Periodontal Medicine Practice Model Mini Me

Home , Clinical attachment loss, Gingival recession, Host modulatory therapy, Junctional epithelium, Mouth assessment, Periodontal pathogen

Periodontal Medicine Practice Model

Mini Me

1. Documentation...... 4 Marginal Plaque Index...... 4 Soft Tissue Management...... 5 Probing Depth Measurement...... 6 Pathogen Profile...... 7 Clinical Case: Pathogen Profile...... 9 Summary Key...... 10 Radiographs...... 14 2. Diagnosis and Risk Assessment...... 17 Attachment Loss...... 17 Innate Risk...... 17 Race...... 17 Genetic Factors...... 18 Systemic Testing...... 19 Systemic Relationships...... 26 Diabetes...... 26 Cardiovascular Disease...... 33 Preterm Low Birth Weight...... 37 Acquired and Environmental Risk...... 44 Age...... 44 Tobacco / Smoking...... 45 Additional Material: PerioSciences...... 50 Cocaine and Other Illicit Drugs...... 53 Obstructive Sleep Apnea...... 54 Psychological Stress...... 55 Depression...... 56 Sarcoidosis...... 56 Rheumatoid Arthritis...... 57 Sexual Behavior...... 61 Kidney Disease...... 62 Alzheimer's Disease...... 63 Cytome Systemic Medication...... 64 Nutrition...... 65 Lifestyle Factors...... 72 3. Gingival Management...... 73 Oral Malodor...... 73

L1 Override ALWAYS Periodontal Medicine Practice Model 1 of 1 L2 Override • Marginal Plaque Index (MPI) L3 Override • Probing Depth Measurements (PD) – 6 Sites Per Tooth • Line Bleeding on Probing (BOP) • Clinical Attachment Loss (CAL) Documentation • Assess Bone Levels – Panorex – Periapical Radiograph – Bitewing – CBCT Scan • Pathogen Profi le

• Risk Prediction Diagnosis and (Innate vs. Acquired and Environmental) Risk Assessment • Genetic Testing – Biomarkers

• Scaling and Root Planing (SRP) – Mechanical Debridement Gingival Management – Ultrasonic Instrumentation (Controlling Local Factors) • Oral Hygiene Instruction • Home Care Management (i.e., toothbrush, fl oss, adjunctive protocols)

• Laser • Photodynamic Therapy • Antimicrobial Attachment Loss – Local Delivery Management – Systemic Delivery • Antiviral Medication • Host Modulation Therapy

• Root Coverage • Pocket Elimination (Horizontal Bone Loss) Surgical Management • Regenerative Therapy (Site Specifi c Defects; Infrabony) • Selective Extraction (Site Specifi c Defects)

• 6 Months – Low Risk Continuous Care • 4 Months – Moderate Risk Frequency • 3 Months – High Risk

© 2018Kois KoisCenter Center,, LLC LLC 3 MINI ME Periodontal Medicine Practice Model | 1. Documentation | Marginal Plaque Index 4 of 78 1. Documentation Marginal Plaque Index Establishment of a New Marginal Plaque Index with High Sensitivity for Changes in Oral Hygiene Deinzer R, Jahns S, Harnacke D. J Periodontol. 2014 Dec;85(12):1730-8.

Materials and Methods TABLE 1.1 Although several plaque indices exist, they Description of Different PIs rarely assess in detail the plaque adjacent to the gingival margin, an area most important for Index Level of Measurement Characteristics periodontal health. This study aims to develop a TQHI Ordinal Rating of plaque extension new marginal plaque index (MPI) and to assess considering the whole tooth; its validity and treatment sensitivity compared values from 0 to 5

to the internationally accepted Turesky Silness and Löe PI Ordinal Rating of plaque extension modification of the Quigley and Hein Index considering the whole tooth; (TQHI). values from 0 to 3

Modified navy PI, Dichotomous Presence or absence of Results O’Leary plaque plaque is assessed for 1. Convergent validity with TQHI is very good. control record/plaque prespecified areas. assessment scoring Concurrent and predictive validity parameters system of the MPI are similar to the TQHI. Axial and the proximal Cardinal Plaque height is measured by 2. The treatment sensitivity of MPI exceeds TQHI plaque extension means of a periodontal probe. by far. This results in a reduction by >70% of index

the sample size needed to discover significant Image analysis Cardinal Pictures of disclosed plaque treatment effects. are taken; plaque extension is measured in square 3. As expected, the largest treatment sensitivity millimeters. was observed for proximal MPI measures in study 1, whereas study 2 showed largest Plaque weight Cardinal Pooled weight of removed plaque is assessed. effects for cervical measures.

FIGURE 1.1 — Plaque is assessed at the proximal and cervical sections of the gingival margin. In order to do this, the gingival margin of each site (oral, vestibular) of a tooth is divided into four equal sections: 1) distal; 2) cervico-distal; 3) cervico-mesial; and 4) mesial. Plaque deposits are disclosed by a disclosure solution; the presence (score 1) or absence (score 0) of staining adjacent to the gingival margin is recorded for each section. Eight measures are thus recorded per tooth: 1) vestibular distal; 2) vestibular cervico-distal; 3) vestibular cervico-mesial; 4) vestibular mesial; 5) oral distal; 6) oral cervico-distal; 7) oral cervico-mesial; and 8) oral mesial. These measures can be aggregated to MPI all values (i.e., percentage of all sections scoring 1), MPI proximal values (i.e., percentage of mesial plus distal sections scoring 1), and MPI cervical values (i.e., percentage of cervico-distal plus cervico-mesial sections scoring 1). The index also allows for separate aggregation of recordings at oral and vestibular sites. d = distal; cd = cervico-distal; cm = cervico-mesial; m = mesial.

Conclusion 1. The MPI allows for valid assessment of oral hygiene. It converges well with TQHI and is demonstrated to have similar concurrent and predictive validity for papillary bleeding. Its treatment sensitivity for interventions aiming at proximal hygiene or tooth brushing exceeds that of the TQHI by far. 2. This leads to a dramatic reduction of the sample size needed to discover statistically significant effects with an acceptable test power. Furthermore, the MPI allows for differentiation between proximal and cervical plaque and responds differently to treatments aiming at one or the other. 3. Because it focuses on plaque accumulation at the gingival margin, it might be of special benefit for research and practice in periodontology in which marginal plaque is of particular importance.

Comparison between Clinical and Digital Soft Tissue Measurements Schneider D, Ender A, Truninger T, Leutert C, Sahrmann P, Roos M, Schmidlin P. J Esthet Restor Dent. 2014 May-Jun;26(3):191-9.

Materials and Methods Gingival recessions and papilla heights were measured at 30 sites by five examiners using the following methods: (A) direct measurements using a periodontal probe intraorally or (B) on cast models using a caliper, (C) digital measurements on virtual models obtained by optical scans taken intraorally, or (D) made of cast models using the same software. Measurements were repeated after 1 week and intraclass, intra-rater, and inter-rater correlations of the measurements using the four different methods were analyzed. Results The greatest disagreement between the 1st and 2nd measurement was identified for method A. Recessions were less reliably measured than papillae. The best agreement between methods was found in the digital ones (C and D). Regarding papilla height, increased values were obtained when method D was applied as compared with both clinical evaluations. For gingival recession, method A measured the highest values.

FIGURE 1.2 — References used for the measurement of gingival FIGURE 1.3 — Digital model of optically scanned recession at tooth 41 recession and papilla height. with scheme of measurement.

Conclusion Within the limitations of the study, the use of digital technologies by intraoral scanning or scanning of cast models improved the reproducibility and lowered the variance of measurements within one individual and between different investigators. Application of the digital work flow for measurements of gingival recessions and papilla height has the potential to improve the quality of data acquisition in clinical research.

Periodontal Probing Depth Measurement: A Review Khan S, Cabanilla LL. Compend Contin Educ Dent. 2009 Jan-Feb;30(1):12-4, 16, 18-21.

FIGURE 1.6 — Proper and improper insertion techniques. Underangulation of probe may lead to inaccurate probing depth (top); proper angulation of probe is parallel to the tooth surface, which allows the tip of the probe to reach the depth of the pocket (center); overangulation of probe may lead to inaccurate probing depth (bottom).

FIGURE 1.4 — Probing depth FIGURE 1.5 — Probing depth of of < 3 mm, with the tip of the 6 mm, with the tip of the probe probe coronal to the junctional apical to the coronal attachment epithelium in healthy gingival. of the junctional epithelium in inflamed gingival tissue.

Conclusion For more than a century, the periodontal probe has played an integral part in the periodontal examination and the detection of periodontal diseases. Its use not only enables treatment to be planned appropriately, but also facilitates longitudinal monitoring so that the response to treatment may be assessed and sites of possible disease progression identified. Yet, periodontal probing is an imprecise technique with several potential sources of error.

Important Differences in Clinical Data From Third, Second, and First Generation Periodontal Probes Breen HJ, Rogers PA, Lawless HC, Austin JS, Johnson NW. J Periodontol. 1997 Apr;68(4):335-45.

Conclusion 1. This study compared relative attachment levels and the probing of crevice depths from 6 probes. 2. Significant inter-probe differences were found. 3. Largest range of difference occurring in the Florida PD probe.

Partial-Mouth Assessment of Periodontal Disease in an Adult Population of the United States Owens JD, Dowsett SA, Eckert GJ, Zero DT, Kowolik MJ. J Periodontol. 2003 Aug;74(8):1206-13.

Conclusion 1. Whole-mouth periodontal examination includes examination of 6 sites per tooth on all existing teeth and is considered the “gold standard.” This method may not always be practical. 2. Comparison of whole-mouth, partial-mouth (6 index teeth – Ramsfjord index), or examination of limited sites per tooth were compared. Half-mouth assessment of 6 sites per tooth demonstrated accurate assessment of disease extent, severity, and prevalence. 3. By contrast, assessment of only 2 sites per tooth or examination of the 6 Ramsfjord teeth UNDERESTIMATED disease extent, severity, and prevalence.

Microbial Profiling in Experimentally Induced Biofilm Overgrowth among Patients with Various Periodontal States Paes Batista da Silva A, Barros SP, Moss K, Preisser J, Marchesan JT, Ward M, Offenbacher S. J Periodontol. 2016 Jan;87(1):27-35.

Materials and Methods In this prospective cohort study, 175 participants with various periodontal states (five biofilm-gingival interface [BGI] groups) abstained from oral hygiene while using an acrylic stent. At day 21, participants reinstituted oral hygiene and were followed for 4 weeks. Clinical parameters were recorded, and subgingival plaque samples were analyzed at baseline, peak of induction (day 21), and resolution using 16S rRNA probes (human oral microbe identification microarray). Using the change score (peak at induction minus baseline) for bleeding on probing and probing depth, the patients were separated FIGURE 1.7 into high and low clinical responders.

Conclusion 1. Synergistetes is associated with more severe forms of periodontal disease, represented by BGI-P2 and -P3. Plaque accumulation prompted substantial changes in subgingival biofilm composition in most BGI groups except BGI-P3, in which the subgingival biofilm seemed to be established. When oral hygiene was resumed and another examination performed after 4 weeks, most bacteria in all BGI groups were reduced to baseline levels. 2. However, some bacterial phyla did not reduce to baseline levels, such as synergistetes in BGI-P1, which were also detected in increased levels in the part of the population that had the greatest change in PD with the accumulation of plaque. Most importantly, higher levels of fusobacteria, proteobacteria, firmicutes, synergistetes, and bacteroidetes are associated with incident increasing probing depth. 3. Taken together, these findings further support the potential critical role of synergistetes (as well as the previously characterized fusobacteria, proteobacteria, firmicutes, and bacteroidetes) in periodontal pathogenesis.

Microbiologic Findings in Relation to Risk Assessment for Periodontal Disease: A Cross-Sectional Study Hur Y, Choi SK, Ogata Y, Stark PC, Levi PA. J Periodontol. 2016 Jan;87(1):21-6.

Materials and Methods Seventy-four patients with moderate and severe periodontitis were selected from patients receiving treatment at Tufts University School of Dental Medicine. Their periodontal risk was analyzed with a periodontitis risk assessment tool, and microbiologic testing was performed. Periodontitis risk assessment and microbiologic testing were examined for a possible association.

Conclusion 1. Patients with periodontitis were identified as high and very high risk compared to the rest of risk categories by a risk assessment tool. Patients who were identified as very high risk showed higher detection of putative periodontal bacteria (except Capnocytophaga species) than the rest of the study population. 2. A pilot model was suggested to evaluate the association of the microbiologic testing and known risk factors to clinical parameters in patients with periodontitis. Future studies with large sample sizes will be required to further explore the hypothesis.

Chronic Periodontitis and C-Reactive Protein Levels Gomes-Filho IS, Freitas Coelho JM, da Cruz SS, Passos JS, Teixeira de Freitas CO, Aragão Farias NS, Amorim da Silva R, Silva Pereira MN, Lima TL, Barreto ML. J Periodontol. 2011 Jul;82(7):969-78.

Conclusion From the data of the present study, along with other recent data, it was concluded that chronic periodontitis may add to the inflammatory burden of individuals and thus raise CRP levels, which may result in a higher risk of cardiovascular diseases. Furthermore, evaluations of this acute-phase protein may constitute an important tool for identifying changes to the periodontal and systemic health of individuals, especially among individuals who are at high risk of periodontitis and cardiovascular diseases.

No Association Between A. Actinomycetemcmitans or P. Gingivalis and Chronic or Aggressive Periodontits Diagnosis Nibali L, D’Aiuto F, Ready D, Parkar M, Yahaya R, Donos N. Quintessence Int. 2012 Mar;43(3):247-54.

FIGURE 1.8 — (A) clinical photograph and (B) panoramic radiograph of a 31-year-old patient diagnosed with AgP.

A B

FIGURE 1.9 — (A) clinical photograph and (B) panoramic radiograph of a 61-year-old patient diagnosed with CP.

A B

Conclusion Detection of known periodontopathogenic bacteria is not able to discriminate different forms of periodontitis.

