (80%) FS-independent subjects exhibited concordance between LSGB and ST results, while only 1/7 (14.3%) FS-dependent subject exhibited concordance. We did not observe such a pattern with UWSF (Figure 5b). \u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe clinical heterogeneity of SjD, encompassing both glandular and extraglandular manifestations, complicates diagnosis, particularly in patients with atypical presentations. While multidisciplinary evaluation is often necessary\u0026mdash;especially in seronegative cases requiring histopathologic confirmation via LSGB)\u0026mdash;our data demonstrate that LSGB provides only modest incremental diagnostic value in seropositive SjD. Most seropositive patients met classification criteria through objective oral/ocular dryness measures, independent of LSGB results. This underscores the utility of integrating these non-invasive tests into routine workflows to reduce biopsy dependence.\u003c/p\u003e\n\u003cp\u003eA key limitation of LSGB lies in its technical variability, which complicates interpretation. Challenges include inconsistent glandular sampling, ambiguous reporting of non-specific chronic sialadenitis, and discrepancies in FS calculation due to ductal atrophy, fibrosis, or inter-observer variability.\u003csup\u003e7\u003c/sup\u003e These issues are particularly problematic in late-stage SjD, where fibrotic or atrophied glands may yield falsely low FS values, risking misclassification. In contrast, contemporaneous ST and UWSF\u0026mdash;central to the 2016 ACR/EULAR criteria\u0026mdash;provide standardized, functional assessments of dryness that circumvent these histopathologic pitfalls.\u003c/p\u003e\n\u003cp\u003eWhile classification criteria are not synonymous with clinical diagnosis,\u003csup\u003e8\u003c/sup\u003e they offer a structured framework to address diagnostic complexity in SjD. For instance, objective dryness may not be evident in SjD in earlier stages of disease, though may be able to still capture subclinical dysfunction.\u003csup\u003e9\u003c/sup\u003e Objective dryness metrics not only quantify disease severity but also bridge the well-documented discordance between subjective symptoms and objective findings.\u003csup\u003e10\u003c/sup\u003e For instance, our cohort included patients with profound ocular damage who lacked subjective dryness complaints, echoing prior reports of asymptomatic disease. Furthermore, 53% of FS-independent subjects in our study would have failed classification criteria without ST or UWSF testing, highlighting the indispensability of these tests in seropositive patients with equivocal or negative biopsies.\u003c/p\u003e\n\u003cp\u003eNotably, ST exhibited stronger correlations with LSGB positivity that were not evident with UWSF. The inverse relationship between ST values and FS, along with 80% concordance between positive ST and LSGB, suggests ST may serve as a surrogate biomarker for LSGB in select cases. Conversely, the fact that low UWSF did not have an association with abnormal FS aligns with mixed findings in prior studies,\u003csup\u003e11-13\u003c/sup\u003e suggesting its diagnostic performance may require refinement. Nevertheless, UWSF remains valuable for objectively capturing oral dryness severity.\u003c/p\u003e\n\u003cp\u003eOur methodology preserved LSGB accessibility for eligible patients but prioritized evaluating the added diagnostic utility of dryness testing. Only 11.8% of seropositive subjects required LSGB for classification, reinforcing that most seropositive SjD cases can be diagnosed without biopsy when ST and UWSF are utilized. Despite barriers such as the non-billable status of dryness testing in the U.S.\u0026mdash;a likely contributor to its underuse\u0026mdash;our findings advocate for its integration into clinical practice. These tests provide timely, actionable insights that enhance diagnostic accuracy while reducing reliance on invasive biopsies, particularly in seropositive populations.\u003c/p\u003e\n\u003cp\u003eThis analysis has several limitations. First, the study\u0026rsquo;s relatively small cohort size may restrict the generalizability of findings, particularly given the heterogeneity inherent to SjD phenotypes. Second, the absence of ocular staining scores\u0026mdash;a component of the ACR/EULAR criteria\u0026mdash;likely influenced the observed reliance on ST and UWSF rates as surrogate dryness measures. This omission precludes definitive conclusions about whether a fully non-invasive diagnostic pathway (e.g., serology, ocular staining, UWSF, and ST) could complement LSGB in borderline cases. For example, the 2/17 anti-Ro-positive subjects who required LSGB for classification despite negative ST/UWSF results might still meet criteria non-invasively if ocular staining data were available, underscoring the need for standardized multimodal dryness assessments. Prospective studies with larger cohorts should prioritize integrating ocular staining scores to validate the robustness of non-invasive classification pathways. Additionally, longitudinal evaluation of oral/ocular dryness metrics could clarify their temporal stability and prognostic utility, particularly in seropositive patients with fluctuating symptom severity.