Search

© 2015 Shiboski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credite

ObjectiveTo evaluate the association between oral candidiasis and tuberculosis (TB) in human immunodeficiency virus (HIV) infected individuals in sub-Saharan Africa, and to investigate oral candidiasis as a potential tool for TB case finding.MethodsProtocol A5253 was a cross-sectional study designed to improve the diagnosis of pulmonary TB in HIV-infected adults in high TB prevalence countries. Participants received an oral examination to detect oral candidiasis. We estimated the association between TB disease and oral candidiasis using logistic regression, and sensitivity, specificity and predictive values.ResultsOf 454 participants with TB culture results enrolled in African sites, the median age was 33 years, 71% were female and the median CD4 count was 257 cells/mm(3). Fifty-four (12%) had TB disease; the prevalence of oral candidiasis was significantly higher among TB cases (35%) than among non-TB cases (16%, P < 0.001). The odds of having TB was 2.4 times higher among those with oral candidiasis when controlling for CD4 count and antifungals (95%CI 1.2-4.7, P = 0.01). The sensitivity of oral candidiasis as a predictor of TB was 35% (95%CI 22-48) and the specificity 85% (95%CI 81-88).ConclusionWe found a strong association between oral candidiasis and TB disease, independent of CD4 count, suggesting that in resource-limited settings, oral candidiasis may provide clinical evidence for increased risk of TB and contribute to TB case finding.

Objective: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.Methods: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American–European Consensus Group (AECG) criteria, a model-based “gold standard”obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development.Results: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications.Conclusion: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks. [ABSTRACT FROM AUTHOR]

Purpose: To examine the ocular signs and symptoms in participants of the Sjögren's International Collaborative Clinical Alliance cohort, and to compare them across Sjögren's disease (SjD) status., Methods: Our study population comprised 3380 Sjögren's International Collaborative Clinical Alliance participants who had no missing data relevant to this study. Participants' SjD status was assessed using the updated 2016 American College of Rheumatism/European League Against Rheumatism SjD classification criteria. Participants completed baseline questionnaires of ocular symptoms and underwent ocular examinations. Differences in the ocular signs and symptoms between SjD and non-SjD groups were assessed. We used multivariable linear and linear mixed-effects models to investigate the impact of SjD on Ocular Surface Disease Index-6 and OSS., Results: Among 1532 participants classified as SjD, their Ocular Surface Disease Index-6 did not clinically differ from those classified as non-SjD (adjusted difference, -0.97; 95% confidence interval, -1.52 to -0.41). However, SjD participants exhibited an elevated ocular staining score (adjusted difference, 3.47; 95% confidence interval, 3.36-3.57; P < 0.001) compared with non-SjD participants. In addition, SjD was associated with increased odds of ocular signs, such as reduced tear break-up time, abnormal Schirmer I test, and corneal abnormalities, and was strongly related to more intense corneal and conjunctival staining, as well as additional corneal staining points., Conclusions: SjD is associated with a higher risk of ocular signs and pathology compared with non-SjD, whereas ocular symptoms remain similar. In addition, corneal abnormalities and corneal staining patterns could serve as a potential biomarker in identifying SjD-related dry eye.

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1 . Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6 , CXCR5 , and lnc-PHLDB1-1 , among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues., Competing Interests: Competing Interests C.J.L.* and A.D.F. have an active collaborative research agreement with Janssen. E.B. has an active research collaboration with Pfizer. T.M. is employed as medical solutions lead in rheumatology at UCB. R.H.S. is a consultant for Jansen Pharmaceuticals. S.J.B. provided consultancy services for Abbvie, BMS, Galapagos, Iqvia, J&J, Kiniksa, and Novartis in 2020–2021. L.R. provided consultancy services for AstraZeneca. B.M.W. has active collaborative research agreements with Astellas Bio and Pfizer, Inc. M.R. received grants from Amgen, AstraZeneca, Bristol Myers-Squibb, Novartis, and Servier for clinical trials in Sjögren’s Syndrome and SLE. All other authors have reported that they have no competing interests to report.

Sjögren's disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren's cases of European ancestry: CD247, NAB1, PTTG1-MIR146A, PRDM1-ATG5, TNFAIP3, XKR6, MAPT-CRHR1, RPTOR-CHMP6-BAIAP6, TYK2, SYNGR1. Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands., (© 2022. The Author(s).)