CLINICAL CASE Pathogen Profi le 1 of 1

Clinical Case: Pathogen Profile

DATA COLLECTION

NAME Cindy DATE 1 11/28/2012 DATE 2 07/15/2014 DATE 3

MEDICAL ALERT None MAXIMUM OPENING (mm) DATE 1 48 DATE 2 48 DATE 3

DATE 3 DATE 3 PROBE DATE 2 �56 656 656 656 656 656 656 656 657 758 8�5 DATE 2 PROBE DATE 1 325 526 523 323 624 �34 423 425 527 625 524 DATE 1 FDI (Internati onal) # 18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28 FDI (Internati onal) # Universal (U.S.) # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Universal (U.S.) #

Facial Facial R L FIGURE 1 FIGURE 2

Lingual Lingual

Universal (U.S.) # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Universal (U.S.) # FDI (Internati onal) # 18 17 16 15 14 13 12 11 21 22 23 24 25 26 27 28 FDI (Internati onal) # DATE 1 465 535 5�3 324 454 323 �34 354 �54 634 425 DATE 1 PROBE DATE 2 ��6 656 656 6�5 ��5 ��5 656 656 657 756 6�5 DATE 2 PROBE DATE 3 DATE 3 DATE 1 DATE 1 MOBILITY DATE 2 DATE 2 MOBILITY DATE 3 DATE 3 Key Reference: BleedingNone DATE points 1 DATE 2 DATE- pathogen 3 overload?

DATE 3 DATE 3 PROBE DATE 2 568 957 656 656 656 656 657 656 656 656 656 645 ��5 DATE 2 PROBE DATE 1 ��4 647 645 624 �45 423 424 324 324 434 325 434 4�3 DATE 1 FDI (Internati onal) # 48 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38 FDI (Internati onal) # Universal (U.S.) # 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Universal (U.S.) # Initial Radiograph Lingual Lingual R 11/24/2014 L R L Facial Facial

Universal (U.S.) # 32 31 30 29 28 27 26 25 24 23 22 21 20 19 18 17 Universal (U.S.) # FDI (Internati onal) # 48 47 46 45 44 43 42 41 31 32 33 34 35 36 37 38 FDI (Internati onal) # DATE 1 435 735 436 7�3 535 523 4�2 325 326 635 �45 623 386 DATE 1 PROBE DATE 2 596 656 656 656 656 6�5 545 545 545 656 656 6�5 575 DATE 2 PROBE DATE 3 DATE 3 DATE 1 DATE 1 MOBILITY DATE 2 DATE 2 MOBILITY DATE 3 DATE 3 None DATE 1 DATE 2 DATE 3

FIGURE 5 FIGURE 6

PRODUCTS Pathogen Profile

• Pathogen Profile – Most Important My PerioPath (OralDNA Labs)

SUMMARY KEY Documentation for Predictive Outcomes

1. Biofilm assessment at the gingival margin is the most predictive for treatment options. Summary Key 2. Digital soft tissue measurements improve the quality of data acquisition. 3. Clinical attachment level combined with bleeding on probing is more predictive than probing depth. 4. Visual reflection of disease sites will reduce underestimation from radiograph probing of furcation involvement. 5. On average, smokers have less bleeding on probing but an increased prevalence of residual probing depths. 6. Fractal analysis may be able to discern changes in the interdental trabecular pattern of patients with moderate periodontitis. 7. The literature indicates that increased probing depths are usually related to loss of clinical attachment; however, they may not reflect periodontal disease or disease progression. 8. When characteristics pertaining to deep and shallow sites are compared, deep sites have more bleeding on probing, elevated bacterial levels, reduced ability of oral hygiene to alter subgingival microflora, less effective root instrumentation, and a greater percentage of pockets that experience disease progression in treated and untreated sites. 9. However, individual deep sites are not good predictors of disease progression. The preponderance of information indicates that it is preferable, but not always essential, to have shallow sites around teeth to attain and maintain periodontal health. Ultimately, therapeutic decisions based on probing depths are influenced by the medical and dental history of the patient, a practical interpretation of the literature, and clinical experiences. 10. In order to monitor Clinical Attachment Loss (CAL) it is more important to reference the CEJ to determine meaningful change, rather than comparing probing depth changes. 11. Prognosis will be more strongly impacted for molars with furcation concerns in order of importance based on Smoking, probing depth greater than 7 mm, mobility, and lastly molar type (Maxillary vs. Mandibular).

Highest Risk

Is Change in Probing Depth a Reliable Predictor of Change in Clinical Attachment Loss? Michalowicz BS, Hodges JS, Pihlstrom BL. J Am Dent Assoc. 2013 Feb;144(2):171-8.

TABLE 1.2

Utility of an Increase (Worsening) in Probing Depth (PD) (≥ 2 millimeters) in Predicting Change in Clinical Attachment Loss (CAL) (≥ 2 mm) in the same direction.*

NO. OF PERCENTAGE WITH PERCENTAGE WITH SITE CHARACTERISTIC SENSITIVITY SPECIFICITY PPV‡ NPV§ SITES PD Increase† CAL Increase†

Tooth Surface

Mesial or distal 18,709 3.0 6.2 0.36 0.99 0.75 0.96

Midfacial or lingual 9,009 1.5 5.2 0.24 1.00 0.84 0.96

Tooth Type

Molars 7,457 4.0 7.4 0.41 0.99 0.75 0.95

Non-molars 20,261 1.9 5.3 0.28 1.00 0.78 0.96

Baseline Probing Depth (Millimeters)

≤ 3 18,139 2.2 5.8 0.29 0.99 0.76 0.96

> 3 and < 7 8,495 2.7 5.5 0.38 0.99 0.77 0.96

≥ 7 1,084 5.2 8.4 0.47 0.99 0.77 0.95

* Sources: Ciancio and Ashley,15 Drisko and colleagues16 and Shevitz (unpublished master’s thesis, February 1999). † Change (either increase or decrease) of 2 or more mm from baseline to 12 months. ‡ PPV: Positive predictive value. § NPV: Negative predictive value.

FIGURE 1.10 — Initial FIGURE 1.11 — Post-initial therapy FIGURE 1.12

Conclusion 1. Using data from clinical trials, we found that use of probing depth alone to assess changes in a patient’s periodontal status frequently fails to detect changes in clinical attachment loss (CAL), especially at initially shallow and moderate sites. 2. Clinicians should consider monitoring the position of the gingival margin relative to the cementoenamel junction, which is used to compute CAL, in patients undergoing periodontal treatment. For researchers, use of CAL as a primary study outcome appears necessary to capture clinical treatment responses more completely. 3. Although CAL assessments require additional examiner training and time, monitoring PD alone in studies of periodontal non-surgical therapy fails to detect many sites that improve or deteriorate for as long as 12 months after treatment.

COMMENTARY Probing Depth

In order to monitor Clinical Attachment Loss (CAL) it is more important to reference the CEJ to determine meaningful change rather than comparing probing depth changes.

Variables Affecting Tooth Survival and Changes in Probing Depth: A Long-Term Follow-Up of Periodontitis Patients Saminsky M, Halperin-Sternfeld M, Machtei EE, Horwitz J. J Clin Periodontol. 2015 Jun;42(6):513-9.

Materials and Methods Patients in a private periodontal office whose files included initial examination, reevaluation and ≥ 10 years after initial examination chartings, and received periodontal therapy and supportive periodontal therapy after reevaluation were included. General health, plaque scores, probing depth, bleeding on probing at six points/tooth, tooth extractions, and supportive periodontal therapy visits were extracted from patient files at initial examination, reevaluation, and ≥ 10 years after initial examination.

TABLE 1.3 Proportional Hazards Model – Predictors of Tooth Loss

Extractions Total Extractions due to Periodontal Disease Parameter Hazard Risk (95%, Confidence Interval) Hazard Risk (95%, Confidence Interval)

Multi-rooted teeth 2 (1.3, 3.0) 1.9 (1.2, 3.1)

Probing depth at reevaluation (mm) 4–6 3.4 (2.1, 5.5) 5.7 (2.9, 10.9) 7 + 9.2 (5.3, 16.1) 17.7 (8.6, 36.6)

SPT < 3 times per years 1.7 (1.2, 2.6) 1.8 (1.11, 2.8)

Age at initial examination >60 2.5 (1.4, 4.8) 3.3 (1.5, 7.2)

Conclusion Regular supportive periodontal therapy was associated with low tooth-loss rates and continuous reductions in probing depth. Probing depth after initial therapy, age above 60, multi-rooted teeth and infrequent supportive periodontal therapy were strong negative prognostic factors for long-term tooth survival among periodontal patients.

Tooth Loss in Molars with and without Furcation Involvement: A Systematic Review and Meta-Analysis Nibali L, Zavattini A, Nagata K, Di Iorio A, Lin GH, Needleman I, Donos N. J Clin Periodontol. 2016 Feb;43(2):156-66.

Conclusion The presence of furcation involvement approximately doubles the risk of tooth loss for molars maintained in supportive periodontal therapy for up to 10–15 years. However, most molars, even with grade III furcation involvement respond well to periodontal therapy, suggesting that every effort should be made to maintain these teeth when possible. Long-term studies reporting patient-reported outcomes are needed to substantiate this conclusion.

Prevalence of Bleeding on Probing: A Cohort Study in a Specialist Periodontal Clinic Farina R, Scapoli C, Carrieri A, Guarnelli ME, Trombelli L. Quintessence Int. 2011 Jan;42(1):57-68.

Conclusion 1. Bleeding on probing (BoP) was highly prevalent and variable in both patients and different areas of the dentition; patient- related factors and site-specific characteristics (such as age, number of periodontal pockets, probing depth, tooth type, and aspects) seem to be partly responsible for the individual variation in BoP. High bleeding response (HB) and low bleeding response (LB) were not significantly different with respect to the investigated predictors. 2. The results of the present study demonstrated that BoP is a highly prevalent sign of gingival inflammation in a cohort of patients with different severity of periodontal disease. Six of 10 examined patients presented a BoP score greater 20% at their initial visit. 3. A wide variability in BoP score was observed in both patients and different areas of the dentition with patient-related factors, such as age and number of periodontal pockets, and site-specific characteristics, such as probing depth, as well as tooth type and aspects, being partly responsible for the individual variation in BoP. When compared in terms of age, sex, smoking, status, daily cigarette consumption, diabetes, and prevalence of sites with PPD ≥ 5 mm, patients with a high bleeding response were not significantly different from patients with a low bleeding response.

FIGURE 1.13 FIGURE 1.14 FIGURE 1.15 FIGURE 1.16

Bleeding on Probing as it Relates to Smoking Status in Patients Enrolled in Supportive Periodontal Therapy for at least 5 Years Ramseier CA, Mirra D, Schütz C, Sculean A, Lang NP, Walter C, Salvi GE. J Clin Periodontol. 2015 Feb;42(2):150-9.

Conclusion Irrespective of the smoking status, increased mean bleeding on probing in supportive periodontal therapy patients relates to disease severity and periodontal instability while smokers demonstrate lower mean bleeding on probing concomitantly with an increased prevalence of residual periodontal probing depths.

Periodontal Probing versus Radiographs for the Diagnosis of Furcation Involvement Graetz C, Plaumann A, Wiebe JF, Springer C, Sälzer S, Dörfer CE. J Periodontol. 2014 Oct;85(10):1371-9.

Materials and Methods In this retrospective clinical cohort study, 215 participants with periodontal disease and at least one molar treated with open flap surgery (OFS) were enrolled, and a total of 834 molars were assigned for furcation involvement (FI) by furcation probing (FP) and in radiographs analyzed by an experienced (EE) and less experienced examiner (LE). For the investigation, 143 panoramic radiographs (OPGs) and 77 intra-oral radiographs (I-Os) were evaluated. FIGURE 1.17 FIGURE 1.18 Results 1. The Class of FI by FP was confirmed in 56%, whereas 15% were overestimated and 29% underestimated. FI Class 0 and I had been detected with high probability (74% and 54%, respectively). 2. Of all FI Class III, 57% were detected correctly by radiographs and 32% by FP. FP and OFS revealed a weighted κ-coefficient (κw) = 0.588; radiographs and OFS had κw = 0.542 (OPG κw = 0.555 and I-O κw = 0.521). 3. The interrater reliability for radiographs was dependent on the experience of the examiner.

TABLE 1.4

Agreement of FI Diagnosed by Clinical Probing With a Nabers Probe (FP) Compared with the Situation Observed During OFS

FP Region Confirmed by OFS (%) Overestimated Compared with OFS (%) Underestimated Compared with OFS (%)

Total 56.2 14.8 29.0

Maxilla 53.8 16.3 29.9

Mandible 59.3 12.9 27.9

Conclusion 1. For experienced operators, the combination of radiographic imaging of furcations and clinical probing is mostly reliable. 2. It cannot be concluded by the data of this study which degree of clinically examined FI necessitates further radiographic diagnostic techniques such as I-O or OPG. 3. It should be noted that all three methods (FP, I-O, and OPG) investigated in this retrospective study underestimated the FI compared with the surgical measurements. 4. Therefore, the gold standard remains visual control during OFS. In the case that an underestimation will result in unfavorable outcomes, e.g., inappropriate planning of regenerative measures, further and more sophisticated diagnostic tools might be used.

Accuracy of Three-Dimensional Imaging in Assessing Maxillary Molar Furcation Involvement Walter C, Weiger R, Zitzmann NU. J Clin Periodontol. 2010 May;37(5):436-41.

A B C

D E

FIGURE 1.20 — Intra-surgical clinical photographs of the left maxillary molars FIGURE 1.19 — Cone beam computed of subject no. 4. (A) Pre-surgical view, (B) tri-section of the distobuccal root in the tomography with horizontal, sagittal and first maxillary molar, (C) theflap is fixed with monofil synthetic sutures 5x0, (D) transversal sections of the first and the 4 months p.o., the wound healing wasuneventful, (E) a crown with an extended second left maxillary molars (subject no. 4). metal margin is placed and the patient is instructedin meticulous oral hygiene.

Conclusion Cone beam computed tomography images demonstrate a high accuracy in assessing the loss of periodontal tissue and classifying the degree of furcation involvement in maxillary molars.

The Accuracy of Cone-Beam Computed Tomography in Assessing Maxillary Molar Furcation Involvement Qiao J, Wang S, Duan J, Zhang Y, Qiu Y, Sun C, Liu D. J Clin Periodontol. 2014 Mar;41(3):269-74.

FIGURE 1.22 — A schematic diagram of intra- surgical measurements of the buccal furcation. FE, furcation entrance; BD, the base of the defect; CEJ, the cementoenamel junction; BL-V, the distance from the furcation entrance to the base of the defect in the vertical direction. RT (the length of FIGURE 1.21 — CBCT with horizontal, the root trunk), the distance from the CEJ to FE. FIGURE 1.23 — Pre-surgical measurements sagittal and transverse sections of the first FW (the width of the furcation entrance), for the of the second left maxillary molar of subject and the second left maxillary molars (subject buccal furcation was the greatest mesial-distal 5: probing pocket depths (mb/b/db/mp/p/dp) No. 5). distance in the furcation. 4/7/5/3/3/5 mm, FI (b/mp/dp) II/0/0.

