Periodontal disease and subgingival microbiota as contributors for rheumatoid arthritis pathogenesis: modifiable risk factors?

PURPOSE OF REVIEW: Since the early 1900s, the role of periodontal disease in the pathogenesis of rheumatoid arthritis has been a matter of intense research. The last decade has witnessed many advances supporting a link between periodontitis, the presence of specific bacterial species (i.e. Porphyromonas gingivalis) and their effects in immune response. This review will examine available evidence on the individuals. RECENT FINDINGS: Epidemiological studies have stressed the commonalities shared by periodontal disease and rheumatoid arthritis. Many groups have focused their attention toward understanding the periodontal microbiota and its alterations in states of health and disease. The presence of circulating antibodies against periodontopathic bacteria and associated inflammatory response has been found in both rheumatoid arthritis (RA) patients and individuals at-risk for disease development. Most recently, the periodontal microbiota of smokers and patients with RA has been elucidated, revealing profound changes in the bacterial communities compared with those of healthy controls. This has led to several small clinical trials of progressive disease treatment as adjuvant for disease-modifying therapy in RA. SUMMARY: Smoking and periodontal disease are emerging risk factors for the development of RA. Epidemiological, clinical, and basic research has further strengthened this association, pointing toward changes in the oral microbiota as possible contributors to systemic inflammation and arthritis.

Treatment responses to tooth whitening in twins.

The aim of this study was to determine heritability estimates of treatment responses to a 10% hydrogen peroxide strip-based whitening system in twins. Eighty-five twin pairs were randomly assigned to 10% hydrogen peroxide whitening strips or placebo strips without peroxide. Both twins (monozygotic or dizygotic) received the same treatment. Maxillary teeth were treated for 30 minutes twice daily for 7 days. Efficacy was measured objectively as L* (light-dark), a* (red-green), and b* (yellow-blue) color change from digital images at baseline (∆) and day 8. Heritability estimates for tooth whitening treatment responses for changes from day 8 to baseline were obtained using variance-component methodologies. Whitening treatment responses were highly heritable (h(2) = 71.0) for ∆b* and ∆a*(p < .0001), but not for ∆L* (h(2) = 27.0), which was essentially modulated by environmental factors. This study has demonstrated that both genetic and environmental factors significantly contributed to seven-day whitening treatment responses achieved with 10% hydrogen peroxide strips.

Child externalizing behavior problems linked to genetic and non-genetic variation in dental caries.

The association of environmental and genetic variation in caries with child externalizing behavior problems (inattention, hyperactivity, impulsivity, and defiance) was studied in a sample of 239 pairs of 3- to 8-year-old impoverished Brazilian twins. It was hypothesized that externalizing problems would show a stronger positive association with environmental than genetic variation in caries. Univariate twin models were estimated to parse variation in caries into three components: additive genetic (A), shared environment (C) and non-shared environment/error (E). Age-adjusted associations between externalizing problems and each variance component were tested. Contrary to the hypothesis, modest but very consistent negative associations were found between externalizing problems and both genetic and environmental variation in caries. Mutans streptococci and sweetness preference did not explain the negative associations of caries and externalizing problems. Externalizing problems in non-medicated children were associated with less dental decay that could be explained by both genetic and environmental factors.

Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis.

