Identification of Salivary Metabolic Signatures Associated with Primary Sjögren's Disease.

Sjögren's disease (SjD) is the second most prevalent autoimmune disorder that involves chronic inflammation of exocrine glands. Correct diagnosis of primary SjD (pSjD) can span over many years since disease symptoms manifest only in advanced stages of salivary and lachrymal glandular destruction, and consensus diagnostic methods have critical sensitivity and selectivity limitations. Using nuclear magnetic resonance (NMR) spectroscopy, we determined the composition of metabolites in unstimulated saliva samples from 30 pSjD subjects and 30 participants who do not have Sjögren's disease (non-Sjögren's control group, NS-C). Thirty-four metabolites were quantified in each sample, and analysis was conducted on both non-normalized (concentration) and normalized metabolomics data from all study participants (ages 23-78) and on an age-restricted subset of the data (ages 30-70) while applying false discovery rate correction in determining data significance. The normalized data of saliva samples from all study participants, and of the age-restricted subset, indicated significant increases in the levels of glucose, glycerol, taurine, and lactate, as well as significant decreases in the levels of 5-aminopentanoate, acetate, butyrate and propionate, in subjects with pSjD compared to subjects in the NS-C group. Additionally, a significant increase in choline was found only in the age-restricted subset, and a significant decrease in fucose was found only in the whole study population in normalized data of saliva samples from the pSjD group compared to the NS-C group. Metabolite concentration data of saliva samples from all study participants, but not from the age-restricted subset, indicated significant increases in the levels of glucose, glycerol, taurine, and lactate in subjects with pSjD compared to controls. The study showed that NMR metabolomics can be implemented in defining salivary metabolic signatures that are associated with disease status, and can contribute to differential analysis between subjects with pSjD and those who are not affected with this disease, in the clinic.

Safety and effectiveness of a two-step dentifrice/gel sequence with medication-associated hyposalivation: A randomized controlled trial in a vulnerable population.

PURPOSE: A randomized controlled trial was conducted to evaluate the safety and effectiveness of a two-step dentifrice/gel oral hygiene sequence in a vulnerable population. METHODS: Prior to the research, institutional review was obtained for the protocol, consent and advertising. The study targeted adults with medication-associated xerostomia, because of the plaque accumulation and possible oral safety risks seen in this population. Eligible subjects with a medication history and measured hyposalivation were randomly assigned to one of two oral hygiene groups:(1) a two-step 0.454% SnF2 dentifrice and 3% H2O2 gel sequence or (2) a regular anticavity toothpaste control. Test products were dispensed with a regular manual brush in blinded over-labeled kits with usage instructions. Subjects were evaluated at baseline and after 2 and 6 weeks of test product use. Safety was assessed as adverse events from clinical examination and interview. Digital plaque image analysis of the anterior facial teeth measured fluorescein-disclosed daytime plaque levels, and unstimulated saliva was collected over a 5-minute period in pre-weighed vials. RESULTS: A total of 49 subjects ranging from 31-80 years of age (53% female) were enrolled, and 45 completed Week 6. Only the two-step dentifrice and gel sequence differed significantly (P< 0.005) from baseline on daytime plaque coverage, and salivary flow increased significantly (P= 0.033) in that group as well. Between-group comparisons for daytime plaque favored the two-step sequence with 41-46% improvements in plaque control. At Week 6, adjusted daytime plaque means (SE) were 5.9 (0.7) and 10.0 (1.1) for the two-step and control groups, respectively (P< 0.004). Adverse events were mild in severity, groups differed significantly (P= 0.02) on occurrence, and events did not contribute to dropout. CLINICAL SIGNIFICANCE: In a randomized controlled trial among a vulnerable population, use of an oral hygiene sequence comprised of stannous fluoride dentifrice and a hydrogen peroxide whitening gel improved daily plaque control without adversely impacting salivary flow or oral health.