Conclusion Cone-beam computed tomography images demonstrate a high accuracy in assessing the loss of periodontal tissue of the furcation involvement and root morphologies in maxillary molars.

Use of Fractal Analysis for the Discrimination of Trabecular Changes Between Individuals With Healthy Gingiva or Moderate Periodontitis Sener E, Cinarcik S, Baksi BG. J Periodontol. 2015 Dec;86(12):1364-9.

FIGURE 1.24 — Digital periapical image demonstrating FIGURE 1.25 — Processing of ROI for FD calculation. (A) Duplicated ROI. (B) ROI blurred by the ROIs (white rectangles) used to calculate the FD. Gaussian filter. (C) The resultant image after subtracting the blurred image from the original and adding 128. (D) Binary and then inverted version of the image. (E) Skeletonized image.

TABLE 1.5 TABLE 1.6 Clinical Periodontal Measurements (mean 6 SD) FD Values (mean 6 SD)

Patients With Patients With Healthy Healthy Parameters Moderate FD Moderate Individuals Individuals Periodontitis Periodontitis

BOP (%) 8.45 ± 10.73 8.80 ± 3.4 First measurement 1.05 ± 0.14 0.81 ± 0.11

PD (mm) 1.95 ± 0.39 5.26 ± 10.73 Second measurement 0.99 ± 0.04 0.85 ± 0.05

CAL (mm) 1.32 ± 0.24 3.20 ± 1.1 Mean 1.02 ± 0.09 0.83 ± 0.08

Conclusion This preliminary study demonstrates that fractal analysis may be able to discern changes in the interdental trabecular pattern of patients with moderate periodontitis. Therefore, as long as digital images are used, fractal analysis is recommended as a quantitative and objective method in early detection of subtle bone changes associated with the early stages of periodontal breakdown.

Clinical and Other Risk Indicators for Early Periodontitis in Adults Tanner A, Kent R, Van Dyke T. J Periodontol. 2005 Apr;76(4):573-81.

Background Periodontal diseases affect over half the adults in the U.S., disproportionately affecting minority populations. Periodontitis can be treated in early stages, but it is not clear what features indicate, or could be risk factors for, early stages of periodontal attachment loss. This study aimed to evaluate associations between clinical and other risk indicators of early periodontitis. Results Subject age, plaque, and measures of gingivitis exhibited associations with attachment loss and probing depth. More periodontal attachment loss was detected in African-American and Hispanic subjects compared to Asian and Caucasian subjects. Smoking history was associated with attachment loss. At interproximal sites, lower molars most frequently had attachment loss, whereas at buccal/lingual sites, higher proportions of lower bicuspid teeth demonstrated attachment loss compared with other sites.

FIGURE 1.26 — Clinical characteristics of subjects by ethic and racial group.

Conclusion In this study of subjects with minimal attachment loss, gingival inflammation was associated with early periodontitis. Lower molar interproximal sites were frequently associated with interproximal attachment loss, whereas lower bicuspid teeth were at risk for gingival recession on buccal surfaces.

BACKSTORY Genetic Factors

1. Evidence indicates that genetically determined susceptibility is a critical determinant in the clinical manifestations of periodontal diseases: studies addressing family aggregation, formal genetic studies of different forms of early onset periodontitis, association with certain Mendellian inherited diseases (e.g., cyclic neutropenia), twin studies, and the finding that certain genetic polymorphisms are associated with an abnormal host response. 2. Studies that address the familial aggregation of early-onset periodontitis support the idea that there is autosomal- dominant inheritance for early-onset periodontitis. Other genetically transmitted diseases (e.g., cyclic neutropenia) result in decreased numbers and altered phagocytic function of neutrophils, predisposing individuals to develop periodontitis. Enhanced susceptibility may also be because of a genetically determined reduced capacity to produce gamma G immunoglobin (lgG)2 during periodontal infections or altered monocyte/macrophage function that results in increased release of proinflammatory mediators, thereby enhancing predisposition to disease. It has been noted that the data found in twin studies suggest that heredity can account for 50% of the enhanced risk for periodontitis. 3. A recent study concluded that susceptibility to severe periodontitis is significantly enhanced when genetic polymorphism of both IL-1α and IL-1β genes is detected. This is based on the supposition that these polymorphisms induce an overproduction of interleukins, thereby inducing greater destruction of periodontal tissues. Another investigation found that a genetic polymorphism of the IL-1β gene alone is sufficient to induce increased risk for periodontitis. These findings need to be examined in longitudinal studies before specific therapeutic approaches are suggested. There appear to be complex interactions between multiple genes and environmental factors that interact to induce disease and modify its expression. As these genes are discovered, it may be possible to integrate their identification into a risk profile that will help identify individuals who are susceptible to periodontitis and early tooth loss.

Aggressive Periodontitis is Likely Influenced by a Few Small Effect Genes De Carvalho FM, Tinoco EMB, Govil M, Marazita ML, Vieira AR. J Clin Periodontol. 2009 Jun;36(6):468-73.

Conclusion This result provides strong support for the hypothesis that genetic factors play a role in aggressive periodontitis and that a few loci, each with relatively small effects, contribute to aggressive periodontitis, with or without interaction with environmental factors.

The Gingival Crevicular Fluid Interleukin-1 Beta and Tumor Necrosis Factor-alpha Levels in a Patient with Rapidly Progressive Periodontitis Yavuzyilmaz E, Yamalik N, Bulut S, Ozen S, Ersoy F, Saatçi U. Aust Dent J. 1995 Feb;40(1):46-9.

Conclusion 1. The cytokines that are present in the bone microenvironment and can modulate osteoclast formation and activity are considered one of the markers of tissue breakdown in periodontal disease. 2. These findings suggest that cytokines may be involved in the pathogenesis of periodontal disease and can help in defining the active phase of periodontal breakdown. FIGURE 1.27

The Cost-Effectiveness of Interleukin-1 Genetic Testing for Periodontal Disease Higashi MK, Veenstra DL, del Aguila M, Hujoel P. J Periodontol. 2002 Dec;73(12):1474-84.

Data Assessment Three parameters in the analysis were highly influential: 1) the compliance rate for maintenance therapy in test positive versus non-tested patients; 2) the effectiveness of non-surgical therapy; 3) the relative risk of disease progression for test positive patients.

Conclusion 1. The models produced a wide range of outcomes reflecting our incomplete understanding of the biology, optimal treatment, and genetic susceptibility of periodontal diseases. 2. However, the model demonstrates that three clinical parameters are highly influential in determining if IL-1 testing can be implemented in a primary care setting in a cost-effective manner.

Clinical Utility of a Genetic Susceptibility Test for Severe Chronic Periodontitis – A Critical Evaluation Greenstein G, Hart TC. J Am Dent Assoc. 2002 Apr;133(4):452-9.

Conclusion Therefore, it is unclear how results of the genetic susceptibility test can be used to alter patients’ periodontal maintenance schedules or to change treatment regimens in periodontally symptomatic or asymptomatic patients. FIGURE 1.28

Interleukin-1 as a Genetic Marker for Periodontitis: Review of the Literature Grigoriadou ME, Koutayas SO, Madianos PN, Strub JR. Quintessence Int. 2010 Jun;41(6):517-25.

Abstract 1. Periodontitis is considered to be a multifactorial disease. Studies have indicated that part of the clinical variability in periodontitis may be explained by genetic factors. Genes can affect the immunoinflammatory host response to bacterial challenge in the periodontal tissues by means of an overproduction of proinflammatory cytokines, such as interleukin-1 (IL- 1). IL-1 plays an important role in the pathogenesis of periodontitis, through its involvement in the regulation of the host’s inflammatory response and bone resorption. Therefore, the genes that encode for IL-1 production have recently received most attention as potential predictors of periodontal disease progression. 2. Hence, the relationship between IL-1 genotype and periodontal disease has been investigated by a number of studies. This review article aimed to determine whether IL-1 could be regarded as a genetic marker for periodontitis by reviewing data concerning susceptibility, clinical parameters, and treatment strategies in relation to the IL-1 genotype. The review concluded that there is currently limited evidence to implicate a specific IL-1 genotype as a risk factor for chronic periodontitis in white populations. However, there is limited evidence that genetic variation in the IL-1B polymorphism could be a risk factor for aggressive periodontitis. FIGURE 1.29 TABLE 1.7 Chronic Periodontitis and IL-1 Genotype

Patients, Controls, n Other Genotype Study Type Race / Ethnicity Smoking Status Conclusions n (Females) (Females) Confounders Testing

Lopez et al Case-control 330 (69%) 101 (72%) Chilean Smokers and - IL-1A Association found between IL-1(+) and P regardless of (2005) Mean age 30 y Mean age 29 y nonsmokers IL-1B smoking status and severity of the disease.

Agrawal et Case-control 30 mild, 30 sex-and Maharashtrian Nonsmokers - IL-1A Association found between composite genotype and al (2006) 30 moderate, age-matched IL-1B severe CP. 30 severe CP

Sakellari et Case-control 56 (29) CP, 90 (46) 44 y Caucasian Smokers and - IL-1A No difference found in carriage rate of Il-1 al (2006) Mean age 51y, nonsmokers IL-1B polymorphisms between case and control subjects. 46 (26) AgP TNF-A Mean age 43 y COL 1A1 Sp1

Cullinan et Prospective 295 P (PD & CAL at - European heritage Smokers and Microbiologic IL-1A+ Interaction found between IL-1 genotype, smoking al (2001) longitudinal baseline, 6, 12, 34, nonsmokers assessment IL-1B age and Porphyromonas gingivalis. Il-1 genotype is a 36, 48 and 60 mo) contributory but not essential risk factor for P.

(P) Periodontitis, (CP) chronic periodontitis, (AgP) aggressive periodontitis, (gen) genotype, (+) positive, (-) negative, (bp) base pair, (VNTR) variable number tandem repeat, (*2) allele 2.

TABLE 1.8 Prevalence of the IL – 1 Genotype in Different Ethnicity / Races

Study No. of Genotyped Subjects Ethnicity/ Race Genotype Testing Prevalence

McGuire and Nunn (1999) 42 SPT Caucasian Composite Genotype 38%

Socransky et al (2000) 108 range of P severities Caucasian Composite Genotype 27%

Lang et al (2000) 323 SPT Caucasian Composite Genotype 35.3%

Sakellari et al (2003) 45 CP/110 healthy Caucasian Composite Genotype 44%/ 38%

Armitage et al (2000) 300 volunteers with different periodontal health Chinese Composite Genotype 2.3%

Walker et al (2000) 34 LAgP/104 healthy African American Composite Genotype 8%/ 14.5%

Caffesse et al (2002) 22 healthy Hispanic Composite Genotype 26%

Lopez et al (2005) 330 patients/101 healthy Chilean Composite Genotype 26%/ 9.9%

Agrawal et al (2006) 30 healthy Maharashtrian Composite Genotype 30%

(LAgP) Localized aggressive periodontitis, (SPT) supportive periodontal therapy, (P) periodontitis, (CP) chronic periodontitis.

Conclusion 1. Currently, there is limited evidence to implicate a specific IL-1 genotype as a risk factor for chronic periodontitis in Caucasian populations. 2. It is questionable whether a specific IL-1 genotype may be a risk factor for aggressive periodontitis. However, there is limited evidence that genetic variation in the IL-1B polymorphism could be a risk factor for this type of periodontitis. 3. There is not enough evidence that a specific IL-1 genotype influences the clinical outcome of periodontal treatment. 4. The IL-1 genotype cannot be used in all ethnic groups to determine susceptibility to periodontitis because of the variability in prevalence in different races.

Validation of an Algorithm for Chronic Periodontitis Risk Assessment and Prognostication: Analysis of an Inflammatory Reactivity Test and Selected Risk Predictors Lindskog S, Blomlöf J, Persson I, Niklason A, Hedin A, Ericsson L, Ericsson M, Järncrantz B, Tellefsen G, Zetterström O, Blomlöf L. J Periodontol. 2010 Jun;81(6):837-47.

TABLE 1.9

Periodontitis Risk Predictors Classified According to Systemic and Local Predictors

Systemic Predictors Local Predictors

Age in relation to history of chronic periodontitis Bacterial plaque (oral hygiene)

Family history of chronic periodontitis Endodontic pathology

Systemic disease* and related diagnoses† Furcation involvement

Result of skin provocation test to assess the patient’s inflammatory reactivity Angular bony destruction

Patient cooperation and disease awareness Radiographic marginal bone loss

Socioeconomic status Periodontal probing depth

Smoking habits Periodontal bleeding on probing

The therapist’s experience with periodontal care Marginal dental restorations

Increased tooth mobility

* Diabetes, immunopathies, and hematologic disorders, hereditary disorders relevant to the formation and maintenance of connective tissue and bone, granulomatous disease, osteoporosis, renal disorders, inflammatory vascular disease, Sjögren’s syndrome, and rheumatism. † Medication leading to decreased salivation, pregnancy, malnutrition and obesity, and alcoholism. This table was previously published (J Periodontol 2010; 81:584-593).

Conclusion Although not widely acknowledged, patients with severe forms of chronic periodontitis present with varying degrees of decreased inflammatory reactivity as demonstrated by an impaired reactivity to a localized peripheral lipid A challenge. Explanatory values for a skin provocation test for inflammatory reactivity ranged between 2.6% and 5.1% with a positive predictive value of 82%. This should be compared to smoking, endodontic pathology, abutment teeth, angular bony destruction, and furcation involvement that presented with individual explanatory values for periodontitis progression between 4% and 13% and highly significant parameter estimates. Because of the complex nature of chronic periodontitis, risk assessment and prognostication show great variability between clinicians and should not be based on just one or a few risk predictors. The clinical use of the skin provocation test in addition to other risk predictors appears to lie in the selection of high risk patients for in-depth analysis tooth by tooth, the results of which should be analyzed together with a sufficient number of other relevant risk predictors.

Relationships among Gingival Crevicular Fluid Biomarkers, Clinical Parameters of Periodontal Disease, and the Subgingival Microbiota Teles R, Sakellari D, Teles F, Konstantinidis A, Kent R, Socransky S, Haffajee A. J Periodontol. 2010 Jan;81(1):89-98.