OBJECTIVE: To profile the abundance and diversity of subgingival oral microbiota in patients with never-treated, new-onset rheumatoid arthritis (RA). METHODS: Periodontal disease (PD) status, clinical activity, and sociodemographic factors were determined in patients with new-onset RA, patients with chronic RA, and healthy subjects. Multiplexed-454 pyrosequencing was used to compare the composition of subgingival microbiota and establish correlations between the presence/abundance of bacteria and disease phenotypes. Anti-Porphyromonas gingivalis antibody testing was performed to assess prior exposure to the bacterial pathogen P gingivalis. RESULTS: The more advanced forms of periodontitis were already present at disease onset in patients with new-onset RA. The subgingival microbiota observed in patients with new-onset RA was distinct from that found in healthy controls. In most cases, however, these microbial differences could be attributed to the severity of PD and were not inherent to RA. The presence and abundance of P gingivalis were also directly associated with the severity of PD and were not unique to RA. The presence of P gingivalis was not correlated with anti-citrullinated protein antibody (ACPA) titers. Overall exposure to P gingivalis was similar between patients with new-onset RA and controls, observed in 78% of patients and 83% of controls. The presence and abundance of Anaeroglobus geminatus correlated with the presence of ACPAs/rheumatoid factor. Prevotella and Leptotrichia species were the only characteristic taxa observed in patients with new-onset RA irrespective of PD status. CONCLUSION: Patients with new-onset RA exhibited a high prevalence of PD at disease onset, despite their young age and paucity of smoking history. The subgingival microbiota profile in patients with new-onset RA was similar to that in patients with chronic RA and healthy subjects whose PD was of comparable severity. Although colonization with P gingivalis correlated with the severity of PD, overall exposure to P gingivalis was similar among the groups. The role of A geminatus and Prevotella/Leptotrichia species in this process merits further study.

The inhibitory activity of typified propolis against Enterococcus species.

Propolis, a natural bee product widely used for its antimicrobial activity, was tested against isolates of Enterococcus from humans, pig-tailed macaques, isolates of refractory endodontic treatment cases, and isolates from Lactobacillus-containing food supplements. Typification of the propolis was performed by high-performance liquid chromatography (HPLC) by which prenylated compounds, cinnamic acid derivatives, and flavonoids were detected as the main constituents. Minimum inhibitory concentrations (MIC) were determined using the agar dilution method. All human and animal Enterococcus isolates demonstrated MIC values of 1600 microg/mL. Enterococcal species of human and animal origin were inhibited by propolis. Particularly, human isolates of E. faecium and E. faecalis of refractory endodontic treatment cases were susceptible to propolis of Brazilian origin.

Low-dose doxycycline plus additional therapies may lower systemic inflammation in postmenopausal women with periodontitis.

SUBJECTS: Enrollment and study protocols took place between June 2002 and October 2005. This study was a supplemental project of a larger trial of cohorts recruited from university settings in Lincoln, Nebraska, and Stony Brook, New York. Female postmenopausal participants who had osteopenia and a history of moderate to advanced chronic periodontitis comprised the test group (n = 51; at baseline, n = 63) and placebo group (n = 62; at baseline, n = 64) after a 2-year study period. KEY EXPOSURE/STUDY FACTOR: Participants were allocated to a test group or a placebo group. Participants who belonged to the test group received subantimicrobial-dose-doxycycline (SDD)(20 mg of doxycycline hyclate) twice daily for 2 years. Participants in the control group received a look-alike placebo twice a day for 2 years. In addition, all patients received periodontal maintenance (every 3-4 months for the duration of the study) and were provided with a supply to be taken twice daily for the duration of the study of calcium (1200 mg) and vitamin D (400 IU). MAIN OUTCOME MEASURE: Markers of systemic inflammation (hs-CRP, myeloperoxidase, MMP-8, TIMP-1, MMP-9, MMP-2, IL-6, TNF-α, and IL-1ß) and lipid profiles (total cholesterol, HDL, LDL and VLDL cholesterol, and triglycerides). MAIN RESULTS: The combined treatment modalities (SDD + periodontal maintenance + dietary supplement) reduced hs-CRP levels as expressed by ratio of medians (SDD/placebo) by 18% compared with placebo (periodontal maintenance + dietary supplement) (0.82; confidence interval [CI] = 0.700.97; P = .02) after the 2-year study period when adjusting for the use of concomitant medications (statin, diuretics, aspirin). The combined treatment modalities significantly reduced MMP-9 (mean scanning units of treatment minus placebo) relative to placebo over the 2-year protocol (-28.44; CI = -40.17 to -16.72, P < .001). There were no statistically significant differences of lipid profiles between the combined treatment modalities and placebo group after a 2-year protocol. CONCLUSIONS: SDD when used as an adjunctive to periodontal maintenance plus dietary supplement significantly lowers serum biomarkers of inflammation in postmenopausal women with history of periodontitis.