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eGiven the underutilization of dryness testing in real-world rheumatologic evaluations for suspected SjD, we aimed to assess the added value of non-invasive ocular and oral dryness tests relative to invasive LSGB. Our findings show that approximately 81% of subjects meeting SjD classification criteria did so based solely on non-invasive testing (anti-Ro positivity and ST and/or UWSF). A significant correlation was observed between abnormal ST and LSGB FS \u0026ge; 1, as well as among FS-independent subjects, though this pattern was not evident with LSGB and anti-Ro serology or UWSF. These results suggest that contemporaneous dryness testing should be integrated into routine rheumatologic care, as many suspected SjD cases meet classification criteria independent of LSGB histopathology.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSjD Sj\u0026ouml;gren\u0026rsquo;s Disease\u003c/p\u003e\n\u003cp\u003eST Schirmer\u0026rsquo;s testing\u003c/p\u003e\n\u003cp\u003eUWSF Unstimulated whole salivary flow\u003c/p\u003e\n\u003cp\u003eLSGB Labial salivary gland biopsy\u003c/p\u003e\n\u003cp\u003eFS Focus score\u003c/p\u003e\n\u003cp\u003eACR/EULAR American College of Rheumatology/European League Against Rheumatism\u003c/p\u003e\n\u003cp\u003eANA Antinuclear Antibody\u003c/p\u003e\n\u003cp\u003eWBC White blood cells\u003c/p\u003e\n\u003cp\u003eHGB Hemoglobin\u003c/p\u003e\n\u003cp\u003ePLT Platelets\u003c/p\u003e\n\u003cp\u003eESR Sedimentation rate\u003c/p\u003e\n\u003cp\u003eCRP C-reactive protein\u003c/p\u003e\n\u003cp\u003eIgG Immunoglobulin G \u003c/p\u003e\n\u003cp\u003eC3 Complement 3\u003c/p\u003e\n\u003cp\u003eC4 Complement 4\u003c/p\u003e\n\u003cp\u003eRF Rheumatoid Factor\u003c/p\u003e\n\u003cp\u003eFree K:L Free kappa light chain to free lambda light chain ratio \u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBML has provided consultancy or expert advice in the area of Sjögren\u0026rsquo;s disease to Novartis and has undertaken clinical trials for Horizon. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eES: Conceptualization, Methodology, Software, Validation, Formal Analysis, Investigation, Data Curation, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eOriginal Draft, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing, Visualization. JA: Investigation, Data Curation, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing. DO: Investigation, Data Curation, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing. TN: Investigation, Data Curation, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing. RWR: Investigation, Resources, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing. BML: Conceptualization, Methodology, Validation, Formal Analysis, Investigation, Resources, Data Curation, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eOriginal Draft, Writing\u003cstrong\u003e\u0026mdash;\u003c/strong\u003eReview and Editing, Visualization, Supervision, Project Administration, Funding Acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Institutes of Health (5T32HL116275-12). \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMariette, X. and Criswell, L.A. (2018). Primary Sj\u0026ouml;gren\u0026rsquo;s Syndrome. \u003cem\u003eNew England Journal of Medicine\u003c/em\u003e, 378(10), pp.931\u0026ndash;939. doi:https://doi.org/10.1056/nejmcp1702514.\u003c/li\u003e\n \u003cli\u003eKuryata, O., Lysunets, T., Karavanska, I. and Semenov, V. (2019). Duration till diagnosis and clinical profile of Sj\u0026ouml;gren\u0026rsquo;s syndrome: Data from real clinical practice in a single-center cohort. \u003cem\u003eThe Egyptian Rheumatologist\u003c/em\u003e, [online] 42(1), pp.41\u0026ndash;46. doi:https://doi.org/10.1016/j.ejr.2019.05.003.\u003c/li\u003e\n \u003cli\u003eHuang, Y.-T., Lu, T.-H., Chou, P.-L. and Weng, M.-Y. (2021). Diagnostic Delay in Patients with Primary Sj\u0026ouml;gren\u0026rsquo;s Syndrome: A Population-Based Cohort Study in Taiwan. \u003cem\u003eHealthcare\u003c/em\u003e, 9(3), p.363. doi:https://doi.org/10.3390/healthcare9030363.\u003c/li\u003e\n \u003cli\u003eShiboski, C.H., Shiboski, S.C., Seror, R., Criswell, L.A., Labetoulle, M., Lietman, T.M., Rasmussen, A., Scofield, H., Vitali, C., Bowman, S.J., Mariette, X., Heidenreich, A.M., Lanfranchi, H., Vollenweider, C., Schi\u0026oslash;dt, M., Devauchelle, V., Gottenberg, J.E., Saraux, A., Pincemin, M. and D\u0026ouml;rner, T. (2016b). 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sj\u0026ouml;gren\u0026rsquo;s Syndrome: A Consensus and Data‐Driven Methodology Involving Three International Patient Cohorts. \u003cem\u003eArthritis \u0026amp; Rheumatology\u003c/em\u003e, 69(1), pp.35\u0026ndash;45. doi:https://doi.org/10.1002/art.39859.