A randomized controlled study to evaluate an experimental moisturizing mouthwash formulation in participants experiencing dry mouth symptoms.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of an experimental moisturizing mouthwash versus water only in participants experiencing dry mouth symptoms, including those with Sjögren syndrome (n = 28). STUDY DESIGN: Participants were randomized to the experimental mouthwash group (n = 53) or the water-only group (n = 47). For 8 days, the mouthwash group used 1 to 2 doses/day at home; both groups could sip water, as needed. Supervised treatment occurred on days 1, 3, and 8, and during this treatment, before and after administration, participants completed the Product Performance and Attributes Questionnaire parts 1 through 4. RESULTS: Significant between-treatment differences on all Product Performance and Attributes Questionnaire questions were shown at most time points. On day 8, at 120 minutes, there was a significant difference on Product Performance and Attributes Questionnaire 3-Question 1 ("Relieves the discomfort of dry mouth"; the predefined primary efficacy variable) in favor of mouthwash versus water (0.63 [95% confidence interval 0.17-1.10]; P = .0084). Subgroup analysis found a significant difference that favored mouthwash in participants without Sjögren syndrome (0.67 [0.11,1.23]; P = .0203) but not with Sjögren syndrome (0.52 [-0.35,1.38; P = .2272). Eight, non-serious, oral treatment-related adverse events were reported by the mouthwash group. CONCLUSIONS: The findings of a subjective questionnaire showed that an experimental moisturizing mouthwash provided greater relief than water only from dry mouth symptoms over 8 days.

Management of dry mouth: assessment of oral symptoms after use of a polysaccharide-based oral rinse.

OBJECTIVE: Salivary dysfunction is associated with a range of oral/dental issues, and management of oral symptoms may improve oral function and overall quality of life. The purpose of this pilot study was to evaluate oral symptoms and function in a xerostomic population after use of a proprietary topical for dry mouth, Moisyn (Synedgen Inc., Claremont, CA), which is a polysaccharide-based product. STUDY DESIGN: A pre- and post-test survey was completed by 57 patients with xerostomia. Patients rated their common oral symptoms, based on the Vanderbilt Head and Neck Symptom Survey, before and after 1-week use of Moisyn rinse and spray. Saliva production under resting and chewing stimulation was also assessed. RESULTS: Most patients reported relief from dry mouth symptoms and thick saliva (81.7% and 76.0%, respectively) for more than 30 minutes after product use. Statistically significant reductions were found in 15 of 33 oral symptoms. Symptom improvement ranged from 10.7% to 28.4% for thick saliva, 8.4% to 30.6% for pain, 5.5% to 30.4% for dry mouth, and 12% to 21.3% for taste/diet change. Whole unstimulated/resting saliva improved by 100%, and whole stimulated saliva improved by 23.8%. CONCLUSIONS: These findings suggest that the product has utility in symptom control in patients with xerostomia and may lead to an increase in saliva production.

Clinical practice guidelines for oral management of Sjögren disease: Dental caries prevention.

BACKGROUND: Salivary dysfunction in Sjögren disease can lead to serious and costly oral health complications. Clinical practice guidelines for caries prevention in Sjögren disease were developed to improve quality and consistency of care. METHODS: A national panel of experts devised clinical questions in a Population, Intervention, Comparison, Outcomes format and included use of fluoride, salivary stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. At least 2 members extracted the data, and the panel rated the strength of the recommendations by using a variation of grading of recommendations, assessment, development, and evaluation. After a Delphi consensus panel was conducted, the experts finalized the recommendations, with a minimum of 75% agreement required. RESULTS: Final recommendations for patients with Sjögren disease with dry mouth were as follows: topical fluoride should be used in all patients (strong); although no study results link improved salivary flow to caries prevention, the oral health community generally accepts that increasing saliva may contribute to decreased caries incidence, so increasing saliva through gustatory, masticatory, or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be considered (weak); and nonfluoride remineralizing agents may be considered as an adjunct therapy (moderate). CONCLUSIONS AND PRACTICAL IMPLICATIONS: The incidence of caries in patients with Sjögren disease can be reduced with the use of topical fluoride and other preventive strategies.

Randomized Controlled Trial Evaluating Use of Two Different Oxalate Products in Adults with Recession-Associated Dentin Hypersensitivity.