TABLE 1.10

Demographic, Immunologic, and Clinical Parameters (mean ± SD) for the Clinical Groups

Parameters Healthy (n=20) Periodontitis (n=20)

Age (years)*† 38 ± 13 55 ± 12

Males (%)‡ 40 35

Smokers (%)‡ 50 40

Cigarettes per day (n)§ 7.5 ± 8.3 12.1 ± 21.1

PD (mm)*† 1.82 ± 0.24 3.66 ± 0.86

Recession (mm)*† 0.11 ± 0.11 1.38 ± 0.71

Percentage of sites with:

Plaque*§ 22 ± 18 75 ± 23

BOP*† 10 ± 8 66 ± 16

Gingival redness*† 3 ± 5 49 ± 32

Suppuration§‼ 0 ± 0 3 ± 4

GCF volume (µl)*† 0.16 ± 0.07 0.49 ± 0.21

IL-1β (pg/site)*† 7.4 ± 4.8 29.9 ± 14.6

IL-8 (pg/site)*† 45.6 ± 35.0 98.8 ± 42.4

MMP-8 (ng/site)†¶ 14.1 ± 15.1 34.7 ± 30.0

* P <0.001. † Unpaired t test. ‡ Fisher exact test. § Mann-Whitney test. ‼ P <0.05. ¶ P <0.01

Conclusion Our data strengthened the association described in the literature between gingival crevicular fluid (GCF) levels of three inflammatory mediators and clinical signs of periodontitis. We also demonstrated that clinically healthy sites in subjects with periodontitis had significantly higher levels of interleukin (IL)-1b and IL-8, an increased volume of GCF, and a higher proportion of orange and red complex species than clinically healthy sites in healthy subjects. These results suggest that clinically healthy sites in subjects with periodontitis might be colonized by higher levels of periodontal pathogens and be exposed to a subclinical level of inflammation, potentially leading to a higher risk for periodontal disease initiation and progression. In addition, our findings suggest that the expression of GCF biomarkers is influenced by the microbial composition of the adjacent subgingival biofilm.

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Inflammation and Genetic Risk Indicators for Early Periodontitis in Adults Stashenko P, Van Dyke T, Tully P, Kent R, Sonis S, Tanner AC. J Periodontol. 2011 Apr;82(4):588-96.

TABLE 1.11

General and Demographic Characteristics of the Study Population at Baseline

Healthy (n = 42) EP1 (n = 103) EP2 (n = 45)

Characteristic

Mean age (years; ± SEM)* 26.8 ± 0.8 29.2 ± 0.6 31.8 ± 1.0

Sex (n [% male])† 12 (29) 46 (45) 24 (53)

Smoking history (n [% clinical group])‡§

Never-smokers (n [%]) 35 (83) 67 (66) 27 (60)

Former smokers (n [%]) 4 (10) 19 (19) 7 (16)

Current smokers (n [%]) 3 (7) 16 (16) 11 (24)

Race/ethnicity (n [% clinical group])||

Asian (n [%]) 3 (7) 10 (11) 3 (7)

African American (n [%]) 2 (5) 15 (15) 13 (29)

Hispanic (n [%]) 5 (12) 2 (2) 7 (15)

White (n [%]) 31 (74) 68 (66) 21 (47)

IL-1 gene polymorphism

All subjects (%)¶ 17 (40) 31 (30) 10 (22)

White never-smoker only by clinical group (n/total [%]) 10/27 (37) 13/44 (30) 4/15 (27)

* P = 0.0007 (one-way analysis of variances of means across clinical categories). † P = 0.02 (Mantel-Haenszel X2 test). ‡ There was one subject without a smoking history in the EP1 category. § P = 0.013 (Mantel-Haenszel X2 test of association between smoking and disease categories). || P = 0.002 X2 test between four major race/ethnic groups. ¶ Subjects in other racial groups are not shown and included one subject in the healthy category, eight subjects in the EP1 category, and one subject in the EP2 category.

Conclusion We performed a cross-sectional and longitudinal evaluation of adult subjects with early periodontitis aged 20 to 40 years. We found that GCF IL-1b levels positively correlated with attachment levels, PDs, the GI, BOP, and smoking. The composite IL-1 genetic-test genotype did not correlate with disease or disease progression. We concluded that indicators of inflammation may be important clinical determinants of future periodontal disease progression, but that the IL-1 genotype was not a risk indictor for early periodontitis as defined in this subject population.

SUMMARY KEY Genetic Risk Indicators

1. The IL-1 genotype is not a risk indicator for early periodontitis. 2. The IL-1B genotype is correlated predictably with aggressive periodontitis. 3. Other Genetic Risk Indicators will need to be paired with specific pathogens to be of prognostic value. 4. The usefulness of a genetic analysis of patients with periodontitis in a clinical setting is still in the future. While clinical examination may not be able to distinguish different forms of the disease with different pathogenesis, in the near future, genetic testing will become an adjunctive tool for the clinician to be able to provide more specific diagnoses, with possible better prognostic data containing different treatment modalities.

Derivation and Validation of the Periodontal and Tooth Profile Classification System for Patient Stratification Morelli T, Moss KL, Beck J, Preisser JS, Wu D, Divaris K, Offenbacher S. J Periodontol. 2017 Feb;88(2):153-65.

Background The goal of this study is to use bioinformatics tools to explore identification and definition of distinct periodontal and tooth profile classes (PPCs/TPCs) among a cohort of individuals by using detailed clinical measures at the tooth level, including both periodontal measurements and tooth loss. Materials and Methods Full-mouth clinical periodontal measurements (seven clinical parameters) from 6,793 individuals from the Dental Atherosclerosis Risk in Communities Study (DARIC) were used to identify PPC. A custom latent class analysis procedure was developed to identify clinically distinct PPCs and TPCs. Three validation cohorts were used: NHANES (2009 to 2010 and 2011 to 2012) and the Piedmont Study population (7,785 individuals). Results The latent class analysis method identified seven distinct periodontal profile classes (PPCs A to G) and seven distinct tooth profile classes (TPCs A to G) ranging from health to severe periodontal disease status. The method enabled identification of classes with common clinical manifestations that are hidden under the current periodontal classification schemas. Class assignment was robust with small misclassification error in the presence of missing data. The PPC algorithm was applied and confirmed in three distinct cohorts.

Conclusion The findings suggest periodontal and tooth profile classes using latent class analysis can provide robust periodontal clinical definitions that reflect disease patterns in the population at an individual and tooth level.These classifications can potentially be used for patient stratification and thus provide tools for integrating multiple datasets to assess risk for periodontitis progression and tooth loss in dental patients.

Genome-Wide Association Study of Biologically Informed Periodontal Complex Traits Offers Novel Insights into the Genetic Basis of Periodontal Disease Offenbacher S, Divaris K, Barros SP, Moss KL, Marchesan JT, Morelli T, Zhang S, Kim S, Sun L, Beck JD, Laudes M, Munz M, Schaefer AS, North KE. Hum Mol Genet. 2016 May 15;25(10):2113-29.

Summary Genome-wide association studies (GWAS) of chronic periodontitis (CP) defined by clinical criteria alone have had modest success to-date. Here, we refine the CP phenotype by supplementing clinical data with biological intermediates of microbial burden (levels of eight periodontal pathogens) and local inflammatory response (gingival crevicular fluid IL-1β) and derive periodontal complex traits (PCTs) via principal component analysis. PCTs were carried forward to GWAS (~2.5 million markers) to identify PCT-associated loci among 975 European American adult participants of the Dental ARIC study. We sought to validate these findings for CP in the larger ARIC cohort (n = 821 participants with severe CP, 2031—moderate CP, 1914— healthy/mild disease) and an independent German sample including 717 aggressive periodontitis cases and 4210 controls. We identified six PCTs with distinct microbial community/IL-1β structures, although with overlapping clinical presentations.

Conclusion The current investigation has provided new data that suggest a genetic basis of periodontal disease defined by microbial community structure and inflammatory characteristics. In addition, our results highlight loci and candidate genes for replication, functional analyses and further characterization as potential risk markers for subsets of individuals with this common disease, which is associated with microbial dysbiosis at the tooth–oral mucosal interface.

BACKSTORY Diabetes

1. There are 2 major types of diabetes: Type 1-insulin dependent and type 2-non insulin dependent. Type 1 is characterized by reduction of insulin caused by destruction of pancreatic beta cells, whereas in Type 2 there is resistance of target tissues to the action of insulin. Investigators have indicated that diabetics have a 2 to 3 times greater chance of developing periodontitis than nondiabetics. On the other hand, patients whose diabetes is medically managed respond normally to therapy and are not at increased risk for periodontitis. 2. No difference in the subgingival microflora was detected among diabetics and nondiabetics. However, it was suggested that diabetics respond differently to pathogens because of impaired host defenses, thereby making them more susceptible to infections. This has been attributed to vascular changes, polymorphonuclear leukocyte dysfunction, and altered immune regulation. Vascular changes seen in diabetics are caused by prolonged exposure to hyperglycemia. This results in formation of advanced glycation endproducts (nonenzymatic glycated proteins and lipids), which induce irregular thickness and rigidity of blood vessels that impair leukocyte diapedesis, oxygen diffusion, and metabolic waste removal. It also results in an increased secretion of proinflammatory cytokines (IL-1β, TNF-α), impaired neutrophil chemotaxis, and altered connective tissue metabolism. These alterations may contribute to a predisposition to the initiation and increased severity of periodontal disease and delayed wound healing among diabetics. The clinical finding of rapid changes in the periodontal status of patients with diabetes should increase the clinician’s suspicion of a change in the metabolic status of the patient, and a medical consultation may be required.

The Relationship Between Diabetes and Periodontal Disease Gian-Grasso JE, Nagelberg SB. Pract Diabetol. 1997 Sep:8-10.

Conclusion 1. Patients with uncontrolled or poorly controlled diabetes have a higher incidence of periodontal diseases, with greater severity of many periodontal conditions. 2. It has been shown that treatment of periodontal disease has the potential to reduce insulin requirements and improve glucose control.

Association between Immunologic Parameters, Glycemic Control, and Postextraction Complications in Patients with Type 2 Diabetes Fernandes KS, Glick M, de Souza MS, Kokron CM, Gallottini M. J Am Dent Assoc. 2015 Aug;146(8):592-9.

Results Even in the presence of impaired neutrophil function and poor glycemic control, we found no increase in the number of postoperative complications. There was no association between delayed wound epithelialization on postoperative day 21 and level of glycemic control, and reduced neutrophil function. On postoperative day 60, all alveolar sockets were epithelialized completely and showed no signs of infection.

Conclusion The study results suggest that type 2 diabetes per se or glycemic control is not a risk factor for experiencing postoperative complications in people undergoing dental extractions. Although people with type 2 diabetes may have impaired neutrophil function, the study results revealed that having this condition was not associated with an increased risk of experiencing postoperative complications. Additional research studies with larger sample sizes of patients who have diabetes are needed to confirm this study’s findings.

COMMENTARY Type 2 Diabetes and Post-extraction Complications

The results allow clinicians to infer that people with type 2 diabetes undergoing dental extractions of erupted teeth that do not have an acute odontogenic infection should not receive antibiotic prophylaxis simply because of their diabetic status or level of glycemic control.

Best Practices for Managing the Diabetic Patient in the Dental Office Mealey BL, Genco RJ, Schallhorn RA. Compend Contin Educ Dent. 2016 Jan;37(1):16-21.

Conclusion 1. Dentists should base their clinical care on science. However, it is important to remember that science is based on means and standard deviations, whereas clinical care must focus on the individual person sitting in the dental chair—and that patient may or may not be average. 2. As the standard bell curve illustrates, only two-thirds of the people in any dental practice fall within the average range, plus or minus one standard deviation. 3. In effect, the science may not apply to a third of the patients; thus, some people with well-controlled diabetes will still have periodontal disease, and some with very poorly controlled diabetes will have a healthy periodontium.

Periodontal Treatment and HbA1c Levels in Subjects with Diabetes Mellitus Altamash M, Klinge B, Engström PE. J Oral Rehabil. 2016 Jan;43(1):31-8.

Background It has earlier been reported that individuals with poorly controlled diabetes have severe periodontal disease (PD) compared to well-controlled diabetes. Materials and Methods This longitudinal interventional study compared periodontal treatment outcomes with HbA1c level changes in four groups of diabetic and non-diabetic patients with or without PD, respectively. HbA1c, bleeding on probing (BOP), plaque index and periodontal pocket depth (PPD) 4 < 6 mm and ≥6 mm were recorded at baseline to 3 months after non-surgical treatment and 3-6 months for surgical treatment in subjects with or without type 2 diabetes, and with or without PD. A total of 129 patients were followed from baseline to 6 months. Results 1. Diabetics with PD and without PD showed reductions in HbA1c levels with a mean value of 0.3% after 3 months and mean values of 1% and 0.8%, respectively, after 6 months. 2. Diabetics with PD showed higher levels of BOP versus non-diabetics without PD and versus diabetics without PD at baseline. 3. After 6 months, diabetics with PD showed higher number of PPD 4 < 6 mm versus diabetics without PD and non-diabetics with PD. Diabetics without PD showed higher levels of PPD 4 < 6 mm versus non-diabetics without PD. 4. Surgical and non-surgical periodontal treatment in all groups improved periodontal inflammatory conditions with a decrease in HbA1c levels in a period of three and 6 months. 5. No change was seen in the number of pockets PPD 4 < 6 mm in diabetic subjects with PD after non-surgical and surgical treatment.

Conclusion Surgical and non-surgical periodontal treatment in all groups improved periodontal inflammatory conditions in subjects with type 2 diabetes along with a decrease in HbA1c levels in a period of 3 and 6 months. There was no decrease in PPD 4 < 6 mm in diabetic subjects with PD after non-surgical and surgical treatment. The reduction in blood sugar levels in subjects with diabetes mellitus requires periodontal treatment for at least 6 months.

Cross-Sectional Analysis of Different Variables of Patients with Non-Insulin Dependent Diabetes and Their Periodontal Status Lu HK, Yang PC. Int J Periodontics Restorative Dent. 2004 Feb;24(1):71-9.

Comparison of Gingival Index and Attachment Level

FIGURE 1.30 — Comparison of Gingival Index (GI) and attachment loss FIGURE 1.31 — Comparison of Gingival Index (GI) and attachment (AL) in NIDDM group stratified by duration of diabetes. AL: duration loss (AL) in NIDDM group stratified by level of disease control. P < .05; 3>durations 1 and 2. P < .05; Scheffe test. Scheffe test.

Conclusion 1. Patients who had had diabetes for more than 10 years had a higher AL than those who had suffered from diabetes for less than 10 years. 2. Patients with average HbA1c values ≥ 10% had more serious mean GI values than those with HbA1c values < 10%. 3. In patients with diabetes, age, plaque accumulation, and calculus formation have more detrimental effects on the periodontal apparatus than in healthy individuals.