\u003c/li\u003e\n \u003cli\u003eMaciel, G., Crowson, C.S., Matteson, E.L. and Cornec, D. (2017b). Prevalence of Primary Sj\u0026ouml;gren\u0026rsquo;s Syndrome in a US Population-Based Cohort. \u003cem\u003eArthritis Care \u0026amp; Research\u003c/em\u003e, [online] 69(10), pp.1612\u0026ndash;1616. doi:https://doi.org/10.1002/acr.23173.\u003c/li\u003e\n \u003cli\u003eGiovelli, R.A., Santos, M.C., Serrano, \u0026Eacute;.V. and Valim, V. (2015b). Clinical characteristics and biopsy accuracy in suspected cases of Sj\u0026ouml;gren\u0026rsquo;s syndrome referred to labial salivary gland biopsy. \u003cem\u003eBMC Musculoskeletal Disorders\u003c/em\u003e, 16(1). doi:https://doi.org/10.1186/s12891-015-0482-9.\u003c/li\u003e\n \u003cli\u003eFisher, B.A., Jonsson, R., Daniels, T., Bombardieri, M., Brown, R.M., Morgan, P., Bombardieri, S., Ng, W.-F., Tzioufas, A.G., Vitali, C., Shirlaw, P., Haacke, E., Costa, S., Bootsma, H., Devauchelle-Pensec, V., Radstake, T.R., Mariette, X., Richards, A., Stack, R. and Bowman, S.J. (2016b). Standardisation of labial salivary gland histopathology in clinical trials in primary Sj\u0026ouml;gren\u0026rsquo;s syndrome. \u003cem\u003eAnnals of the Rheumatic Diseases\u003c/em\u003e, 76(7), pp.1161\u0026ndash;1168. doi:https://doi.org/10.1136/annrheumdis-2016-210448.\u003c/li\u003e\n \u003cli\u003eJune, R.R. and Aggarwal, R. (2014). The use and abuse of diagnostic/classification criteria. \u003cem\u003eBest Practice \u0026amp; Research Clinical Rheumatology\u003c/em\u003e, 28(6), pp.921\u0026ndash;934. doi:https://doi.org/10.1016/j.berh.2015.04.004.\u003c/li\u003e\n \u003cli\u003ePijpe, J., Kalk, W.W.I., Bootsma, H., Spijkervet, F.K.L., Kallenberg, C.G.M. and Vissink, A. (2006). Progression of salivary gland dysfunction in patients with Sjogren\u0026rsquo;s syndrome. \u003cem\u003eAnnals of the Rheumatic Diseases\u003c/em\u003e, 66(1), pp.107\u0026ndash;112. doi:https://doi.org/10.1136/ard.2006.052647.\u003c/li\u003e\n \u003cli\u003eRipsman, D.A. and Bookman, A.A.M. (2021b). Correlation Between Subjective and 360 Objective Severity of Oral and Ocular Dryness in Primary Sj\u0026ouml;gren Syndrome. The Journal of 361 rheumatology, [online] 48(8), pp.1290\u0026ndash;1294. doi:https://doi.org/10.3899/jrheum.200907.\u003c/li\u003e\n \u003cli\u003eSebastian, A., Patryk Woytala, Madej, M., Krzysztof Proc, Katarzyna Czesak-Woytala, Sebastian, M., Zub, K. and Wiland, P. (2021). Is it possible to not perform salivary gland biopsy in targeted patients according to unstimulated salivary flow results in patients with suspected Sj\u0026ouml;gren\u0026rsquo;s syndrome? \u003cem\u003eRheumatology International\u003c/em\u003e, 41(6), pp.1125\u0026ndash;1131. doi:https://doi.org/10.1007/s00296-021-04840-4.\u003c/li\u003e\n \u003cli\u003eLacombe, V., Lacout, C., Lozac\u0026rsquo;h, P., Ghali, A., Gury, A., Lavigne, C. and Urbanski, G. (2020). Unstimulated whole saliva flow for diagnosis of primary Sj\u0026ouml;gren\u0026rsquo;s syndrome: time to revisit the threshold? \u003cem\u003eArthritis research \u0026amp; therapy\u003c/em\u003e, [online] 22(1), p.38. doi:https://doi.org/10.1186/s13075-020-2132-3.\u003c/li\u003e\n \u003cli\u003eArthur, Shen, H., Cook, R.J., Bailey, D., R. John McComb, Rutka, J.A., Slomovic, A.R. and Caffery, B. (2011). Whole stimulated salivary flow: Correlation with the pathology of inflammation and damage in minor salivary gland biopsy specimens from patients with primary Sj\u0026ouml;gren\u0026rsquo;s syndrome but not patients with sicca. \u003cem\u003eArthritis \u0026amp; Rheumatism\u003c/em\u003e, 63(7), pp.2014\u0026ndash;2020. doi:https://doi.org/10.1002/art.30295.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eDemographic, clinical, and serologic data of subjects.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"698\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 234px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 168px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeet\u0026nbsp;\u003cbr\u003e\u0026nbsp;Classification Criteria\u003cbr\u003e\u0026nbsp;N=39\u003cbr\u003e\u0026nbsp;n/N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 181px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDo Not Meet\u003cbr\u003e\u0026nbsp;Classification Criteria\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=15\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en/N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e38/39 (97.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e15/15 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eANA\u0026nbsp;\u0026ge;\u0026nbsp;1:320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e18/33 (56.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e6/15\u0026nbsp;(40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.3502\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003ePositive Anti-Ro\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e34/39 (87.