Resemblance of tongue anatomy in twins.

This study compared the anatomical features of the tongue in nine pairs of twins - six monozygotic and three dizygotic. The aim of the project was to determine if tongues, like any other anatomical structure, could be used to reliably predict relatedness given that tongue shape, presentation and surface can be influenced by environment. Using the method of forced choice, 30 subjects were asked to match the photographs of tongues from twins. Our data indicate that, based on visual assessment, monozygotic twins have highly similar tongues (60% matches); similarly, dizygotic twins were matched 31% of the time, which is a higher probability than would be expected from random selection. This study should help identify baseline and control data in future behavioral studies of taste, which has a genetic basis.

Environmental and genetic contributions to indicators of oral malodor in twins.

This study aimed to: (1) determine concordance rates of self-reported and subjectively determined indicators of oral malodor in twins; (2) determine the relative contributions of genetic and environmental factors to levels of volatile sulfur compounds (VSCs) in intraoral and exhaled breath. Fifty-one twin pairs participated in the study. Measurements of VSCs were obtained by a halimeter. The presence of tongue coatings was determined and twins filled out a 32-item questionnaire on oral malodor indicators independently of one another. Estimates of heritability (h2) for halimeter measurements were computed by SOLAR. The concordance rates for the presence of tongue coating among identical and fraternal twins were 67% and 11%, respectively. In the 10 most informative items, 70% exhibited higher concordance rates for identical than for fraternal twins. Of particular interest were the differences in concordance rates for dry mouth, sinus infection and unusual sweating. The h2 for intraoral breath was 0.28 +/- 0.17 (NS), whereas the h2 for exhaled breath was 0.50 +/- 0.20 (p = .0207). The concordance rates of tongue coatings and malodor indicators were higher in identical twins than in fraternal twins. Intraoral breath VSC values were primarily attributable to environmental factors, whereas exhaled breath VSC values were partially explained by genetic factors.

Emerging technologies for the prevention of dental caries. Are current methods of prevention sufficient for the high risk patient?

Fluorides and chlorhexidine are technologies that are 65 and 40 years old, respectively. This overview argues that current methods of caries prevention are not effective for the high caries risk patient. In this review examples, arguments and recommendations are provided to address the high caries risk patient that include: failure of comprehensive chemical modalities treatments to address the high caries risk patient; ecological alteration - would this be an effective approach?; and biomaterials and oral microbiome research to address the high caries risk patient.

Dental caries pathogenicity: a genomic and metagenomic perspective.

In this review we address the subject of dental caries pathogenicity from a genomic and metagenomic perspective. The application of genomic technologies is certain to yield novel insights into the relationship between the bacterial flora, dental health and disease. Three primary attributes of bacterial species are thought to have direct impact on caries development, these include: adherence on tooth surfaces (biofilm formation), acid production and acid tolerance. Attempts to define the specific aetiological agents of dental caries have proven to be elusive, supporting the notion that caries aetiology is perhaps complex and multi-faceted. The recently introduced Human Microbiome Project (HMP) that endeavors to characterise the micro-organisms living in and on the human body is likely to shed new light on these questions and improve our understanding of polymicrobial disease, microbial ecology in the oral cavity and provide new avenues for therapeutic and molecular diagnostics developments.

Low-dose doxycycline plus additional therapies may lower systemic inflammation in postmenopausal women with periodontitis.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: The effect of subantimicrobial-dose-doxycycline periodontal therapy on serum biomarkers of systemic inflammation: a randomized, double-masked, placebo-controlled clinical trial. Payne JB, Golub LM, Stoner JA, Lee H-M, Reinhardt RA, Sorsa T, Slepian MJ. J Am Dent Assoc 2011;142;262-73. REVIEWER: Walter A. Bretz, DDS, PhD. PURPOSE/QUESTION: To determine whether long-term subantimicrobial-dose-doxycycline (SDD) periodontal therapy could reduce serum biomarkers of systemic inflammation and improve lipid profiles in postmenopausal women who have systemic osteopenia and chronic periodontitis. SOURCE OF FUNDING: NIH/NIDCR grant R01DE012872. TYPE OF STUDY/DESIGN: Randomized controlled trial. LEVEL OF EVIDENCE: Level 2: Limited-quality, patient-oriented evidence. STRENGTH OF RECOMMENDATION GRADE: Not applicable.