Insulin Sensitivity and Periodontal Infection in a Non-Diabetic, Non-Smoking Adult Population Timonen P, Suominen-Taipale L, Jula A, Niskanen M, Knuuttila M, Ylöstalo P. J Clin Periodontol. 2011 Jan;38(1):17-24.

Results We found that insulin sensitivity was associated with periodontal infection in the age group 30–49, but not in persons aged 50–64. Controlling for body weight made the association between insulin sensitivity and periodontal infection disappear.

Conclusion The lack of knowledge of the underlying causal model prevents making definite conclusions about the role of reduced insulin sensitivity in the pathogenesis of periodontal infection.

Effect of Non-Surgical Periodontal Therapy on C-Reactive Protein, Oxidative Stress, and Matrix Metalloproteinase (MMP)-9 and MMP-2 Levels in Patients with Type 2 Diabetes: A Randomized Controlled Study Koromantzos PA, Makrilakis K, Dereka X, Offenbacher S, Katsilambros N, Vrotsos IA, Madianos PN. J Periodontol. 2012 Jan;83(1):3-10.

Background It is well accepted that glycemic control in patients with diabetes mellitus (DM) is affected by systemic inflammation and oxidative stress. The effect of periodontal therapy on these systemic factors may be related to improvement on glycemic status. The aim of the present study is to assess over a period of 6 months the effect of non-surgical periodontal therapy on serum levels of high-sensitivity C-reactive protein (CRP), d-8-iso prostaglandin F2a (d-8-iso) as a marker of oxidative stress, and matrix metalloproteinase (MMP)-2 and MMP-9 on patients with type 2 DM. Results Although there was a trend to a reduction in hsCRP, d-8-iso and MMP-9 it did not reach statistical significance. MMP-2 levels remained unchanged after periodontal treatment.

Conclusion Effective non-surgical periodontal treatment of participants with type 2 DM and moderate to severe periodontal disease improved A1c levels significantly but did not result in a statistically significant improvement in CRP, d-8-iso, MMP-2, and MMP-9 levels.

Pre-Diabetes and Well-Controlled Diabetes are Not Associated with Periodontal Disease: The SHIP Trend Study Kowall B, Holtfreter B, Völzke H, Schipf S, Mundt T, Rathmann W, Kocher T. J Clin Periodontol. 2015 May;42(5):422-30.

Conclusion Periodontitis and edentulism were associated with poorly controlled type 2 diabetes, but not with pre-diabetes and well- controlled diabetes.

Association between Periodontitis and Preeclampsia in Never-Smokers: A Prospective Study Ha JE, Jun JK, Ko HJ, Paik DI, Bae KH. J Clin Periodontol. 2014 Sep;41(9):869-74.

Materials and Methods 1. Pregnant women were recruited at 21 to 24 weeks of gestation from March 2009 to June 2013. 2. Information on demographics, health behaviors, obstetric history, and systemic diseases that can influence periodontal status and preeclampsia was collected. 3. Full-mouth periodontal probing was performed by two trained examiners. The inter-examiner Kappa value was 0.822 for clinical attachment loss. 4. Periodontitis was defined as clinical periodontal attachment loss of 4.0 mm or greater on 2 or more sites not on the same tooth. 5. Information on the occurrence of preeclampsia was collected by five obstetricians. Results 1. We studied a total of 283 subjects, comprised of 67 subjects with periodontitis and 216 subjects without periodontitis. 2. Of these, 13 (4.6%) women were diagnosed with preeclampsia. 3. After adjusting for all confounders, the adjusted odds ratio of periodontitis for preeclampsia was 5.56.

Conclusion 1. This study revealed that periodontitis increased the risk of preeclampsia among never-smokers. 2. As periodontitis can be associated with the increased risk of preeclampsia, oral health care for periodontitis need to be recommended before and during pregnancy.

Clinical and Metabolic Evaluation of One-Stage, Full-Mouth, Ultrasonic Debridement as a Therapeutic Approach for Uncontrolled Type 2 Diabetic Patients with Periodontitis Cirano FR, Pera C, Ueda P, Casarin RC, Ribeiro FV, Pimentel SP, Casati MZ. Quintessence Int. 2012 Sep;43(8):671-81.

Materials and Methods 1. Sixteen patients diagnosed with generalized severe chronic periodontitis and type 2 diabetes mellitus were allocated to the diabetic group; another 15 subjects with periodontitis but without metabolic disorders were placed in the non-diabetic group. 2. Both groups were treated using the full-mouth, ultrasonic debridement (FMUD) protocol, a unique 45-minute session of ultrasonic debridement of all sites presenting periodontal disease. 3. Patient were analyzed for the following parameters: plaque and bleeding indices, gingival recession, probing depth, and clinical attachment level. further, diabetic subjects were assessed using fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) tests. Results 1. Both groups showed improved periodontal health after treatment. There were no significant differences between the groups for any of the parameters assessed. 2. Diabetic subjects treated with FMUD had a clinical response similar to that of non-diabetic subjects at all pocket depths. 3. No adverse effects or medical disturbances were observed in either group during treatment. FPG and HbA1c levels remained unaltered after treatment.

Conclusion The results indicate that full-mouth, ultrasonic debridement treatment promotes clinical improvements in patients with type 2 uncontrolled diabetes and generalized severe chronic periodontitis.

PRINCIPLES Diabetes Risk Factors for Periodontal Disease

Adequacy of Control of Diabetes

Hemoglobin A1c Average Blood Sugar Level of Control

< 7% < 140 mg/dL Good

7 – 9% 140-220 mg/dL Fair

> 9% > 330 mg/dL Poor (red flag)

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COMMENTARY Diabetes

There is insufficient evidence to alter our concerns in the diabetic patient. However, full-mouth ultrasonic debridement is a viable alternative.

Cardiovascular Disease

Effect of Non-Surgical Periodontal Treatment on Clinical and Biochemical Risk Markers of Cardiovascular Disease: A Randomized Trial Hada DS, Garg S, Ramteke GB, Ratre MS. J Periodontol. 2015 Nov;86(11):1201-11.

Background Various studies have shown periodontal disease is one of the risk factors for coronary heart disease (CHD), and periodontal treatment of patients with CHD has also been correlated with reduction in systemic markers of CHD. The aim of this study is to evaluate the effect of non-surgical periodontal treatment on the cardiovascular clinical and biochemical status of patients with CHD.

Conclusion 1. Non-surgical periodontal treatment (in the form of scaling and root planing) positively affects limited cardiovascular (clinical and biochemical) status of patients with CHD. 2. Reduction in triglyceride, very-low-density lipoprotein, total white blood cell, lymphocyte, and neutrophil counts and increase in high-sensitivity C-reactive protein, total cholesterol, high-density lipoprotein, and low-density lipoprotein levels were observed. 3. Highly significant reduction in very-low-density lipoprotein cholesterol levels and systolic blood pressure was observed among the various parameters measured.

The American Journal of Cardiology and Journal of Periodontology Editors’ Consensus: Perdiodontitis and Atherosclerotic Cardiovascular Disease Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A, Libby P, Offenbacher S, Ridker PM, Van Dyke TE, Roberts WC. J Periodontol. 2009 Jul;80(7):1021-32.

I. Patient Information Recommendation A: Patients with moderate to severe periodontitis should be informed that there may be an increased risk for atherosclerotic cardiovascular disease (CVD) associated with periodontitis. Confidence and evidence level: 2C Recommendation B: Patients with moderate to severe periodontitis who have one known major atherosclerotic CVD risk factor, such as smoking, immediate family history of CVD, or history of dyslipidemia, should consider a medical evaluation if they have not done so in the past 12 months. Confidence and evidence level: 3D Recommendation C: Patients with periodontitis who have ≥2 known atherosclerotic CVD major risk factors should be referred for medical evaluation if they have not done so in the past 12 months. Confidence and evidence level: 2D

II. Medical and Dental Evaluation In concert with the following recommendations, it is recommended that patients with periodontitis assess their risk for future (next 10 years) CVD events (e.g., stroke, myocardial infarction) by completing either the Reynolds Risk Score (http://www. reynoldsriskscore.org) or, for risk assessment for coronary artery disease (CAD) events only, the National Cholesterol Education Program Risk Calculator (http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof), based on the Framingham Heart Study.

III. Risk Factor Treatment: Abnormal Lipids Recommendation A: Patients with periodontitis and ≥1 abnormal serum lipid and/or elevated plasma high-sensitivity C-reactive protein (hsCRP) are recommended to follow a multifaceted lifestyle approach to reduce atherosclerotic CVD risk according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Confidence and evidence level: 1C According to Adult Treatment Panel III guidelines, emphasis on weight loss and physical activity to enhance weight reduction in subjects with elevated serum low-density lipoprotein (LDL) cholesterol should be undertaken. Goals for LDL cholesterol levels are based on CVD risk assessment: (1) one atherosclerotic CVD risk factor and LDL cholesterol >160 mg/dl: target LDL cholesterol <160 mg/dl; (2) ≥2 atherosclerotic CVD risk factors and LDL cholesterol >130 mg/dl: target LDL cholesterol <130 mg/dl; an optional target is LDL cholesterol <100 mg/dl if factors such as age, metabolic syndrome, abnormal plasma hsCRP, or abnormal coronary calcium score (75th percentile) are present; (3) atherosclerotic CVD disease is present or there are CAD risk equivalents, such as diabetes mellitus: target LDL cholesterol <100 mg/dl or an optional target of <70 mg/dl if atherosclerotic CVD is present and there are high-risk features, such as diabetes mellitus, metabolic syndrome, heavy cigarette smoking, or acute coronary syndromes. Lifestyle changes that should be undertaken are reduced intake of saturated fats (<7% of total calories) and low levels of trans fats and dietary cholesterol (<200 mg/day); enhancement of LDL lowering with optional dietary strategies, such as ingesting plant stanols or sterols (2 g/day) and increased viscous (soluble) fiber (10 to 25 g/day); weight reduction; increased physical activity; and limited alcohol ingestion (‘‘Moderation is defined as the consumption of up to one drink per day for women and up to two drinks per day for men. Twelve fluid ounces of regular beer, 5 fluid ounces of wine, or 1.5 fluid ounces of 80- proof distilled spirits count as one drink. This definition of moderation is not intended as an average over several days but rather as the amount consumed on any single day.’’) However, alcohol does not add to atherosclerotic CVD risk and may convey some protective effect against future CVD events. Patients who need to lose weight should be cautioned, however, that alcohol is high in caloric content. Subjects who do not drink alcohol should not be advised to begin drinking alcohol for the purpose of CVD risk modification, because other risks of alcohol consumption, such as higher frequencies of accidents and medical illnesses, outweigh the possible CVD-preventive benefits of alcohol. Recommendation B: Drug therapy for elevated LDL cholesterol should be prescribed in patients with periodontitis in whom target LDL cholesterol levels are not achieved with lifestyle changes. Confidence and evidence level: 2D

IV. Risk Factor Treatment: Cigarette Smoking Recommendation: All patients with periodontitis who smoke tobacco should discontinue this habit because this is a major risk factor for atherosclerotic CVD and periodontitis. Confidence and evidence level: 1C V. Risk Factor Treatment: Hypertension Recommendation A: All patients with periodontitis and elevated blood pressure should be treated to target levels as defined by the seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7). Confidence and evidence level: 1C JNC-7 defines hypertension as follows: (1) prehypertension: systolic blood pressure 120 to 139mmHg or diastolic blood pressure 80 to 89 mm Hg; (2) stage 1 hypertension: systolic blood pressure 140 to 159 mm Hg or diastolic blood pressure 90 to 99 mm Hg; and (3) stage 2 hypertension: systolic blood pressure >160mmHg or diastolic blood pressure >100mmHg. Using JNC-7 recommendations, the target blood pressures in patients with periodontitis are (1) <140/90 mm Hg in all patients with periodontitis and ≤2 major risk factors for CAD and (2) <130/80 mm Hg in patients with previous atherosclerotic CVD, diabetes mellitus, chronic renal disease, or ≥3 major risk factors. Recommendation B: All patients with periodontitis and elevated blood pressure should undertake lifestyle changes. Confidence and evidence level: 1A Elevated blood pressure can be significantly decreased by lifestyle changes, including (pressures in parentheses indicate changes that can be anticipated with adequate patient compliance) weight reduction in subjects who are overweight (systolic blood pressure reduction 5 to 20 mm Hg), a diet high in potassium and calcium (the American Heart Association DASH diet; systolic blood pressure reduction 4 to 8 mm Hg), a diet low in sodium (systolic blood pressure reduction 2 to 8 mm Hg), physical activity (systolic blood pressure reduction 4 to 9 mm Hg), and moderation of alcohol intake (systolic blood pressure reduction 2 to 4 mm Hg). In addition to lowering blood pressure, lifestyle modifications also increase the efficacy of antihypertensive drug therapy and decrease the risk for atherosclerotic CVD. Recommendation C: All patients with periodontitis and elevated blood pressure not controlled to target levels with lifestyle changes should be treated with pharmacologic therapy. Confidence and evidence level: 2D The following drug classes are approved for the initial treatment of hypertension: thiazide-type diuretics, angiotensin- converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors, ß blockers, and calcium channel blockers (see recommendation D). Recommendation D: Patients with periodontitis prescribed calcium channel blockers for hypertension or any other indication should be monitored for worsening of periodontitis in association with gum hyperplasia. Confidence and evidence level: 1D Gingival hyperplasia has been reported with all three classes of calcium channel blockers. This effect is reported most often with nifedipine, occurring in up to 6% of patients, and less often with diltiazem, amlodipine, and verapamil. The mechanism is unknown but may be due to increased gingival collagen production by fibroblasts. However, there are no specific reports of the effect of calcium channel blockers on the severity of periodontitis.

Periodontitis in Coronary Heart Disease Patients: Strong Association between Bleeding on Probing and Systemic Biomarkers Bokhari SA, Khan AA, Butt AK, Hanif M, Izhar M, Tatakis DN, Ashfaq M. J Clin Periodontol. 2014 Nov;41(11):1048-54.

Materials and Methods Angiographically proven coronary heart disease patients with periodontitis (n = 317), aged >30 years and without other systemic illness were examined. Periodontal clinical parameters of bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) and systemic levels of high-sensitivity C-reactive protein (CRP), fibrinogen (FIB) and white blood cells (WBC) were noted and analyzed to identify associations through linear and stepwise multiple regression analyses. Results Unadjusted linear regression showed significant associations between periodontal and systemic parameters; the strongest association was found between BOP and CRP levels, the periodontal and systemic inflammation marker, respectively. Stepwise regression analysis models revealed that BOP was a predictor of systemic CRP levels. BOP was the only periodontal parameter significantly associated with each systemic parameter (CRP, FIB, and WBC).