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/15 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001****\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eLSGB\u0026nbsp;FS\u0026nbsp;\u0026ge; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e18/26 (69.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/9 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0003***\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eST\u0026nbsp;\u0026le;\u0026nbsp;5mm/5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e20/38 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/14 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0030**\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eUWSF\u0026nbsp;\u0026le;\u0026nbsp;0.1 mL/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e25/31 (80.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e7/12 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.2407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eWBC \u0026lt; 4.5 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e11/38 (28.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e3/14 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.7325\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eHGB \u0026lt; 12.0 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e15/38 (39.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e4/14 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.4690\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003ePLT \u0026lt; 150 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e5/38 (13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/14 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eAbsolute Neutrophils \u0026lt;1.8 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e3/38 (7.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/14 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.6024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eAbsolute Lymphocytes \u0026lt;1.8 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e10/38 (26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/14 (14.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.4753\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003ePositive ESR \u0026gt; 19 mm/h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e11/29 (37.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e4/15 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.5204\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003ePositive CRP \u0026gt; 8.0 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e11/33 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e4/15 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.6442\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eTotal IgG \u0026gt; 1295 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e16/35 (45.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/12 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0342*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eC3 \u0026lt; 81 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1/33 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/15 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.2266\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eC4 \u0026lt; 12 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e1/35 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/15 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003ePositive RF \u0026gt; 14 IU/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e18/33 (54.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/15 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0003***\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eFree K:L \u0026gt; 1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e16/34 (47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/14 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0016**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003ePercentages of subjects with abnormal results are categorized based on meeting or not meeting the threshold for ACR/EULAR SjD classification criteria. Unless indicated (\u0026dagger;: Chi-squared test), \u003cem\u003eP\u003c/em\u003e-values listed were calculated by Fisher\u0026rsquo;s test. Significant\u0026nbsp;\u003cem\u003ep\u003c/em\u003e-values comparing percentages are labeled as follows: *p\u0026lt;0.05, p**\u0026lt;0.01, ***p\u0026lt;0.001, ****p\u0026lt;0.0001.\u0026nbsp;\u003cbr\u003e\u0026nbsp;ANA: antinuclear antibody, WBC: white blood cells, HGB: hemoglobin, PLT: platelets, ESR: sedimentation rate, CRP: C-reactive protein, IgG: immunoglobulin G, C3: complement 3, C4: complement 4, RF: rheumatoid factor, Free K:L: free kappa light chain to free lambda light chain ratio\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eDemographic, clinical, and serologic data of FS-independent and FS-dependent subjects that meet SjD classification.