Objective: The objective of this study was to examine the association of smoking with Primary Sjögren syndrome (pSS) classification and pSS diagnostic test results. We hypothesized that past and current smokers would have lower odds of being classified as having Sjögren syndrome (SS) and lower odds of having abnormal individual SS diagnostic test results compared with nonsmokers., Methods: Participants with suspected or established pSS were enrolled into the Sjögren's International Collaborative Clinical Alliance (SICCA) registry and had oral, ocular, and rheumatologic examinations performed; blood and saliva samples collected; and labial salivary gland biopsy examinations performed; they also completed questionnaires at baseline. Logistic regression was used to determine whether smoking status was associated with pSS classification and individual pSS diagnostic test results., Results: A total of 3514 participants were enrolled in SICCA. A total of 1541 (52.9%) met classification criteria for pSS. Compared with never smokers, current smokers had reduced odds of being classified as having pSS, reduced odds of having a focus score ≥ 1 and serologic positivity for anti-SSA/anti-SSB antibodies, and lower odds of having abnormal signs or test results of dry eye disease. Compared with never smokers, past smokers did not have a statistically significant reduction in odds of being classified as having pSS and of having abnormal individual pSS diagnostic test results., Conclusion: Compared with never smokers, current smokers in the SICCA cohort had lower odds of being classified as having pSS, lower odds of exhibiting abnormal signs and test results for dry eye disease, and lower odds of having a labial salivary gland biopsy supportive of pSS classification. Such negative associations, however, do not suggest that current smoking is of any benefit with respect to pSS., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion., Methods: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS., Results: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%., Conclusion: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

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 characterize the oral bacterial microbiome in HIV-infected participants at baseline and after 24 weeks of EFV/FTC/TDF., Design: Thirty-five participants co-enrolled in two AIDS Clinical Trials Group (ACTG) studies, A5272 and A5280, with paired saliva samples and complete data sets were assessed., Methods: Paired saliva samples were evaluated for bacterial microbiome using 16S rDNA PCR followed by Illumina sequencing. Diversity and differential abundance was compared between groups. A random forest classification scheme was used to determine the contribution of parameters in classifying participants' CD4+ T-cell count., Results: Bacterial communities demonstrated considerable variability both within participants and between timepoints, although they became more similar after 24 weeks of ART. At baseline, both the number of taxa detected and the average alpha diversity were variable between participants, but did not differ significantly based on CD4+ cell count, viral load or other factors. After 24 weeks of ART samples obtained from participants with persistently low CD4+ T-cell counts had significantly higher bacterial richness and diversity. Several differentially abundant taxa, including Porphyromonas species associated with periodontal disease, were identified, which discriminated between baseline and posttreatment samples. Analysis demonstrated that although inflammatory markers are important in untreated disease, the salivary microbiome may play an important role in CD4+ T-cell count recovery after ART., Conclusion: Shifts in the oral microbiome after ART initiation are complex, and may play an important role in immune function and inflammatory disease.

Background: Microbially mediated oral diseases can signal underlying HIV/AIDS progression in HIV-infected adults. The role of the oral microbiota in HIV-infected youth is not known. The Adolescent Master Protocol of the Pediatric HIV/AIDS Cohort Study is a longitudinal study of perinatally HIV-infected (PHIV) and HIV-exposed, uninfected (PHEU) youth. We compared oral microbiome levels and associations with caries or periodontitis in 154 PHIV and 100 PHEU youth., Results: Species richness and alpha diversity differed little between PHIV and PHEU youth. Group differences in average counts met the significance threshold for six taxa; two Corynebacterium species were lower in PHIV and met thresholds for noteworthiness. Several known periodontitis-associated organisms (Prevotella nigrescens, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and Filifactor alocis) exhibited expected associations with periodontitis in PHEU youth, associations not observed in PHIV youth. In both groups, odds of caries increased with counts of taxa in four genera, Streptococcus, Scardovia, Bifidobacterium, and Lactobacillus., Conclusions: The microbiomes of PHIV and PHEU youth were similar, although PHIV youth seemed to have fewer "health"-associated taxa such as Corynebacterium species. These results are consistent with the hypothesis that HIV infection, or its treatment, may contribute to oral dysbiosis.

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., (© 2017, American College of Rheumatology.)