Conclusion In coronary heart disease patients with periodontitis, BOP is strongly associated with systemic CRP levels; this association possibly reflects the potential significance of the local periodontal inflammatory burden for systemic inflammation.

The Effect of Periodontal Therapy on Cardiovascular Risk Markers: A 6-Month Randomized Clinical Trial Caúla AL, Lira-Junior R, Tinoco EM, Fischer RG. J Clin Periodontol. 2014 Sep;41(9):875-82.

Conclusion The non-surgical periodontal treatment was effective in reducing the levels of systemic inflammation markers and improved the lipid profile in subjects with severe chronic periodontitis.

Association of Simvastatin and Hyperlipidemia with Periodontal Status and Bone Metabolism Markers Magán-Fernández A, Papay-Ramírez L, Tomás J, Marfil-Álvarez R, Rizzo M, Bravo M, Mesa F. J Periodontol. 2014 Oct;85(10):1408-15.

Conclusion 1. Within the limits of this study, the findings suggest that the intake of simvastatin is associated with increasing serum osteoprotegerin concentrations, and this could have a protective effect against bone breakdown and periodontal attachment loss. 2. The baseline systemic inflammatory state of patients with hyperlipidemia is indicated by their increased erythrocyte sedimentation rate.

Preterm Low Birth Weight

Periodontal Infection as a Possible Risk Factor for Preterm Low Birth Weight Offenbacher S, Katz V, Fertik G, Collins J, Boyd D, Maynor G, McKaig R, Beck J. J Periodontol. 1996 Oct;67(10 Suppl):1103-13.

Conclusion These data indicate that periodontal diseases represent a previously unrecognized and clinically significant risk factor for preterm low birth weight as a consequence of either preterm labor (PTL) or preterm rupture of membranes (PROM).

Effects of Periodontal Therapy During Pregnancy on Periodontal Status, Biologic Parameters, and Pregnancy Outcomes: Pilot Study Offenbacher S, Lin D, Strauss R, McKaig R, Irving J, Barros SP, Moss K, Barrow DA, Hefti A, Beck JD. J Periodontol. 2006 Dec;77(12):2011-24.

Conclusion 1. Results from this pilot study (67 subjects) provide further evidence supporting the potential benefits of periodontal treatment on pregnancy outcomes. 2. Treatment was safe, improved periodontal health, and prevented periodontal disease progression. 3. Preliminary data show a 3.8-fold reduction in the rate of preterm delivery, a decrease in periodontal pathogen load, and a decrease in both GCF IL-1β and serum markers of IL-6 response. However, further studies will be needed to substantiate these early findings.

Persistently High Levels of Periodontal Pathogens Associated with Preterm Pregnancy Outcome Lin D, Moss K, Beck JD, Hefti A, Offenbacher S. J Periodontol. 2007 May;78(5):833-41.

Conclusion 1. High levels of periodontal pathogens and low maternal IgG antibody response to periodontal bacterial during pregnancy are associated with an increased risk for preterm delivery. 2. Further studies elucidating the role of the microbial load and maternal immune response as related to pregnancy outcome seem merited.

Does Pregnancy Have an Impact on the Subgingival Microbiota? Adriaens LM, Alessandri R, Spo¨rri S, Lang NP, Persson RG. J Periodontol. 2009 Jan;80(1):72-81.

Background Several studies suggested that gingivitis and periodontitis seem to be independent risk factors for preterm birth/low birth weight. It was proposed that periodontal infections may cause systemic host responses, with an up regulation of serum cytokines, and that this may be a potential mechanism that induces a preterm birth. However, conflicting results have been published. Thus, further studies are needed to identify etiologic factors that might explain this disputed relationship. Therefore, the aim of the present study was to assess the natural evolution of the subgingival microbiota from week 12 of pregnancy until postpartum using an assay including 37 bacterial species. Results

TABLE 1.12

Proportional Distribution of Bacteria Commonly Associated with Periodontitis, at the Different Time Points

Week 12 Week 28 Week 36 4 to 6 Week Postpartum Species 1.0 x 104 1.0 x 105 1.0 x 104 1.0 x 105 1.0 x 104 1.0 x 105 1.0 x 104 1.0 x 105

A. actinomycetemcomitans (Y4) 97.1 22.8 90.0 24.7 89.6 28.4 91.0 26.4

P. gingivalis 75.1 19.4 81.8 20.4 62.7 18.4 71.9 22.1

T. forsythia 100.0 61.4 100.0 53.1 100.0 53.1 52.8 54.2

T. denticola 78.6 10.4 72.7 14.3 68.7 10.4 66.3 10.1

Between weeks 12, 28, and 36 and 4 to 6 weeks postpartum, statistical analysis by Friedman ANOVA and repeat Wilcoxon signed-rank test failed to identify statistically significant differences in levels for these four bacterial species.

Conclusion The present study suggested that decreases in the levels of 17of 37 species studied are found during a normal pregnancy. Nevertheless, subgingival levels of A.actinomycetemcomitans, P.gingivalis, T.forsythia, and T denticola did not change. At week 12 of pregnancy, elevated levels of P.gingivalis and T.forsythia were associated with bleeding on probing (BOP).

Oral Health and Dental Care During Pregnancy Steinberg BJ, Hilton IV, Iada H, Samelson R. Dent Clin North Am. 2013 Apr;57(2):195-210.

TABLE 1.13

Pharmacologic Considerations for Pregnant Women

Pharmaceutical Agent Indications, Contraindication, and Special Consideration

Analgesics Acetaminophen with codeine, hydrocodone, or oxycodone May be used during pregnancy Codeine Meperidine Morphine Aspirin May be used in short duration during pregnancy; 48-72 h. Avoid in first and third trimesters Ibuprofen Naproxen Antibiotics Amoxicillin May be used during pregnancy Cephalosporins Clindamycin Metronidazole Penicillin Ciprofloxacin Avoid during pregnancy Clarithromycin Levofloxacin Moxifloxacin Tetracycline Never use during pregnancy Anesthetics Consult with a prenatal care health professional before using intravenous sedation or general anesthesia Local anesthesia with epinephrine (e.g., bupivacaine, lidocaine, mepivacaine) May be used during pregnancy Nitrous oxide (30%) May be used during pregnancy when topical or local anesthetics are inadequate. Pregnant woman require lower levels of nitrous oxide to achieve sedation; consult with prenatal care health professional. Over-the-counter antimicrobials Use alcohol-free products during pregnancy Cetylpyridinium Chloride mouth rinse May be used during pregnancy Chlorhexidine mouth rinse Xylitol

Caries 1. The relationship between dental caries and pregnancy is not well defined. Changes in salivary composition in late pregnancy and during lactation may temporarily predispose to erosion as well as dental caries. There are no convincing data, however, to show that the incidence of dental caries increases during pregnancy or in the immediate post-partum period, although existing untreated caries will likely progress. 2. Pregnancy may cause food cravings, and if these are for cariogenic foods, the pregnant woman may increase her risk for caries at this time. All pregnant patients, therefore, should be advised to bolster their daily oral hygiene routine. For recommendations per the National Consensus, see the earlier section on recommended oral hygiene. Xerostomia Some pregnant women may experience temporary dryness of the mouth, for which hormonal alterations associated with pregnancy are a possible explanation. More frequent consumption of water and sugarless candy or gum may help alleviate this problem. More frequent fluoride exposure (toothpaste, mouth rinse) is also recommended for women who experience xerostomia, to help remineralize teeth and reduce the risk for caries. Perimylolysis 1. Although nausea and vomiting are predominantly associated with early pregnancy, some women continue to experience this past the first trimester. Hyperemesis gravidarum, a severe form of nausea and vomiting that occurs in 0.3% to 2% of pregnant women, can lead to loss of surface enamel (perimylolysis) primarily through acid-induced erosion. 2. Pregnant patients should be queried about nausea and vomiting during their dental visits. Those who experience vomiting should be instructed to rinse the mouth immediately afterward with a teaspoon of baking soda dissolved in a cup of water, which can prevent acid from attacking teeth. These patients should also be advised to avoid brushing teeth immediately after vomiting. More frequent fluoride exposure to remineralize teeth is also recommended for women who experience repeated nausea and vomiting during pregnancy. Tooth Mobility Generalized tooth mobility in the pregnant patient is probably related to the degree of gingival diseases that disturb the attachment apparatus and to mineral changes in the lamina dura. Longitudinal studies demonstrate that as gingival inflammation increases, so do probing depths attributable to the swelling of the gingiva. Although most research concludes that generally no permanent loss of clinical attachment occurs during pregnancy, in some individuals the progression of periodontitis occurs, and may be permanent.xerostomia, to help remineralize teeth and reduce the risk for caries.

Scaling and Root Planing Treatment for Periodontitis to Reduce Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Kim AJ, Lo AJ, Pullin DA, Thornton-Johnson DS, Karimbux NY. J Periodontol. 2012 Dec;83(12):1508-19.

Conclusion 1. The main implication for public health practice from this review is that, for the general population undergoing pregnancy, there is not sufficient evidence to support the need for treatment of periodontitis to reduce the risk of preterm birth. 2. This is similar to the results shown in the 2011 meta-analysis, which concluded that, ‘‘the pooled estimates failed to sustain the argument that the treatment can decrease the risk of preterm birth,’’ based on their subgroup analysis by definitions of periodontitis. However, the analyses of this study included a post-hoc subgroup analysis based on the risks of preterm birth, which indicated a statistically significant association between the treatment of periodontitis and reduction in the risk of preterm birth for groups with high risks of preterm birth. 3. Given the possible benefit of periodontitis treatment in only the studied populations at high risk for preterm birth and the significance of preterm birth as a health problem, future research should attempt to further define the population in which risk reduction may be possible.

BACKSTORY Preeclampsia

1. Formerly called toxemia, preeclampsia is a condition that pregnant women develop. It is marked by high blood pressure and a high level of protein in the urine after week 20 of gestation. Preeclamptic women will often also have swelling in the feet, legs, and hands. This condition usually appears during the second half of pregnancy, often in the latter part of the second or in the third trimesters, although it can occur earlier. 2. If undiagnosed, preeclampsia can lead to eclampsia, a serious condition that can put women and their babies at risk, and in rare cases, cause death. Women with preeclampsia who have seizures are considered to have eclampsia. 3. There is no cure for preeclampsia, but it can be easier to manage if caught early. Therefore, pregnant women should know the symptoms of preeclampsia and receive regular prenatal care.

Periodontitis as a Risk Factor for Preeclampsia Moura da Silva G, Coutinho SB, Piscoya MD, Ximenes RA, Jamelli SR. J Periodontol. 2012 Nov;83(11):1388-96.

Conclusion 1. Preeclampsia is a multisystem disorder of unclear etiology that is exclusive to human pregnancy. The prevalence of this condition ranges from 2% to 7% in developed countries, resulting in high maternal and neonatal morbidity and mortality rates attributable to complications affecting different organs and systems. 2. The results suggest that within the population studied, periodontitis was a risk factor for preeclampsia.

Drug Therapy for the Pregnant Dental Patient Mendia J, Cuddy MA, Moore PA. Compend Contin Educ Dent. 2012 Sep;33(8):568-70, 572, 574-6.

TABLE 1.14

Updated Drugs and Pregnancy Categories

Generic Name Brand Name Pregnancy Category Potential Risk

Local Anesthetics Articaine with epinephrine Septocaine C Bupivacaine with epinephrine Marcaine C Fetal bradycardia Lidocaine with epinephrine Xylocaine B Mepivicaine plain Carbocaine C Fetal bradycardia Mepivicaine with levonorfefrin Carbocaine with Neo-Cobefrin C Prilocaine plain Citanest B Potential Methemoglobinemia Prilocaine with epinephrine Citanest Forte C Potential Methemoglobinemia Benzocaine Topical Orajel C Potential Methemoglobinemia Peripherally Acting Analgesics Acetaminophen Tylenol B Post-partum hemorrhage: premature closure of ductus arteriosus Aspirin Bayer C/D3 Post-partum hemorrhage: premature closure of ductus arteriosus Ibuprofen Advil, Motrin B/D3 Post-partum hemorrhage: premature closure of ductus arteriosus Ketorolac Toradol B/D3 Post-partum hemorrhage: premature closure of ductus arteriosus Naproxen Aleve, Anaprox B/D3 Post-partum hemorrhage: premature closure of ductus arteriosus Centrally Acting Opioid Analgesics Codeine with Acetaminophen Tylenol with codeine C/D3 Neonatal respiratory depression and opioid withdrawal Hydrocodone with Acetaminophen Vicodin C/D3 Neonatal respiratory depression and opioid withdrawal Hydrocodone with Ibuprofen Vicoprofen C/D3 Neonatal respiratory depression and opioid withdrawal Oxycodone Oxycontin B/D3 Neonatal respiratory depression and opioid withdrawal Oxycodone with Acetaminophen Percocet C/D3 Neonatal respiratory depression and opioid withdrawal Oxycodone with Ibuprofen Combunox C/D3 Neonatal respiratory depression and opioid withdrawal; premature closure of ductus arteriosus

Tamadol Ultram C Antibiotics Amoxicillin Amoxil B Amoxicillin and Clavulanate Augmentin B Azithromycin Zithromax, Z-Pack B Cephalexin Keflex B Clindamycin Cleocin B Doxycycline Doryx D Tooth discoloration and inhibition of bone development Erythromycin base E-mycin B Avoid estolate salt Fluconazole Diflucan C Fetal brachycephaly, cleft palate, thinning of the bones Gentamicin Garamycin C/D3 Ototoxicity potential in fetus Metronidazole Flagyl B Minocycline Dynacin, Minocin D Congenital anomalies and enamel hypoplasia Penicillin V Pen-Vee K B Tetracycline Tetracycline generic D Maternal hepatoxicity and enamel hypoplasia; tooth discoloration Sedative/Anxiolytics Alprazolam Xanax D Congenital malformations, withdrawal symptoms Diazepam Valium D Congenital malformations, withdrawal symptoms Lorazepam Ativan D Congenital malformations, withdrawal symptoms Midazolam Versed D Congenital malformations, withdrawal symptoms Triazolam Halcion X Congenital malformations, withdrawal symptoms Other Diphenhydramine Benadryl B Epinephrine Epinephrine C Potential for fetal hypoxemia Flumazenil Romaziicon C Avoid during labor and delivery

Phentolamine OraVerse C Avoid during labor and delivery D3 = Avoid in third trimester. Designated D3 drugs are considered Pregnancy Category D when taken in third trimester.