\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"698\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 228px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 174px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFS-Independent\u003cbr\u003e\u0026nbsp;N=30\u003cbr\u003e\u0026nbsp;n/total (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 181px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFS-Dependent\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=7\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en/total (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eMean Age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e30/30 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e6/7 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.1892\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eANA\u0026nbsp;\u0026ge;\u0026nbsp;1:320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e14/24 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e3/7 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.6705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003ePositive Anti-Ro\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e30/30 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/7 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e\u0026lt;0.0001****\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eLSGB\u0026nbsp;FS\u0026nbsp;\u0026ge; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e9/17 (52.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e7/7 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0538\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eST\u0026nbsp;\u0026le;\u0026nbsp;5mm/5 min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e19/29 (73.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/7 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0298*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eUWSF\u0026nbsp;\u0026le;\u0026nbsp;0.1 mL/min\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e20/24 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e5/7 (71.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.5959\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eWBC \u0026lt; 4.5 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e8/29\u0026nbsp;(27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/7 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eHGB \u0026lt; 12.0 g/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e12/29 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/7 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.2092\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003ePLT \u0026lt; 150 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e4/29 (13.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e1/7 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eAbsolute Neutrophils \u0026lt;1.8 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e3/29 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/7 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eAbsolute Lymphocytes \u0026lt;1.8 K/uL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e8/29 (27.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/7 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003ePositive ESR \u0026gt; 19 mm/h\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e9/22 (40.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/6 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003ePositive CRP \u0026gt; 8.0 mg/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e9/25 (36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e2/7 (28.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eTotal IgG \u0026gt; 1295 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e15/27 (55.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/6 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.0213*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eC3 \u0026lt; 81 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1/24 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/7 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eC4 \u0026lt; 12 mg/dL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e1/26 (3.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/7 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e1.0000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003ePositive RF \u0026gt; 14 IU/mL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e14/24 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e3/7 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.6705\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 222px;\"\u003e\n \u003cp\u003eFree K:L \u0026gt; 1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e5/26 (19.