A randomized positively controlled trial was conducted to evaluate the durable effects of 1.5% oxalate strips on dentin hypersensitivity. Informed consent and baseline measurements were obtained from adults with recession and air-related dentin hypersensitivity. Eligible subjects were randomized to one of two oxalate groups, either 1.5% oxalate gel strips (Crest® Sensi-Stop™ Strips, Procter and Gamble) or a professional oxalate-acid, potassium-salt solution (Super Seal® Dental Desensitizer Liner, Phoenix Dental). Test products were professionally administered at examiner-identified sensitive test sites following each manufacturer's instructions. Subjects received a blinded overwrapped anticavity paste and manual brush, two additional reapplication visits were scheduled over a 1-week period, and subjects returned 1 month later for evaluation. Sensitivity was evaluated using air and water stimuli measured by clinicians (Schiff Index) and subjects (visual analog scale), while safety was assessed by examination. The population (N = 80) was diverse with respect to gender, ethnicity, and age (22 to 82 years). At baseline, the overall mean (SD) air sensitivity was 1.34 (0.47), with individual subject means ranging from 1 to 2.5. Repeated treatment with both the commercial and professional oxalate treatments resulted in significant (P less than .05) reductions in sensitivity for all stimuli and methods. At the 1-month posttreatment recall, there were 84% to 86% reductions in clinically measured cool-air sensitivity for each oxalate group. Groups did not differ significantly (P > .57) on examiner or self-graded air or water sensitivity. In a clinical study, use of 1.5% oxalate gel strips yielded similar benefits as professionally applied oxalate treatments for adults with recession-based dentin hypersensitivity.

Oral implications of polypharmacy in the elderly.

One of the major side effects of medications prescribed to elderly patients is the qualitative and quantitative alteration of saliva (salivary hypofunction). Saliva plays a pivotal role in the homeostasis of the oral cavity because of its protective and functional properties, including facilitating speech, swallowing, enhancing taste, buffering and neutralizing intrinsic and extrinsic acid, remineralizing teeth, maintaining the oral mucosal health, preventing overgrowth of noxious microorganisms, and xerostomia. With salivary hypofunction, a plethora of complications arise, resulting in decreased quality of life. The anticholinergic effects of medications can be overcome, and the oral cavity can be restored to normalcy.

Predictors of coronal caries progression in adults: results from the Prevention of Adult Caries Study.

OBJECTIVES: This secondary analysis of data from the Prevention of Adult Caries Study (PACS) assesses risk factors for progression of coronal caries. METHODS: Participants (n = 983) were adults at increased caries risk with at least one cavitated and one noncavitated lesions who were enrolled in a randomized clinical trial to test the effect of a 10% w/v chlorhexidine varnish coating on caries progression. Calibrated examiners scored tooth surfaces using a modified International Caries Detection and Assessment System (ICDAS) classification at baseline and at 7 and 13 months postrandomization. Potential baseline predictors of caries risk were used in adjusted negative binomial regression models to predict net D2FS increment and in linear regression models to predict the rank-normalized net D12FS increment. RESULTS: Mean (SD) D2FS and D12FS increments were and 2.4 (3.1) and 2.1 (6.9), respectively. In multivariate analyses, two or more baseline D2 lesions, consumption of acidic drinks, and increasing age were all significantly associated with increased D2FS and D12FS risk. Daily flossing also was associated with increased D2FS risk. More frequent dental care at baseline was associated with significantly decreased caries risk for both increments. CONCLUSIONS: The general concordance of risk factors in the D12FS and D2FS models lends support to the hypothesis that the D1 increment is an intermediate stage in the progression to fully cavitated lesions.

Discovery of putative salivary biomarkers for Sjögren's syndrome using high resolution mass spectrometry and bioinformatics.

The purpose of the current study was to determine if saliva contains biomarkers that can be used as diagnostic tools for Sjögren's syndrome (SjS). Twenty seven SjS patients and 27 age-matched healthy controls were recruited for these studies. Unstimulated glandular saliva was collected from the Wharton's duct using a suction device. Two µl of salvia were processed for mass spectrometry analyses on a prOTOF 2000 matrix-assisted laser desorption/ionization orthogonal time of flight (MALDI O-TOF) mass spectrometer. Raw data were analyzed using bioinformatic tools to identify biomarkers. MALDI O-TOF MS analyses of saliva samples were highly reproducible and the mass spectra generated were very rich in peptides and peptide fragments in the 750-7,500 Da range. Data analysis using bioinformatic tools resulted in several classification models being built and several biomarkers identified. One model based on 7 putative biomarkers yielded a sensitivity of 97.5%, specificity of 97.8% and an accuracy of 97.6%. One biomarker was present only in SjS samples and was identified as a proteolytic peptide originating from human basic salivary proline-rich protein 3 precursor. We conclude that salivary biomarkers detected by high-resolution mass spectrometry coupled with powerful bioinformatic tools offer the potential to serve as diagnostic/prognostic tools for SjS.