TABLE 1.15

Use-in- Pregnancy Rating For Dental Drugs

Category A: Controlled studies show no risk Adequate well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy.

Category B: No evidence of risk in humans Adequate well-controlled studies in pregnant woman have not shown increased risk of fetal abnormalities despite adverse findings in animals. OR In the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility.

Category C: Risk cannot be ruled out Adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus or are lacking as well. There is a chance of fetal harm if administered during pregnancy, but the potential benefits may outweigh the potential risk.

Category D: Positive evidence of risk Studies in humans, or investigational or post-marketing date, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective.

Category X: Contraindicated in pregnancy Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk that clearly out-weighs any possible benefit to the patient.

Conclusion Maintaining a healthy lifestyle, including optimal oral health, is essential for women who are currently pregnant or are planning a pregnancy. Dental practitioners should provide all necessary care for pregnant patients, particularly when managing an acute infection.

The Association between Periodontal Inflammation and Labor Triggers (Elevated Cytokine Levels) in Preterm Birth: A Cross-Sectional Study Perunovic NDj, Rakic MM, Nikolic LI, Jankovic SM, Aleksic ZM, Plecas DV, Madianos PN, Cakic SS. J Periodontol. 2016 Mar;87(3):248-56.

Conclusion This study shows that women with preterm birth had higher rates of periodontitis, worse periodontal parameters, and significantly increased GCF levels of PGE2 and IL-6 compared with women with full-term birth. Although serum levels of labor triggers did not differ between cases and controls, findings of significantly increased serum TNF-a and PGE2 in women with periodontitis compared with periodontally healthy individuals, together with confirmed association of increased serum levels of PGE2 with PD and CAL and GCF levels of TNF-a in preterm birth, indicate the potential impact of periodontitis in an overall increase of labor triggers.

Adverse Pregnancy Outcomes and Periodontitis: A Systematic Review and Meta-Analysis Exploring Potential Association Corbella S, Taschieri S, Del Fabbro M, Francetti L, Weinstein R, Ferrazzi E. Quintessence Int. 2016 Mar;47(3):193-204.

Conclusion The present systematic review reported a low but existing association between periodontitis and adverse pregnancy outcomes. This assumption is the result of proper corrections of biased methodologies and of heterogeneity of studies.

MH Question No. 16

Changes in Periodontal Parameters and C-Reactive Protein after Pregnancy Raga LG, Mínguez I, Caffesse R, Llambés F. J Periodontol. 2016 Dec;87(12):1388-95.

Conclusion Postpartum, there was a dramatic reduction in progesterone and C-reactive protein, together with an improvement in bleeding on probing, probing depth, and clinical attachment level in the absence of periodontal treatment. Decrease in C-reactive protein was related to an improvement in periodontal bleeding.

Regular Consumption of Lactobacillus Reuteri-Containing Lozenges Reduces Pregnancy Gingivitis: An RCT Schlagenhauf U, Jakob L, Eigenthaler M, Segerer S, Jockel-Schneider Y, Rehn M. J Clin Periodontol. 2016 Nov;43(11):948-54.

Conclusion The consumption of Lactobacillus reuteri lozenges may be a useful adjunct in the control of pregnancy gingivitis.

PRODUCTS Lozenges for Pregnancy Gingivitis

• Prodentis Lozenges (BioGaia)

PRINCIPLES Pregnancy - Pregnant Woman vs. Fetus

Mother Fetus • # Caries risk • Preterm low birth weight • Xerostomia • Concerns to reduce oral inflammatory burden. • Perimylolysis –– Beginning of second trimester pathogen load increases. • Tooth mobility –– Recommend SRP beginning second trimester. • Preeclampsia –– Outcome benefit evidence based still questionable. Do it anyway! Both • Pharmacological considerations.

SUMMARY KEY Acquired and Environmental Risk – Age

• There seems to be little doubt that the prevalence of periodontal disease increases with age and, in general, we should expect to find more periodontal disease in older adults. Yet, it is not clear if becoming older is related to a worsening periodontium or whether the worsening periodontium is really related to other characteristics that are byproducts of aging or disease. • One might argue that some loss of alveolar bone and periodontal attachment is actually part of the normal physiology of aging and not a consequence of infectious pathology. • Furthermore, among adults, it also is not clear whether older adults have a higher incidence of periodontal disease than younger adults, controlling for other characteristics. • In addition, few studies have investigated the biological mechanisms involved in the affects of aging on the pathogenesis of periodontal disease. • Finally, it is not clear whether it is profitable to continue the debate of whether age is a risk factor, since we unfortunately cannot test whether the risk for periodontal disease is reduced by intervention (i.e. making people younger).

Modifiable Risk Factors in Periodontitis: at the Intersection of Aging and Disease Reynolds MA. Periodontol 2000. 2014 Feb;64(1):7-19.

Conclusion Chronic inflammation is a prominent feature of aging and of age-related diseases. Periodontitis and other common chronic inflammatory diseases share a relatively small set of common modifiable risk factors, which can contribute to increases in systemic markers of inflammation and modify gene regulation through a variety of biologic mechanisms. Interventions that target modifiable risk factors have the potential to improve risk profiles for periodontitis as well as for other chronic diseases. An understanding of modifiable risk factors is essential for clinical practice.

SUMMARY KEY Acquired and Environmental Risk – Tobacco / Smoking

• Tobacco smoking is a major risk factor for developing severe periodontitis. Individuals classified as light smokers and heavy smokers have a greater chance of developing severe periodontitis (2 and 7 times greater, respectively). • A meta-analysis performed for the 1996 World Workshop on Periodontics indicated that smokers have a 2.8 times greater chance of developing periodontitis than nonsmokers. • Tobacco use is also related to disease recurrence and decreased response to therapy. The underlying mechanism has not been defined, but it may be related to an increased bacterial load detected subgingivally. This may occur because of decreased oxygen tension, which encourages the growth of periodontal pathogens. • Systemic alterations in the host response among smokers include impaired chemotaxis and phagocytosis by neutrophils, reduced antibody production, and increased circulating levels of TNF-α. Smoking is also associated with delayed healing after nonsurgical and surgical therapy. • Smoking appears to be associated with a reduction in tissue inflammation and bleeding on probing because of nicotineinduced vasoconstriction of blood vessels subjacent to the junctional epithelium. This can mask severe pocketing and alveolar bone loss. • Clinicians should counsel patients regarding the negative impact of smoking on their periodontal health. Since smokers are high-risk individuals for additional disease recurrence, they should be monitored more closely and provided with quarterly maintenance visits to help them manage their bacterial challenge.

Smoking and Inflammation: Evidence for a Synergistic Role in Chronic Disease Johannsen A, Susin C, Gustafsson A. Periodontol 2000. 2014 Feb;64(1):111-26.

FIGURE 1.32 — Effect of smoking on pathogenesis of periodontitis. Numbers indicate the following effects: 1. impaired chemotaxis, impaired phagocytosis; 2. decreased levels of immunoglobulins; 3. increased release of collagenase; 4. decreased or increased generation of reactive oxygen species (ROS); 5. increased release of serine proteases, such as elastase; 6. impaired fibroblast attachment and decreased collagen synthesis; 7. increased or decreased release of cytokines and chemokines; 8. increased RANKL ⁄ osteoprotegerin ratio. LPS, lipopolysaccharide; PNM, polymorphonuclear neutrophil.

Conclusion 1. Tobacco smoking seems to induce changes such as decreased leukocyte chemotaxis and decreased production of immunoglobulins, and impaired phagocytosis, but the findings of only minor differences in the microflora between clinically similar sites in smokers and nonsmokers suggest that these changes are not the main reason for the elevated prevalence of periodontitis in smokers. Smoking also appears to cause a stronger inflammatory reaction with an increased release of tissue destructive substances (e.g., reactive oxygen species, collagenase, serine proteases and proinflammatory cytokines). An increased inflammatory response is in line with the overall hypothesis that periodontitis is a hyperinflammatory condition rather than a hypo-inflammatory condition. 2. A gene–environment interaction, as described for other chronic inflammatory diseases and smoking has not been reported for periodontitis and smoking. This line of research could generate new important knowledge, not only about smoking but also about periodontal pathogenesis in general.

Cigarette Smoking and the Periodontal Patient Johnson GK, Hill M. J Periodontol. 2004 Feb;75(2):196-209.

Discussion Evidence from cross-sectional and case-control studies in various populations demonstrates that adult smokers are approximately three times as likely as non-smokers to have periodontitis. The association between smoking and attachment loss is even stronger when the definition of periodontitis is restricted to the most severely affected subjects. Smokers have a diminished response to periodontal therapy and show approximately half as much improvement in probing depths and clinical attachment levels following non-surgical and various surgical modalities of therapy. Implant failures in smokers are twice those of non-smokers, with a higher failure rate in the maxillary arch accounting for the majority of the difference. Tobacco- induced alterations in microbial and host factors contribute to these deleterious effects of smoking on the periodontium. In longitudinal studies, the rate of periodontal disease progression is increased in smokers, but decreases to that of a non- smoker following tobacco cessation. Likewise, recent non-smokers respond to periodontal therapy in a manner similar to patients who have never smoked.

Longitudinal Study of the Association Between Smoking as a Periodontitis Risk and Salivary Biomarkers Related to Periodontitis Kibayashi M, Tanaka M, Nishida N, Kuboniwa M, Kataoka K, Nagata H, Nakayama K, Morimoto, Shizukuishi S. J Periodontol. 2007 May;78(5):859-67.

Background Insufficient data exist regarding the long-term influence of lifestyle factors including smoking on periodontal health. The objective of this study was to examine the prospective association between smoking and periodontal disease progression and the effects of smoking on salivary biomarkers related to periodontitis.

Conclusion 1. Smoking exerted the greatest influence on periodontitis risk among lifestyle factors. 2. Smoking may suppress the host-defense system, which may promote periodontal disease progression.

Cigarette Smoking and Alveolar Bone in Young Adults: A Study Using Digitized Radiographs Rosa GM, Lucas GQ, Lucas ON. J Periodontol. 2008 Feb;79(2):232-44.

Background 1. Eighty-one dental students (mean age: 20.5 years), considered not to have periodontitis according to clinical criteria, participated in this study. Forty-two subjects were smokers (mean consumption was 14.1 cigarettes/day for ≥2 years), and 39 subjects had never smoked. All subjects took part in a dental hygiene program (DHP) that included oral hygiene instructions, mechanical debridement, and polishing. 2. The following clinical variables were measured before and after the DHP: plaque index (PI), gingival crevicular fluid (GCF) flow FIGURE 1.33 — CADIA was performed at three proximal sites per radiographic image. Two AOIs were selected positioned rate, gingival index (GI), probing depth, and clinical attachment at the alveolar bone crest of each site for measurement. In level (CAL). Standardized posterior vertical bitewing radiographs this radiographic image taken on day 365 of the follow-up, were taken and digitized preexperimentally and on days 180, 365, the boxes represent the approximate size and position of each AOI. and 545. The following analyses were performed: bone height measurement (BHM), computer-assisted densitometric image analysis (CADIA), and qualitative analysis of digital subtraction radiography (DSR). Results

FIGURE 1.35 — Qualitative analysis of DSR. Example of a pair of radiographs taken in a smoker: baseline image (A) FIGURE 1.34 — Radiographic CEJ-ABC distance (mean ± SE), in each group during and 545-day follow-up (B). (C) Corresponding generated the experimental period. The measurements were made at 12 posterior proximal subtraction image in which two interproximal sites indicated sites per subject. *Significant differences within groups (with day 0): P< 0.01; loss of crestal alveolar bone density because they were †Significant differences between groups: P < 0.01. represented as dark gray areas (arrows).

Conclusion Smoking produces an adverse effect on clinical periodontal variables and alveolar bone height and density, acting asa potential risk factor for alveolar bone loss, even at an early age with low tobacco consumption. It is very important to inform young smokers about the risk of this habit in relation to periodontal health.

Comparison of Clinical and Radiographic Periodontal Status between Habitual Water-Pipe Smokers and Cigarette Smokers Javed F, Al-Kheraif AA, Rahman I, Millan-Luongo LT, Feng C, Yunker M, Malmstrom H, Romanos GE. J Periodontol. 2016 Feb;87(2):142-7.

Results The duration of each smoking session for water-pipe smokers and cigarette smokers was 50.2 ± 6.7 and 15.3 ± 0.4 minutes, respectively. Number of missing teeth, plaque index, clinical attachment loss, probing depth ≥4 mm, and marginal bone loss) was significantly higher among water-pipe smokers and cigarette smokers than controls. Bleeding on probing was significantly higher among controls than water-pipe smokers and cigarette smokers. There was no statistically significant difference in the aforementioned parameters between water-pipe smokers and cigarette smokers.

Conclusion Males in a Saudi Arabian community who were water-pipe smokers or cigarette smokers had more missing teeth and poorer periodontal condition than never smokers. The periodontal condition of water-pipe smokers was equally as poor as cigarette smokers. Additional clinical observational studies with emphasis on sex and sociodemographic characteristics are needed.

Associations between Cannabis Use and Physical Health Problems in Early Midlife: A Longitudinal Comparison of Persistent Cannabis vs. Tobacco Users Meier MH, Caspi A, Cerdá M, Hancox RJ, Harrington H, Houts R, Poulton R, Ramrakha S, Thomson WM, Moffitt TE. JAMA Psychiatry. 2016 Jul 1;73(7):731-40.

Materials and Methods Participants belonged to a representative birth cohort of 1037 individuals born in Dunedin, New Zealand, in 1972 and 1973 and followed to age 38 years, with 95% retention (the Dunedin Multidisciplinary Health and Development Study). We tested whether cannabis use from ages 18 to 38 years was associated with physical health at age 38, even after controlling for tobacco use, childhood health, and childhood socioeconomic status. We also tested whether cannabis use from ages 26 to 38 years was associated with within-individual health decline using the same measures of health at both ages. We assessed frequency of cannabis use and cannabis dependence at ages 18, 21, 26, 32, and 38 years. Results We obtained laboratory measures of physical health (periodontal health, lung function, systemic inflammation, and metabolic health), as well as self-reported physical health, at ages 26 and 38 years.

Conclusion 1. This study has a number of implications. First, cannabis use for up to 20 years is not associated with a specific set of physical health problems in early midlife. The sole exception is that cannabis use is associated with periodontal disease. 2. Second, cannabis use for up to 20 years is not associated with net metabolic benefits (i.e., lower rates of metabolic syndrome). 3. Third, our results should be interpreted in the context of prior research showing that cannabis use is associated with accidents and injuries, bronchitis, acute cardiovascular events, and, possibly, infectious diseases and cancer, as well as poor psychosocial and mental health outcomes.