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 181px;\"\u003e\n \u003cp\u003e0/6 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e0.5546\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003ePercentages of subjects with abnormal results are listed. \u003cem\u003eP\u003c/em\u003e-values listed were calculated by Fisher\u0026rsquo;s test; significant\u0026nbsp;\u003cem\u003ep\u003c/em\u003e-values comparing percentages are labeled as follows: *p\u0026lt;0.05, p**\u0026lt;0.01, ***p\u0026lt;0.001, ****p\u0026lt;0.0001.\u0026nbsp;\u003cbr\u003e\u0026nbsp;ANA: antinuclear antibody, WBC: white blood cells, HGB: hemoglobin, PLT: platelets, ESR: sedimentation rate, CRP: C-reactive protein, IgG: immunoglobulin G, C3: complement 3, C4: complement 4, RF: rheumatoid factor, Free K:L: free kappa light chain to free lambda light chain ratio\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"735f221e-dac7-4ba9-b981-b742b586ebc5","identifier":"10.13039/100000002","name":"National Institutes of Health","awardNumber":"5T32HL116275-12","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Massachusetts General Hospital","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Sjögren’s disease, dry eye, dry mouth, anti-Ro serology, labial salivary gland biopsy, Schirmer’s test, unstimulated whole salivary flow, sicca","lastPublishedDoi":"10.21203/rs.3.rs-7011813/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7011813/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Sjögren’s disease is an autoimmune condition requiring a systemic evaluation that integrates serologic, histopathologic, and glandular assessments for diagnosis. Current 2016 ACR/EULAR classification criteria includes anti-Ro serology, labial salivary gland biopsy (LSGB), and measures of oral/ocular dryness. However, oral/ocular dryness evaluations are rarely performed by rheumatologists during routine clinical care. Thus, the real-world diagnostic value of contemporaneous oral/ocular dryness testing remains poorly understood.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: To evaluate the incremental value of contemporaneous testing of oral/ocular dryness (Schirmer’s test and unstimulated whole salivary flow) in meeting classification criteria for subjects evaluated with suspected Sjögren’s disease.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: 73 subjects referred for suspected Sjögren’s disease were evaluated. Correlations between LSGB results and dryness tests, as well as LSGB results and anti-Ro serology, were evaluated.\u003cstrong\u003e \u003c/strong\u003e31 subjects completed testing of oral/ocular dryness (Schirmer’s test and unstimulated whole salivary flow), anti-Ro serology, and LSGB. Diagnostic pathways were analyzed to assess the contributions of non-invasive tests (serologies and oral/ocular dryness tests) and invasive testing (LSGB) in meeting the threshold for classification criteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: A significant association (\u003cem\u003ep\u003c/em\u003e-value = 0.0263) was observed between LSGB positivity and positive Schirmer’s testing. No significant association was observed between LSGB positivity and anti-Ro positivity, or between LSGB positivity and low unstimulated whole salivary flow. Among those classified, 81% (30/37) met classification independently of LSGB results. Of those who completed testing, 22 met classification criteria for Sjögren’s disease, among whom 68% (15/22) fulfilled criteria independently of LSGB results. Of these 15 subjects, 8 (53%) had negative LSGB with a focus score \u0026lt; 1. While a positive LSGB was mandatory to confirm classification for seronegative subjects, only 11.8% (2/17) of anti-Ro-positive subjects required LSGB for classification.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Objective oral/ocular dryness testing, though rarely performed in routine rheumatologic care, is a valuable complement to serology and biopsy in diagnosing Sjögren’s disease. While LSGB is essential for confirming classification in anti-Ro-negative subjects, it adds only modest value to meeting classification criteria in anti-Ro-positive subjects relative to contemporaneous glandular dryness testing. These findings support integrating objective dryness measures into routine diagnostic workflows to reduce reliance on invasive biopsies and improve diagnostic accuracy, especially in seropositive populations.\u003c/p\u003e","manuscriptTitle":"Real-world Diagnostic Value of Integrating Oral and Ocular Dryness Testing in Suspected Sjögren’s Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-03 11:53:58","doi":"10.21203/rs.3.rs-7011813/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"497a9412-d432-4ab6-967e-4a90f729066d","owner":[],"postedDate":"July 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50808087,"name":"Rheumatology"}],"tags":[],"updatedAt":"2025-07-03T11:53:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-03 11:53:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7011813","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7011813","identity":"rs-7011813","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}