Objective: To examine health-related quality of life (HRQoL) and depression among participants in an international Sjögren's syndrome (SS) registry, comparing those with and without SS., Methods: Cross-sectional study of participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. The 2016 American College of Rheumatology/European League Against Rheumatism SS classification criteria were used to determine disease status. HRQoL was assessed using the Short Form 12, version 2 Health Survey to derive scores for physical component summary (PCS) and mental component summary (MCS). Depression was assessed using the 9-Item Patient Health Questionnaire. Multivariate linear and logistic regression analyses were performed to identify predictors of HRQoL and depression while controlling for potential confounders., Results: Among 2401 SICCA participants who had symptoms of dry eyes and dry mouth, 1051 had SS (44%) and 1350 did not (56%). After controlling for confounders, when compared with non-SS participants, those with SS had better PCS (p<0.001, β=2.43, 95% CI 1.57 to 3.29), MCS (p=0.002, β=1.37, 95% CI 0.50 to 2.23) and lower adjusted odds of depression (p<0.001, OR 0.67, 95% CI 0.55 to 0.81). Other significant predictors of HRQoL and depression included employment, country of residence and use of medication with anticholinergic effect or for management of SS-related signs and symptoms., Conclusion: Our results suggest that among symptomatic patients, having a diagnosis of SS may be associated with better emotional and psychological well-being compared with patients without a diagnosis. Having a definitive diagnosis of SS may encourage patients to obtain a better understanding of their disease and have coping mechanisms in place to better manage their symptoms., Competing Interests: Competing interests: None declared.

Objective: Herpesvirus shedding in the oral cavity was analyzed to determine if presence in the oral compartment correlates with systemic changes in HIV-associated immune deficiency as measured by CD4 cell counts, plasma HIV viral load and presence of AIDS-defining events., Design: A5254 is a multicenter, cross-sectional, single-visit study to evaluate oral complications of HIV/AIDS and determine the association between clinical appearance, herpesvirus shedding, and immune status as ascertained by CD4 cell count and HIV viral load. In total, 307 HIV-infected individuals were evaluated and throat wash collected., Methods: Fisher's exact test and Kruskal-Wallis test were used to assess the association between presence of herpesviruses and the state of immunodeficiency as stratified by a combination of CD4 cell count and HIV viral load. Relationship between pathogens and HIV viral load in plasma was modeled by logistic regression., Results: The presence of cytomegalovirus (CMV) and herpes simplex virus-1 in throat wash was associated with decreased CD4 cell counts. By contrast, Kaposi sarcoma-associated herpesvirus and Epstein-Barr virus were similarly detectable across all levels of CD4 cell counts. One unit increase in log10 (HIV viral load) was associated with 1.31 times higher odds of detecting CMV in throat wash when controlling for oral candidiasis, CD4 cell count, and sites (95% confidence interval 1.04-1.65, P = 0.02)., Conclusion: Oral CMV shedding was significantly higher in highly immunocompromised HIV participants. Our finding supports the recommendations to start antiretroviral therapy independent of CD4 cell count as this may have the added benefit to lower the risk of herpesvirus transmission among persons infected with HIV and their partners.