Examiner training and reliability in two randomized clinical trials of adult dental caries.

OBJECTIVES: This report describes the training of dental examiners participating in two dental caries clinical trials and reports the inter- and intra-examiner reliability scores from the initial standardization sessions. METHODS: Study examiners were trained to use a modified International Caries Detection and Assessment System II system to detect the visual signs of non-cavitated and cavitated dental caries in adult subjects. Dental caries was classified as no caries (S), non-cavitated caries (D1), enamel caries (D2), and dentine caries (D3). Three standardization sessions involving 60 subjects and 3,604 tooth surface calls were used to calculate several measures of examiner reliability. RESULTS: The prevalence of dental caries observed in the standardization sessions ranged from 1.4 percent to 13.5 percent of the coronal tooth surfaces examined. Overall agreement between pairs of examiners ranged from 0.88 to 0.99. An intra-class coefficient threshold of 0.60 was surpassed for all but one examiner. Inter-examiner unweighted kappa values were low (0.23-0.35), but weighted kappas and the ratio of observed to maximum kappas were more encouraging (0.42-0.83). The highest kappa values occurred for the S/D1 versus D2/D3 two-level classification of dental caries, for which seven of the eight examiners achieved observed to maximum kappa values over 0.90. Intra-examiner reliability was notably higher than inter-examiner reliability for all measures and dental caries classifications employed. CONCLUSION: The methods and results for the initial examiner training and standardization sessions for two large clinical trials are reported. Recommendations for others planning examiner training and standardization sessions are offered.

Long-term clinical observation of dental caries in salivary hypofunction patients using a supersaturated calcium-phosphate remineralizing rinse.

OBJECTIVE: One therapeutic approach to the management of xerostomia and its related oral sequelae is the use of a supersaturated Ca2+/PO4(3-) rinse in conjunction with fluoride. This study evaluated the use of the supersaturated rinse in high-risk patients from a single dental clinic. METHODS: Patients (n = 134) at high risk for caries due to xerostomia were prescribed the calcium phosphate rinse and 1.1% NaF for daily use, and were evaluated for caries incidence over an average observation period of five years. All patients were instructed to use the rinse three to four times a day, depending on the severity of dryness of the mouth and rate of salivary flow. Compliance, or regular use of the rinse, was determined through monitoring by staff at each visit, a self-administered clinic questionnaire pertaining to usage of the rinse, and records from a single hospital pharmacy that supplied the rinse to all participating patients. Those patients who were found to typically use the remineralizing solution at least once a day during the entire follow-up period were classified as compliant. All individual surfaces at risk for caries (SAR) were examined and recorded at each visit to determine changes in average SAR per patient RESULTS: Patients who regularly used the supersaturated rinse, along with commercially available prescription sodium fluoride, were found to experience a significant increase in reversals of caries, and a significant decrease in net coronal and root surface caries increment. The mean for the compliant group was 0.034 (SD 0.303), and the non-compliant mean was 0.315 (SD 0.735) with p > 0.0001 per surfaces/month. CONCLUSION: These observations suggest that long-term compliance with the daily supersaturated rinse was protective against caries progression in a high-risk population.

Placebo-controlled clinical trial of use of 10% hydrogen peroxide whitening strips for medication-induced xerostomia.

