Caroline H. Shiboski

Heterogeneity in Sjögren’s syndrome (SS), increasingly called Sjögren’s disease, suggests the presence of disease subtypes, which poses a major challenge for the diagnosis, management, and treatment of this autoimmune disorder. Previous work distinguished patient subgroups based on clinical symptoms, but it is not clear to what extent symptoms reflect underlying pathobiology. The purpose of this study was to discover clinical meaningful subtypes of SS based on genome-wide DNA methylation data. We performed a cluster analysis of genome-wide DNA methylation data from labial salivary gland (LSG) tissue collected from 64 SS cases and 67 non-cases. Specifically, hierarchical clustering was performed on low dimensional embeddings of DNA methylation data extracted from a variational autoencoder to uncover unknown heterogeneity. Clustering revealed clinically severe and mild subgroups of SS. Differential methylation analysis revealed that hypomethylation at the MHC and hypermethylation at other genome regions characterize the epigenetic differences between these SS subgroups. Epigenetic profiling of LSGs in SS yields new insights into mechanisms underlying disease heterogeneity. The methylation patterns at differentially methylated CpGs are different in SS subgroups and support the role of epigenetic contributions to the heterogeneity in SS. Biomarker data derived from epigenetic profiling could be explored in future iterations of the classification criteria for defining SS subgroups.

Background: We investigated trends in incidence rates, stage at diagnosis and relative survival rates among adults with oral cancer in relation to race in the context of previously uncovered cancer-specific health disparities. Methods: We analyzed 2000—2017 SEER data among adults with oral cancer from 18 registries. We used SEER*Stat to compute proportions for each oral cancer site by stage at diagnosis and race and five-year relative survival rates by sex, cancer site, stage at diagnosis, age and race and explored trends over time. Results: Among 95,040 oral cancer cases reported to SEER, the most prevalent site was the tongue. While the rate among Black men decreased from 12.9 to 8/100,000, Blacks had significantly higher proportions of oral cancer that had spread at diagnosis than whites. Survival rates were substantially lower among Blacks than whites. Conclusions: The steep decline in oral cancer incidence rates in Black men is encouraging, although the persistent racial disparity with respect to late diagnosis and poor survival is alarming, requiring targeted interventions. Practical implications: Highlighting racial disparities with respect to oral cancer to increase awareness is the first step in developing interventions to address these disparities.

Purpose: To evaluate the ocular signs and tests for keratoconjunctivitis sicca (KCS) in the absence of a gold standard.Methods: Cross-sectional study of participants from the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Participants had oral/ocular/rheumatologic examinations, blood/saliva samples collected, and salivary gland biopsy. Latent class analysis (LCA) identified clusters of patients based on 3 to 4 predictor variables relating to signs or tests of KCS. The resulting model-based “gold standard” classification formed the basis for estimated sensitivity and specificity associated with these predictors.Results: A total of 3514 participants were enrolled into SICCA, with 52.9% classified as SS. LCA revealed a best-fit model with 2 groups. For the gold standard–positive group, an abnormal tear breakup time, ocular staining score (OSS), and Schirmer I had a sensitivity of 99.5%, 91.0%, and 47.4%, respectively. For the gold standard–negative group, an abnormal tear breakup time, OSS, and Schirmer I had a specificity of 32.0%, 84.0%, and 88.5%, respectively. OSS components (fluorescein and lissamine staining), exhibited a sensitivity of 82.6% and 90.5%, respectively, in the gold standard–positive group, whereas these signs in the gold standard–negative group had a specificity of 88.8% and 73.0%, respectively.Conclusions: OSS and its components (fluorescein and lissamine staining) differentiated 2 groups from each other better than other KCS parameters and had relatively high sensitivity and specificity.

Objectives: This study explores the association between combination antiretroviral therapy (cART) and oral health outcomes (dental and periodontal) among perinatally HIV-infected (PHIV) youth. Methods: We conducted a cross-sectional study of oral health among PHIV youth participating in the Oral Health substudy of the Pediatric HIV/AIDS Cohort Study (PHACS). Dentists at research sites were trained/calibrated on how to perform a standardized oral mucosal, dental and periodontal examination. They assessed the decayed-missing-filled-surfaces and teeth index (DMFS/T). The number of decayed surfaces and teeth and the number of teeth with gingival bleeding on probing for each participant were derived from the examination. Data for analysis included lifetime measurements of CD4⁺ cell count and viral load, sociodemographic information and current/past history of ART. Results: Among 209 PHIV youth, 95% were on ART at the time of enrolment. Among 143 PHIV youth on the same cART for at least 1 year, we found that the mean decayed teeth score of those receiving cART containing an integrase inhibitor was 86% higher than that of those on cART without an integrase inhibitor after adjusting for age, lifetime proportion of unsuppressed viral load and CD4⁺ cell count nadir. Initiating protease inhibitors before age 6 years was associated with a significantly lower DMFT score than participants who initiated at age 6 years and older. Conclusion: Our study revealed that PHIV youth who received cART containing an integrase inhibitor had a significantly higher number of untreated active caries than those on cART without an integrase inhibitor. This may warrant closer dental surveillance of those receiving an integrase inhibitor.