Objective: The Sjögren's International Collaborative Clinical Alliance (SICCA) is an international data registry and biorepository derived from a multisite observational study of participants in whom genotyping was performed on the Omni2.5M platform and who had undergone deep phenotyping using common protocol-directed methods. The aim of this study was to examine the genetic etiology of Sjögren's syndrome (SS) across ancestry and disease subsets., Methods: We performed genome-wide association study analyses using SICCA subjects and external controls obtained from dbGaP data sets, one using all participants (1,405 cases, 1,622 SICCA controls, and 3,125 external controls), one using European participants (585, 966, and 580, respectively), and one using Asian participants (460, 224, and 901, respectively) with ancestry adjustments via principal components analyses. We also investigated whether subphenotype distributions differ by ethnicity, and whether this contributes to the heterogeneity of genetic associations., Results: We observed significant associations in established regions of the major histocompatibility complex (MHC), IRF5, and STAT4 (P = 3 × 10 -42 , P = 3 × 10 -14 , and P = 9 × 10 -10 , respectively), and several novel suggestive regions (those with 2 or more associations at P < 1 × 10 -5 ). Two regions have been previously implicated in autoimmune disease: KLRG1 (P = 6 × 10 -7 [Asian cluster]) and SH2D2A (P = 2 × 10 -6 [all participants]). We observed striking differences between the associations in Europeans and Asians, with high heterogeneity especially in the MHC; representative single-nucleotide polymorphisms from established and suggestive regions had highly significant differences in the allele frequencies in the study populations. We showed that SSA/SSB autoantibody production and the labial salivary gland focus score criteria were associated with the first worldwide principal component, indicative of higher non-European ancestry (P = 4 × 10 -15 and P = 4 × 10 -5 , respectively), but that subphenotype differences did not explain most of the ancestry differences in genetic associations., Conclusion: Genetic associations with SS differ markedly according to ancestry; however, this is not explained by differences in subphenotypes., (© 2017, The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Compare the safety and efficacy of topical gentian violet with that of nystatin oral suspension (NYS) for the treatment of oropharyngeal candidiasis in HIV-1-infected adults in resource-limited settings., Design: Multicenter, open-label, evaluator-blinded, randomized clinical trial at eight international sites, within the AIDS Clinical Trials Group., Study Participants and Intervention: Adult HIV-infected participants with oropharyngeal candidiasis, stratified by CD4 cell counts and antiretroviral therapy status at study entry, were randomized to receive either gentian violet (0.00165%, BID) or NYS (500 000 units, QID) for 14 days., Main Outcome Measure(s): Cure or improvement after 14 days of treatment. Signs and symptoms of oropharyngeal candidiasis were evaluated in an evaluator-blinded manner., Results: The study was closed early per Data Safety Monitoring Board after enrolling 221 participants (target = 494). Among the 182 participants eligible for efficacy analysis, 63 (68.5%) in the gentian violet arm had cure or improvement of oropharyngeal candidiasis versus 61 (67.8%) in the NYS arm, resulting in a nonsizable difference of 0.007 (95% confidence interval: -0.129, 0.143). There was no sizable difference in cure rates between the two arms (-0.0007; 95% confidence interval: -0.146, 0.131). No gentian violet-related adverse events were noted. No sizable differences were identified in tolerance, adherence, quality of life, or acceptability of study drugs. In gentian violet arm, 61 and 39% of participants reported 'no' and 'mild-to-moderate' staining, respectively. Cost for medication procurement was significantly lower for gentian violet versus NYS (median $2.51 and 19.42, respectively, P = 0.01)., Conclusion: Efficacy of gentian violet was not statistically different than NYS, was well tolerated, and its procurement cost was substantially less than NYS.

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 mm 2 , 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., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

In contrast to high rates of oral human papillomavirus (HPV) found in human immunodeficiency virus (HIV)-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV-exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV.

Objective: 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., Design: Prospective, observational study., Methods: 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., Results: 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)., Conclusion: 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.

Objective: Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features., Methods: Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed., Results: A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high-titer antinuclear antibody, anti-SSA, and high focus score on labial salivary gland [LSG] biopsy). Three distinct patterns of IFN were evident: type I-predominant, type II-predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II-predominant IFN., Conclusion: The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN-targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient., (© 2015, American College of Rheumatology.)

Objective: 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., Methods: 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., Results: Among 324 participants, the majority were black (73%), men (66%), and the median CD4+ cell count 138 cells/mm(3). 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/mm(3) 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., Conclusion: 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.

The incidence of human papillomavirus (HPV)-associated epithelial lesions is substantially higher in human immunodeficiency virus (HIV)-infected individuals than in HIV-uninfected individuals. The molecular mechanisms underlying the increased risk of HPV infection in HIV-infected individuals are poorly understood. We found that HIV proteins tat and gp120 were expressed within the oral and anal mucosal epithelial microenvironment of HIV-infected individuals. Expression of HIV proteins in the mucosal epithelium was correlated with the disruption of epithelial tight junctions (TJ). Treatment of polarized oral, cervical and anal epithelial cells, and oral tissue explants with tat and gp120 led to disruption of epithelial TJ and increased HPV pseudovirion (PsV) paracellular penetration in to the epithelium. PsV entry was observed in the basal/parabasal cells, the cells in which the HPV life cycle is initiated. Our data suggest that HIV-associated TJ disruption of mucosal epithelia may potentiate HPV infection and subsequent development of HPV-associated neoplasia., (© 2013 Elsevier Inc. All rights reserved.)