Propolis reduces the stemness of head and neck squamous cell carcinoma.

OBJECTIVE: To evaluate the effect of Brazilian propolis on head and neck cancer stem cells in vitro. METHODS: Head and neck squamous cell carcinoma (HNSCC) cell lines (UM-SCC-17B and UM-SCC-74A), human keratinocytes (HK), and primary human dermal microvascular endothelial cells (HDMEC) were treated with 0.5, 5.0, or 50 µg/mL green, brown or red Brazilian propolis or vehicle control for 24, 36, and 72 h. Cell viability was evaluated by Sulforhodamine B assay. Western blots evaluated expression of cancer stem cell (CSC) markers (i.e. ALDH, CD44, Oct-4, Bmi-1) and flow cytometry was performed to determine the impact of propolis in the fraction of CSC, defined as ALDHhighCD44high cells. RESULTS: propolis significantly reduced cell viability of HNSCC and HDMEC cells, but not HK. Notably, red propolis caused a significant reduction in the percentage of CSC, reduced the number of orospheres, and downregulated the expression of stem cell markers. CONCLUSIONS: Collectively, our data demonstrate an anti-CSC effect of propolis, and suggest that propolis (i.e. red propolis) might be beneficial for patients with head and neck cancer.

Hemostasis in periodontally treated patients on oral antithrombotic therapy may be possible.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Hemostatic management for periodontal treatments in patients on oral antithrombotic therapy: a retrospective study. Morimoto Y, Niwa H, Minematsu K. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108(6):889-96. REVIEWER: Walter A. Bretz, DDS, PhD. PURPOSE/QUESTION: The authors attempted to evaluate hemostatic management of periodontal treatment in patients on oral antithrombotic therapy. SOURCE OF FUNDING: Information not available. TYPE OF STUDY/DESIGN: Retrospective case series LEVEL OF EVIDENCE: Level 3: Other evidence. STRENGTH OF RECOMMENDATION GRADE: Not applicable.

Anti-inflammatory effects of a bioavailable compound, Artepillin C, in Brazilian propolis.

Artepillin C is the major compound in the Brazilian green propolis from Baccharis dracunculifolia. Our aim in this study was to investigate the anti-inflammatory effects, absorption, and bioavailability of Artepillin C in mice. The animals used were male Swiss mice subjected to: paw oedema by carrageenan (300 microg/paw), carrageenan-induced peritonitis, and prostaglandin E(2) determination. We also measured in vitro nitric oxide production by RAW 264.7 cells and NF-kappaB activity in HEK 293 cells. Finally, we measured the absorption and bioavailability of Artepillin C in plasma from mice by means of GC-MS after a single oral dose (10 mg/kg). In vivo, Artepillin C produced a maximal inhibition of 38% after 360 min on paw oedema. Artepillin C also decreased the number of neutrophils during peritonitis (IC(50): 0.9 (0.5-1.4) mg/kg). Treatment with Artepillin C decreased prostaglandin E(2) by 29+/-3% and 58+/-5% at 1 and 10 mg/kg, respectively, with a mean ID(50) of 8.5 (8.0-8.7) mg/kg). Similarly, in in vitro models, Artepillin C (3, 10, or 100 microM) decreased nitric oxide production by RAW 264.7 cells with a mean IC(50) of 8.5 (7.8-9.2) microM. In HEK 293 cells, Artepillin C reduced NF-kappaB activity with a mean IC(50) of 26 (22-30) mug/ml), suggesting anti-inflammatory activity, particularly during acute inflammation. Lastly, Artepillin C was absorbed after an oral dose (10 mg/kg) with maximal peaks found at 1 h (22 microg/ml). Collectively, Artepillin C showed anti-inflammatory effects mediated, at least in part, by prostaglandin E(2) and nitric oxide inhibition through NF-kappaB modulation, and exhibited bioavailability by oral administration.