Objective: To explore changes in the phenotypic features of Sjögren's syndrome (SS), and in SS status among participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry over a 2–3‐year interval.Methods: All participants in the SICCA registry who were found to have any objective measures of salivary hypofunction, dry eye, focal lymphocytic sialadenitis in minor salivary gland biopsy, or anti‐SSA/SSB antibodies were recalled over a window of 2 to 3 years after their baseline examinations to repeat all clinical examinations and specimen collections to determine whether there was any change in phenotypic features and in SS status.Results: As of September 15, 2013, a total of 3,514 participants had enrolled in SICCA, and among 3,310 eligible, 771 presented for a followup visit. Among participants found to have SS using the 2012 American College of Rheumatology (ACR) classification criteria, 93% again met the criteria after 2 to 3 years, and this proportion was 89% when using the 2016 ACR/European League Against Rheumatism (EULAR) criteria. Among those who did not meet ACR or ACR/EULAR criteria at baseline, 9% and 8%, respectively, had progressed and met them at followup. Those with hypergammaglobulinemia and hypocomplementemia at study entry were, respectively, 4 and 6 times more likely to progress to SS by ACR criteria than those without these characteristics (95% confidence interval 1.5–10.1 and 1.8–20.4, respectively).Conclusion: While there was stability over a 2–3‐year period of both individual phenotypic features of SS and of SS status, hypergammaglobulinemia and hypocomplementemia at study entry were predictive of progression to SS.

Objective: To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS.Methods: We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi‐criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non‐SS controls, with case/non‐case status derived from expert clinical judgment. We then validated the performance of the classification criteria in a separate cohort of patients.Results: The final classification criteria are based on the weighted sum of 5 items: anti‐SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm², each scoring 3; an abnormal ocular staining score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 minutes, and an unstimulated salivary flow rate of ≤0.1 ml/minute, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician‐expert–derived case/non‐case status in the final validation cohort were high, i.e., 96% (95% confidence interval [95% CI] 92–98%) and 95% (95% CI 92–97%), respectively.Conclusion: Using methodology consistent with other recent ACR/EULAR‐approved classification criteria, we developed a single set of data‐driven consensus classification criteria for primary SS, which performed well in validation analyses and are well‐suited as criteria for enrollment in clinical trials.

The incidence of human papillomavirus (HPV)-related oral malignancies is increasing among HIV-infected populations, and the prevalence of oral warts has reportedly increased among HIV patients receiving antiretroviral therapy (ART). We explored whether ART initiation among treatment-naive HIV-positive adults is followed by a change in oral HPV infection or the occurrence of oral warts. Prospective, observational study. HIV-1 infected, ART-naive adults initiating ART in a clinical trial were enrolled. End points included detection of HPV DNA in throat-washes, changes in CD4 T-cell count and HIV RNA, and oral wart diagnosis. Among 388 participants, 18% had at least one HPV genotype present before initiating ART, and 24% had at least one genotype present after 12-24 weeks of ART. Among those with undetectable oral HPV DNA before ART, median change in CD4 count from study entry to 4 weeks after ART initiation was larger for those with detectable HPV DNA during follow-up than those without (P = 0.003). Both prevalence and incidence of oral warts were low (3% of participants having oral warts at study entry; 2.5% acquiring oral warts during 48 weeks of follow-up). These results suggest: effective immune control of HPV in the oral cavity of HIV-infected patients is not reconstituted by 24 weeks of ART; whereas ART initiation was not followed by an increase in oral warts, we observed an increase in oral HPV DNA detection after 12-24 weeks. The prevalence of HPV-associated oral malignancies may continue to increase in the modern ART era.

Many studies include oral HIV-related endpoints that may be diagnosed by non-oral-health specialists (non-OHS) like nurses or physicians. Our objective was to assess the accuracy of clinical diagnoses of HIV-related oral lesions made by non-OHS compared to diagnoses made by OHS. A5254, a cross-sectional study conducted by the Oral HIV/AIDS Research Alliance within the AIDS Clinical Trial Group, enrolled HIV-1-infected adults participants from six clinical trial units (CTU) in the US (San Francisco, New York, Chapel Hill, Cleveland, Atlanta) and Haiti. CTU examiners (non-OHS) received standardized training on how to perform an oral examination and make clinical diagnoses of specific oral disease endpoints. Diagnoses by calibrated non-OHS were compared to those made by calibrated OHS, and sensitivity and specificity computed. Among 324 participants, the majority were black (73%), men (66%), and the median CD4+ cell count 138 cells/mm³. The overall frequency of oral mucosal disease diagnosed by OHS was 43% in US sites, and 90% in Haiti. Oral candidiasis (OC) was detected in 153 (47%) by OHS, with erythematous candidiasis (EC) the most common type (39%) followed by pseudomembranous candidiasis (PC; 26%). The highest prevalence of OC (79%) was among participants in Haiti, and among those with CD4+ cell count ≤ 200 cells/mm³ and HIV-1 RNA > 1000 copies/mL (71%). The sensitivity and specificity of OC diagnoses by non-OHS were 90% and 92% (for EC: 81% and 94%; PC: 82% and 95%). Sensitivity and specificity were also high for KS (87% and 94%, respectively), but sensitivity was < 60% for HL and oral warts in all sites combined. The Candida culture confirmation of OC clinical diagnoses (as defined by ≥ 1 colony forming unit per mL of oral/throat rinse) was ≥ 93% for both PC and EC. Trained non-OHS showed high accuracy of clinical diagnoses of OC in comparison with OHS, suggesting their usefulness in studies in resource-poor settings, but detection of less common lesions may require OHS.