Objective: To study the prevalence of extraglandular manifestations in primary Sjögren's syndrome (SS) among participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry., Methods: A total of 1,927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European Consensus Group (AECG) criteria for primary SS, 830 "intermediate" cases who had some objective findings of primary SS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities, specific rheumatologic examination findings, and physician-confirmed thyroid, liver, and kidney disease, as well as lymphoma among SICCA participants., Results: Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia, and hypocomplementemia, frequently occurred among primary SS cases and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among primary SS cases. In contrast, the frequency of physician-confirmed diagnoses of thyroid, liver, and kidney disease and lymphoma was low and only primary biliary cirrhosis was associated with primary SS case status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status., Conclusion: Data from the international SICCA registry support the systemic nature of primary SS, manifested primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic, or other systemic manifestations., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS)., Methods: The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features., Results: LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS., Conclusion: Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity., (Copyright © 2011 by the American College of Rheumatology.)

Objectives: To estimate oral disease prevalence among Zimbabwean women by HIV serostatus and CD4 cell count and to assess accuracy of oral disease diagnoses made by nurses as compared with an oral surgeon., Methods: Standardized oral mucosa examinations were performed by trained nurse-examiners and by an oral surgeon among women recruited in Harare, Zimbabwe., Results: A total of 461 women (320 HIV-infected, 141 uninfected) were seen by nurses and an oral surgeon within a 2-week period. Oral candidiasis (OC) was the most common lesion diagnosed in nearly one quarter of HIV-infected women, whereas hairy leukoplakia and Kaposi sarcoma were found in <3%. The prevalence of OC diagnosed by nurses or the surgeon was significantly higher among women with a CD4 count <200 cells/mm than in women with a CD4 count from 200 to 499 cells/mm3 or a CD4 count >499 cells/mm3. The sensitivity of nurse examinations compared with examinations by the oral surgeon among HIV-infected women for the diagnosis of OC was 73%, the specificity was 95%, and the kappa-statistic was 0.71., Conclusions: OC was the most common lesion in HIV-infected women and was strongly associated with a low CD4 cell count. Interexaminer agreement was good for the diagnosis of OC among HIV-infected women. This study suggests that OC may play a role, in combination with other clinical indicators as a marker of disease progression in resource-poor settings.

Purpose: Although an important risk factor for oral cancer is the presence of epithelial dysplasia, many lesions will not progress to malignancy. Matrix metalloproteinases (MMPs) are zinc-dependent proteinases capable of digesting various structural components of the extracellular matrix. Because MMPs are frequently overexpressed in oral squamous cell carcinoma (SCC), we hypothesized that they are also overexpressed in oral dysplasias; we also hypothesized that those dysplasias that progress to oral cancer express higher levels of MMPs than those lesions that do not progress., Experimental Design: In this retrospective study, we examined changes in MMP-1, -2, and -9 mRNA expression using quantitative TaqMan reverse transcription-polymerase chain reaction in 34 routinely processed oral dysplasias and 15 SCCs obtained from 34 patients. After several years of close follow-up, 19 dysplasias progressed to oral SCC and 15 did not., Results: Overall, MMP-1 mRNA was overexpressed (>2-fold) in 24 of 34 (71%) dysplasias and 13 of 15 (87%) oral SCCs. MMP-2 overexpression was seen in 11 of 34 (32%) dysplasias and 7 of 15 (47%) cancers; for MMP-9, overexpression was identified in 29 of 34 (85%) dysplasias and 15 of 15 (100%) cancers. MMP-1 and -9 levels were significantly higher in the SCCs compared with all oral dysplasias (P = 0.004 and P = 0.01, respectively). MMP-1 and -9 mRNA levels were significantly higher in the oral dysplasias that progressed to oral cancer compared with those that did not (P = 0.04 and P = 0.002, respectively)., Conclusions: Levels of MMP-1 and -9 mRNA may be markers of malignant transformation of oral dysplasia to oral cancer.

We examined HIV infection and estimated the population-attributable risk percentage (PAR%) for HIV associated fellatio among men who have sex with other men (MSM). Among 239 MSM who practised exclusively fellatio in the past 6 months, 50% had three partners, 98% unprotected; and 28% had an HIV-positive partner; no HIV was detected. PAR%, based on the number of fellatio partners, ranges from 0.10% for one partner to 0.31% for three partners. The risk of HIV attributable to fellatio is extremely low.