Treatment outcomes of dental flossing in twins: molecular analysis of the interproximal microflora.

BACKGROUND: The purpose of this study was to assess the effects of dental flossing on the microbial composition of interproximal plaque samples in matched twins. METHODS: The study was a two-treatment, examiner-masked, randomized, parallel-group, controlled study. Fifty-one twin pairs between 12 and 21 years of age were randomized to a 2-week supervised and unsupervised treatment regimen consisting of tongue brushing and toothbrushing or tongue brushing and toothbrushing plus flossing. The reverse-capture checkerboard hybridization assay was used to assess levels (abundance) of 26 microbial species in interproximal plaque samples collected from six sites per subject. An integrative computational predictive model estimated average changes in microbial abundance patterns of selected bacterial species from baseline to 2 weeks by comparing treatment groups. RESULTS: After the 2-week study period, putative periodontal pathogens and cariogenic bacteria were overabundant in the group that did not floss compared to the group that performed flossing. Those included Treponema denticola, Porphyromonas gingivalis, Tannerella forsythia (previously T. forsythensis), Prevotella intermedia, Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), and Streptococcus mutans. Microbial species that are not consistent with the development of periodontal disease or dental caries were overabundant in the group that did floss compared to the non-flossing group. CONCLUSION: In a well-matched twin cohort, tooth and tongue brushing plus flossing significantly decreased the abundance of microbial species associated with periodontal disease and dental caries after a 2-week program.

Heritability of oral microbial species in caries-active and caries-free twins.

Oral microbes that colonize in the mouths of humans contribute to disease susceptibility, but it is unclear if host genetic factors mediate colonization. We therefore tested the hypothesis that the levels at which oral microbes colonize in the mouth are heritable. Dental plaque biofilms were sampled from intact tooth surfaces of 118 caries-free twins. An additional 86 caries-active twins were sampled for plaque from carious lesions and intact tooth surfaces. Using a reverse capture checkerboard assay the relative abundance of 82 bacterial species was determined. An integrative computational predictive model determined microbial abundance patterns of microbial species in caries-free twins as compared to caries-active twins. Heritability estimates were calculated for the relative microbial abundance levels of the microbial species in both groups. The levels of 10 species were significantly different in healthy individuals than in caries-active individuals, including, A. defectiva, S. parasanguinis, S. mitis/oralis, S. sanguinis, S. cristatus, S. salivarius, Streptococcus sp. clone CH016, G. morbillorum and G. haemolysans. Moderate to high heritability estimates were found for these species (h(2) = 56%-80%, p < .0001). Similarity of the overall oral microbial flora was also evident in caries-free twins from multivariate distance matrix regression analysis. It appears that genetic and/or familial factors significantly contribute to the colonization of oral beneficial species in twins.

Benefits of additional courses of systemic azithromycin in periodontal disease case report.

The strong association of subgingival anaerobic bacteria, such as Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, with destructive periodontal disease has been well documented in the literature. Several double-blind studies have also shown the beneficial use of systemic antimicrobials that are active against these microorganisms in conjunction with conventional periodontal treatment, especially when periodontal abscesses and/or suppuration upon probing are present. Four cases with periodontal abscesses were treated with scaling/root planing in conjunction with systemic azithromycin. Partial improvement led to retreatment with two additional courses of azithromycin. Bone formation was noted on periapical radiographs after the patients took additional courses of azithromycin. In view of the benefits of using additional courses of azithromycin in the treatment of destructive periodontal disease, we conclude that the single course of systemic antimicrobials currently used in periodontal therapy may be insufficient to reach necessary therapeutic levels in infected sites.