OBJECTIVE: A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the effectiveness and safety of peroxide-containing strip-based tooth whitening among subjects with medication-induced hyposalivation. METHODS: Eligibility for this tooth whitening study was limited to dentate adults taking xerogenic medications with an unstimulated salivary flow < or = 0.2 ml/min. After giving informed consent, 42 subjects were randomized using a 2:1 ratio to 10% hydrogen peroxide whitening strips (Crest Whitestrips Premium) or placebo strips without peroxide. Strips were used for 30 min twice daily for a 14-day period. Usage was unsupervised, and only the maxillary arch was treated. On days 8 and 15, efficacy was assessed from standard digital images of the anterior dentition and quantified using the Cielab color system, while safety was assessed from interviews and clinical examinations. RESULTS: At day 8, the peroxide group experienced significant (p < 0.001) color improvement relative to baseline and placebo. Adjusted means +/- standard errors for yellowness reduction were -1.65 +/- 0.115 units for the peroxide group and -0.32 +/- 0.170 units for the placebo group. For the increase in lightness, adjusted means +/- standard errors on day 8 were 1.53 +/- 0.130 units for the peroxide group and 0.37 +/- 0.191 units for the controls. Continued strip use through day 15 yielded incremental color improvement for the peroxide group. Mild and transient tooth sensitivity represented the most common adverse events. No subject discontinued treatment due to a product-related adverse event. CONCLUSION: Twice daily use of 10% hydrogen peroxide whitening strips by adults with medication-induced xerostomia was well tolerated, with significant tooth color improvement evident within 7 days.

Caries clinical trial of a remineralising toothpaste in radiation patients.

OBJECTIVES: The purpose of this study was to determine the efficacy and safety of a specially formulated remineralising toothpaste in controlling caries in a high-risk population: head and neck radiation patients. DESIGN: The study compared the performance of the remineralising toothpaste with a conventional fluoride dentifrice using double-blind randomisation. MATERIALS AND METHODS: Test products: The products compared contained equivalent quantities of fluoride (1100 p.p.m.). The dual-phase remineralising toothpaste, Enamelon, also delivered soluble calcium and phosphate ions, essential components of teeth, from separate phases. Both groups had all caries restored at baseline and used a fluoride rinse daily. SUBJECTS: Fifty-seven subjects who received radiation to the head and neck causing saliva hypofunction, entered the study, while 44 completed the 10-12 month visit. MEASUREMENTS: Examinations included coronal and root caries using the Pitts Diagnostic Criteria, salivary flow rate, plaque and gingival indices and microbiological counts over a 1-year period. RESULTS: The average net increment per year for root caries per subject was 0.04 (+/-.052) in subjects completing the study using the remineralising toothpaste and 1.65 (+/-0.51) for root caries in subjects completing the study using the conventional fluoride dentifrice. The difference was statistically significant (p = 0.03), suggesting lower net root surface increment/year for the remineralising toothpaste relative to the conventional toothpaste. No significant differences were noted on coronal surfaces. CONCLUSION: The results indicate that the remineralising toothpaste provides a significant benefit in preventing and remineralising root caries in high-risk patients.

Comparative efficacy of stabilized stannous fluoride/sodium hexametaphosphate dentifrice and sodium fluoride/triclosan/copolymer dentifrice for the prevention of periodontitis in xerostomic patients: a 2-year randomized clinical trial.

BACKGROUND: The primary objective of this study was to compare the efficacy of a stannous fluoride (SnF2) dentifrice relative to a positive control triclosan dentifrice for prevention of clinical attachment loss (CAL) in xerostomic patients. A secondary objective was to compare the dentifrices for root caries remineralization. METHODS: This was a 2-year, randomized, double-masked, parallel-group study. A 0.454% SnF2/sodium hexametaphosphate dentifrice was tested versus a positive control dentifrice (sodium fluoride/0.30% triclosan/copolymer) in 440 medication-induced xerostomic adults identified in a 1-year, run-in phase (no treatment) as high risk for periodontitis and root caries. During the study phase, subjects were stratified based on gender and attachment level into two groups. Subjects brushed twice a day for 60 seconds using their assigned product. Clinical examinations including probing depth, attachment level, bleeding on probing, and root caries remineralization were performed at baseline and 1 and 2 years. RESULTS: A total of 334 subjects were evaluable. During run-in, average CAL relative to initial examination was 1.33 mm. Probing depth increased 0.95 mm. At year 2 in the treatment phase, attachment gain was 0.77 mm for the test group and 0.79 mm for the control group versus baseline. Probing depth decreased 0.57 mm for the test group, similar to the control group (0.53 mm). These changes versus baseline were statistically significant (P <0.01) for each group. Products were not statistically significantly different from each other. Both treatments resulted in similar remineralization for root caries lesions at study completion (P = 0.40). CONCLUSION: The results establish comparable benefits for the SnF2 dentifrice in preventing CAL and root caries versus the sodium fluoride/triclosan/copolymer control in xerostomic patients.