Objectives: To identify factors associated with the use of medical services, and to test a model of access to care, among HIV-infected women., Methods: A cross-sectional telephone survey was administered to 213 HIV-infected women. Outcomes were having a primary care provider, and use of primary care and emergency health services. Predictors included characteristics of the population-at-risk and of the health care system., Results: Ninety-three percent of respondents had a primary care provider. Linear regression found age >45 years (p = .002), perceiving greater barriers to getting to a clinic (p = .04) and greater benefits from medications (p = .03), lack of problems with appointment times (p = .02), having AIDS (p = .01), shorter appointment waiting times (p = .0003), and greater cost of travel to care (p = .001) were associated with a greater number of primary care visits. Thirty-seven percent missed at least 1 primary care appointment. In logistic regression, lack of insurance (odds ratio [OR] = 2.76), current injection drug use (OR = 2.89) and difficulty remembering appointments (OR = 2.36) were associated with having missed any appointments., Conclusions: Characteristics of the population-at-risk and of the health care system both make important contributions to primary care service use.

We sought to determine whether hairy leukoplakia (HL), an Epstein-Barr virus-related oral lesion, is associated with receptive oral sex activity and cigarette smoking among HIV-positive gay men. Oral examinations were conducted every 6 months among San Francisco Men's Health Study participants over a 6-year period. We fitted time-to-lesion regression models to compare the incidence of HL among men who had mouth-to-penis contact with various numbers of partners, while controlling for cigarette smoking and CD4 count. The 6-year incidence of HL was 32% among 291 HIV-positive men. We found no significant increase in the hazard of developing HL for each additional insertive-oral-sex male partner in the past 6 months (relative hazard = 1.01; 95% confidence interval [CI], 0.99, 1.02), and a similar lack of association when number of sex partners was categorized. However, the hazard of developing HL doubled with any 300-unit decrease in CD4 count (95% CI, 1.4, 2.7), or if men smoked > or =20 cigarettes/day compared with nonsmokers (95% CI, 1.2, 3.9). This finding, which may suggest one effect that smoking produces on the oral mucosa's local immune response, merits further investigation.

Objectives: This study sought to identify predictors of dental care use in HIV-infected women., Methods: In a cross-sectional survey of HIV-infected women enrolled in the northern California site of the Women's Interagency HIV Study, dental care use and unmet need were assessed in relation to selected variables., Results: Among 213 respondents, who were predominantly Black and younger than 45 years, 43% had not seen a dentist and 53% (among dentate women) reported no dental cleaning in more than a year (although 67% had dental insurance coverage, mainly state Medicaid). Nine percent were edentulous. Among nonusers of dental care, 78% reported that they wanted care but failed to get it. Barriers included fear of and discomfort with dentists, not getting around to making an appointment, and not knowing which dentist to visit. Multivariate analysis showed that lack of past-year dental care was associated mainly with unemployment, a perception of poor oral health, and edentulism., Conclusions: HIV-positive women appear to be underusing dental care services. Fear and lack of information regarding available resources, in addition to unemployment and perception of poor oral health, may be important barriers.

The goals of this study were to compare the prevalence of oral lesions in women infected with human immunodeficiency virus (HIV) and HIV-negative women, and to determine the association of oral lesions with route of HIV transmission and with level of immunosuppression in infected women. As part of a prospective 4-year study, oral examinations and blood tests were performed, at 6-month intervals, on 176 HIV-infected women and on 117 HIV-negative women at risk for HIV infection. We evaluated participants for the following oral conditions: hairy leukoplakia, candidiasis, ulcers, warts, non-Hodgkin's lymphoma, Kaposi's sarcoma, and parotid enlargement. As previously reported in men, the prevalence of oral lesions was significantly higher among HIV-infected (22%) than HIV-negative women (3%) [odds ratio (OR) = 8.2; 95% confidence interval (CI) 2.8, 23.5], particularly candidiasis (14%) and hairy leukoplakia (10%). Among HIV-infected women with CD4 cell count nadir > or = 200 cells/microliters, the prevalence of hairy leukoplakia was higher among those infected heterosexually than among injection drug users (OR = 5.5; 95% CI: 1.5; 19). The OR for the association between oral lesions and CD4 cell count nadir (< 200 vs. > 500 cells/microliters) was 8.9 (95% CI: 2.6, 30), indicating a strong positive association with level of immunosuppression.