Reduction in caries rate among patients with xerostomia using a power toothbrush.

The purpose of this study was to evaluate whether the use of a Sonicare toothbrush could be beneficial in reducing coronal and/or root caries among patients with medication-induced xerostomia. Eighty subjects with drug-induced xerostomia using either a Sonicare toothbrush (SC) or a manual toothbrush (MTB) were included in the study. Control subjects using a MTB were frequency-matched to 40 subjects using a SC, based on age, gender, number of teeth at baseline, and salivary flow rates. Subjects were individually matched according to the type of xerostomic medication they were taking. Caries were assessed at baseline, and subjects were instructed to have carious teeth restored. Summary statistics were assessed and computed by treatment group for incipient and frank coronal and root caries after one year. Statistical comparisons of the number of frank and incipient coronal and root caries between treatment groups were conducted using paired t-tests. After one year of use, the numbers of incipient and frank root caries were significantly lower among subjects using SC compared to subjects using MTB. Subjects using SC also exhibited somewhat lower incipient and frank coronal caries than subjects using MTB, although their differences were not statistically significant. The authors concluded that the Sonicare toothbrush may be beneficial in reducing root caries among older adults with medication-induced xerostomia.

Stimulation of salivary flow with a powered toothbrush in a xerostomic population.

The purpose of this study was to determine if using a Sonicare toothbrush was a beneficial treatment of xerostomia. Sixty-one subjects with medication-induced xerostomia were randomly assigned a Sonicare (SC) or manual toothbrush (MTB). Subjects were followed for four visits (one month apart); after two months, the MTB group crossed over to using a SC. At each visit, saliva flow was measured by subjects expectorating for five minutes at four collection periods. For the first sample subjects were asked to spit while brushing for three minutes and for two minutes after brushing. Five-minute saliva collections were taken at 15-, 30- and 45-minute intervals. Questionnaires were administered at the end of the study period and three years later. Paired analysis on the MTB group that crossed over to SC showed significant increase in salivary flow at all post-brushing collections (p < 0.01). The end-of-study questionnaire showed that 96.4% of subjects found the SC comfortable to use, 98.2% had enhanced salivary flow, and 92.7% would use it to increase salivary flow. After three years, subjects rated the cleaning effect of the SC more than 4.5 (where 5 = excellent). The Sonicare toothbrush may help in the treatment of xerostomia. The use of a Sonicare resulted in a statistically significant increase in post-brushing salivary flow rates in persons with medcation-induced xerostomia.

A study to assess the safety and tolerability of three toothbrushes.

This study evaluated the oral soft tissue safety and tolerability of an experimental powered toothbrush (Crest SpinBrush Pro) compared to two leading manual toothbrushes: an advanced-design manual toothbrush (Oral-B CrossAction) and a flat-trimmed toothbrush (Oral-B 40 Indicator). Manual brushes are generally viewed as safe for use, and as such are appropriate controls. A total of 140 subjects was enrolled in this single-center, randomized, examiner-blind parallel study over a four-week test period. Subjects were instructed to brush in their normal manner, twice per day for 60 seconds per use. An oral soft tissue interview and examination were conducted by a trained dentist examiner at baseline, as well as three days and four weeks after baseline to assess clinical signs and symptoms of oral irritation associated with use of the toothbrushes. Overall, there were 19 adverse events reported for 18 subjects (13% of the population). The adverse events were distributed across test groups with five subjects in the experimental powered brush group, eight in the advanced design manual toothbrush group and five in the flat-trimmed toothbrush group experiencing at least one adverse event. The most frequently reported adverse event was localized irritation/inflammation of the gingiva. All adverse events were mild in severity except for one report of severe hyperesthesia (tooth sensitivity) in the advanced-design manual toothbrush group. There were no statistically significant differences between the groups for the proportion of subjects reporting adverse events at either three days or four weeks of product use. The results of this study indicate that daily use with the Crest SpinBrush Pro powered toothbrush is at least as safe as two leading manual toothbrushes.