Antioxidants Counteract Nicotine and Promote Migration via RacGTP in Oral Fibroblast Cells Symone M. San Miguel, Lynne A. Opperman, Edward P. Allen, Jan Zielinski, Kathy K.H. Svoboda. J Periodontol. 2010 Nov;81(11):1675-90.

FIGURE 1.36 — RacGTP was decreased in Nic-treated cells and expressed FIGURE 1.37 — RacGTP was decreased in Nic-treated cells and more intensely in the leading edge of AO-treated HGF cells. RacGTP (green) in intense in AO-treated HPDL cells. RacGTP (green) was in the cells at the white arrows was visualized in whole cells by phalloidin staining of F-actin leading edge (white arrows) of the wound in HPDL cells (F-actin [red]). filaments (red) at the leading edge of a scratch wound in theHGFmonolayer Confocal z stacks were projected into single confocal micrographs. (A) using projected confocalmicroscopy z stacks projected into one image. The Untreated control. (B through D) Six, 8, and 10 mM Nic. (E) F + Nic. (F) black void area in the center is the in vitro scratch wound in the monolayer. RF + Nic. (G) PF + Nic. (H) PFR + Nic. (I) The mean pixel intensity (n = (A) Untreated control. (B through D) Six, 8, and 10mM Nic. (E) F + Nic. (F) RF four fields per treatment group) was measured (I) and expressed as the + Nic. (G) PF + Nic. (H) PFR + Nic. The mean pixel intensity (n = four fields percentage of mean pixel intensity compared to the untreated group per treatment group) was measured (I) and expressed as the percentage of (set at 100). A dose-dependent decrease in RacGTP-positive pixels was mean pixel intensity compared to the untreated group (set at 100). A dose- observed in Nictreated cells (6, 8, and 10 mM). Cells treated with Nic (6 dependent decrease in RacGTP-positive pixels was observed in Nic-treated mM) and AOs (single, double, and triple) increased RacGTP compared cells (6, 8, and 10 mM). Cells treated with Nic (6 mM) and AOs (single, to untreated controls and 6 mM Nic. Scale bar = 300 µm. double, and triple) increased RacGTP compared to untreated controls and 6 mM Nic. Scale bar = 300 µm.

Conclusion Treatment with AO combinations clearly counteracted the effects of nicotine by restoring and increasing cell-migration rates. We found the combination of PFR was the most effective in HGFs, whereas, RFT was the most effective combination in HPDL fibroblast. These results clearly demonstrate that PF, RFT, and PFR counteract the negative effects of nicotine on cultured oral fibroblasts via the RacGTP signal-transduction pathway.

Antioxidant Combinations Protect Oral Fibroblasts Against Metal-Induced Toxicity San Miguel SM, Opperman LA, Allen EP, Zielinski JE, Svoboda KK. Arch Oral Biol. 2013 Mar;58(3):299-310.

Objective In dentistry, the use of metals in fillings, braces, implants, bridges and other prosthodontic restorations is a common practice. Previous studies revealed that zinc (Zn) and copper (Cu) released from gold alloys, and nickel (Ni) released from nickel–chromium alloys, have a highly cytotoxic effect on fibroblast cell cultures. Our working hypothesis is that oral fibroblasts are susceptible to damage from metals because they elevate reaction oxygen species (ROS). In this study, we investigated specific antioxidant (AO) combinations to determine if they counteract the effects of Cu, Ni and Zn on cultured oral fibroblast proliferation and oxidative damage.

Conclusion This data clearly indicates that metal stressors may increase gingival cellular damage by decreasing cell viability, and proliferation while increasing ROS. Moreover, these pure AO products may have complementary or synergistic mechanisms to counteract the detrimental effects of the metal stressors to decrease ROS and increase cell viability and DNA synthesis.

PRODUCTS Antioxidant Therapy

• AO ProVantage (PerioSciences) • AO ProRinse (PerioSciences) Additional Material: PerioSciences

Click to view Additional Material PerioSciences

Effect of Smoking Cessation on Non-Surgical Periodontal Therapy: Results after 24 Months Rosa EF, Corraini P, Inoue G, Gomes EF, Guglielmetti MR, Sanda SR, Lotufo JP, Romito GA, Pannuti CM. J Clin Periodontol. 2014 Dec;41(12):1145-53.

Results 1. From the 116 enrolled subjects, 61 remained up to 24 months of follow-up. Of these, 18 quit smoking (Q), 32 continued smoking (NQ) and 11 oscillated (O) at 24 months of follow-up. 2. Thereby, Q showed significantly higher mean CAL gain in diseased sites and higher reduction in the proportion of sites with clinical attachment loss ≥ 3 mm, when compared to NQ. 3. In addition, Q presented significantly higher mean probing depth reduction relative to NQ.

Conclusion Smoking cessation promoted additional benefits on non-surgical periodontal therapy in chronic periodontitis subjects.

Tobacco Consumption Induces Alveolar Crest Height Loss Independently of Mandibular Bone Mass and Bone Density Mesa F, Souki N, Galindo-Moreno P, Velasco-Torres M, O’Valle F, Bravo M. Clin Oral Implants Res. 2014 Sep;25(9):1034-40.

Conclusion 1. In a Caucasian population aged 21-46 years, tobacco consumption was significantly associated with alveolar crest height loss. 2. However, alveolar crest height loss showed no significant relationship with mandibular bone mass estimated either as mandibular cortical width index or bone density on digital panoramic radiographs or as bone density on CBCT. 3. Alveolar crest height loss was a local event independent of mandibular bone mass status.

Detection and Quantification of Periodontal Pathogens in Smokers and Never- Smokers with Chronic Periodontitis by Real-Time Polymerase Chain Reaction Guglielmetti MR, Rosa EF, Lourenção DS, Inoue G, Gomes EF, De Micheli G, Mendes FM, Hirata RD, Hirata MH, Pannuti CM. J Periodontol. 2014 Oct;85(10):1450-7.

Results 1. Smokers had greater overall mean probing depth and attachment loss and fewer bleeding on probing sites. 2. An association was observed between smoking status and the presence of A. actinomycetemcomitans. The counts of A. actinomycetemcomitans, P. gingivalis , and T. forsythia were significantly higher in smokers.

Conclusion 1. Smokers showed significantly greater amounts of P. gingivalis, A. actinomycetemcomitans, and T. forsythia than never- smokers. 2. There was a significant association between smoking and the presence ofA. actinomycetemcomitans.

Investigating the Association Between Obstructive Sleep Apnea and Periodontitis Loke W, Girvan T, Ingmundson P, Verrett R, Schoolfield J, Mealey BL. J Periodontol. 2015 Feb;86(2):232-43.

Materials and Methods One hundred patients from a large veterans administration sleep study center (n = 26 normal, n = 21 mild, n = 19 moderate, n = 34 severe) diagnosed with an overnight polysomnogram underwent a comprehensive periodontal examination. Periodontal parameters measured included the following: 1) mean periodontal probing depth (PD); 2) clinical attachment level (CAL); 3) gingival recession; and 4) percentage of sites with bleeding on probing, plaque, PD ≥5 mm, and CAL ≥3 mm. Results Seventy-three percent of the sampled population had moderate/severe periodontal disease. χ(2) analyses revealed no significant differences in the prevalence of periodontal disease between the apnea-hypopnea index (AHI) groups, witha negligible Spearman correlation coefficient of 0.246 between AHI severity and periodontal disease severity categories. Analysis of covariance indicated a significant association between AHI severity categories and percentage of sites with plaque, after adjusting for age. Multivariable logistic regression analysis predicting moderate/severe periodontitis with AHI score, age, and smoking status indicated a significant association with age but no significant association with the other two predictors.

Conclusion This is the first cross-sectional study showing that OSA, when defined in AHI severity categories, is not significantly associated with the prevalence of periodontitis in this specific VA population. Furthermore, none of the clinical periodontal parameters except percentage plaque were significantly related to severity of OSA. In addition, when AHI was expressed in absolute values, there was no correlation with any periodontal parameters measured.

MH Question No. 53 Electronic Cigarette Explosions Involving the Oral Cavity Harrison R, Hicklin D Jr. J Am Dent Assoc. 2016 Nov;147(11):891-6.

Background and Overview The use of electronic cigarettes (e-cigarettes) is a rapidly growing trend throughout the United States. E-cigarettes have been linked to the risk of causing explosion and fire. Case Description Data are limited on the associated health hazards of e-cigarette use, particularly long-term effects, and available information often presents conflicting conclusions. In addition, an e-cigarette explosion and fire can pose a unique treatment challenge to the dental care provider because the oral cavity may be affected heavily. In this particular case, the patient's injuries included intraoral burns, luxation injuries, and alveolar fractures.

A B C D FIGURE 1.38 — (A) Initial appearance in the emergency department, with the patient displaying burns to the dorsal surface of the tongue, maxillary gingiva, and mucosa. (B) Sagittal computed tomographic scan showing multiple alveolar fractures. (C) Sagittal computed tomographic scan shows tooth no. 9 displaced from the socket. (D) Appearance at follow-up in the dental center 3 days after the explosion. Tooth no. 9 is displaced 6 millimeters to the palate and extruded 4 mm.

Conclusion 1. E-cigarettes are a new nicotine-based product with a novel delivery system and have the potential to affect public health significantly. E-cigarette explosions and fires pose unforeseen risks and may cause damage to the dentition and soft tissues of the mouth. 2. This case report aims to help clinicians gain an increased knowledge about e-cigarette design, use, and risks; discuss the risk of spontaneous failure and explosion of e-cigarettes with patients; and understand the treatment challenges posed by an e-cigarette explosion.

Cocaine and Other Illicit Drugs

MH Question No. 46

Association among Periodontitis and the Use of Crack Cocaine and Other Illicit Drugs Antoniazzi RP, Zanatta FB, Rösing CK, Feldens CA. J Periodontol. 2016 Dec;87(12):1396-405.

Conclusion 1. Occurrence of periodontitis, visible plaque, and gingival bleeding was significantly higher among crack users, and crack use was associated with occurrence of periodontitis. 2. The present study makes an important contribution to knowledge on association between crack cocaine use and other illicit drugs, and periodontal status. Prevalence of periodontitis was significantly higher among users than controls, and crack cocaine use was associated with occurrence of periodontitis after adjustments for confounding variables. These findings could assist in establishment of oral health care for individuals with a crack cocaine dependency.

MH Question No. 16

Does Obstructive Sleep Apnea Increase the Risk for Periodontal Disease? A Case-Control Study Gamsiz-Isik H, Kiyan E, Bingol Z, Baser U, Ademoglu E, Yalcin F. J Periodontol. 2017 May;88(5):443-9.

Materials and Methods A case-control study was performed that included 163 individuals: 83 individuals (18 females and 65 males) with obstructive sleep apnea (OSA) and 80 non-OSA individuals (23 females and 57 males) as controls. The test group was classified according to OSA severity. Clinical periodontal measurements were recorded, and gingival crevicular fluid (GCF) samples were collected. Gingival crevicular fluid (GCF) high-sensitive C-reactive protein (hs-CRP), levels of interleukin (IL)-lβ, and tumor necrosis factor (TNF)-α levels were analyzed using an enzyme-linked immunosorbent assay method. Serum hs-CRP was measured by latex- enhanced immunoturbidimetric assay. Results Prevalence of periodontitis in the OSA group (96.4%) was significantly higher than in the control group (75% [P <0.001]). Severe periodontitis prevalence was higher in the OSA group than control group. All periodontal clinical parameters and GCF IL-lβ concentrations were significantly higher in patients with OSA than in controls (P = 0.001). No significant differences were found between the mild OSA and moderate-to-severe OSA groups. Additionally, there was no significant difference in GCF TNF-α and hs-CRP levels between the groups. Serum hs-CRP levels were significantly higher in patients with OSA. A significant correlation was found between GCF IL-1β and all clinical parameters.

Conclusion Present results indicate that obstructive sleep apnea (OSA) is associated with higher periodontal indices and local inflammatory parameters such as IL-1β. In addition, prevalence of severe periodontitis was higher in patients with moderate-to-severe OSA. To confirm a cause–effect relationship between periodontitis and OSA, intervention studies are needed to evaluate both effect of periodontal treatment on patients with OSA and effect of OSA treatment on periodontal status.

The Association between Periodontitis and Sleep Duration Romandini M, Gioco G, Perfetti G, Deli G, Staderini E, Laforì A. J Clin Periodontol. 2017 May;44(5):490-501.

Results Compared to the group sleeping ≤5 h/day, the adjusted odds ratios for periodontitis prevalence defined as Community Periodontal Index (CPI) = 4 were OR = 2.46 (95% CI: 1.20-5.06) in the 6 h/day sleepers group, OR = 2.66 (95% CI: 1.35-5.25) in the 7 h/day sleepers group, OR = 2.29 (95% CI: 1.13-4.63) in the 8 h/day sleepers group and OR = 4.27 (95% CI: 1.83-9.97) in the ≥9 h/day sleepers group. The association has shown to be highlighted in middle-aged people, females, non-smokers, lower educated, with lower lead and higher cadmium blood levels and with higher carotene dietary intake ones and to be partially mediated by lipid profile alterations, diabetes, serum Vitamin D levels and white blood cell count.

Conclusion 1. This study has highlighted an independent direct association between sleep duration and periodontitis prevalence; 2. The association was masked by a profound confounding: age and consumption frequency of coffee, tea, chocolate and red wine seemed to be the main confounders; 3. The association has shown to be highlighted in middle-aged people, females, non-smokers, lower educated, with lower lead blood levels, with higher cadmium blood levels and with higher carotene dietary intake; 4. The association has shown to be partially mediated by lipid profile alteration, diabetes, serum Vitamin D levels and white blood cell count; 5. New studies are required in order to expand this new apparently highly interesting field of research.

SUMMARY KEY Psychological Stress

• Several studies suggest that stress can reduce the efficacy of the immune response. There is strong historical evidence that the development of acute necrotizing ulcerative gingivitis is at least in part stress related. • However, at present there are no longitudinal psychoneuroimmunologic studies that address alterations in host defenses to periodontal organisms in patients experiencing psychoemotional stress. • A possible mechanism for stress to influence pathogenesis could be corticosteroids exerting an inhibitory effect on inflammatory cells. • Stress is a potential risk factor for periodontal disease, but the underlying mechanisms need to be thoroughly evaluated.

A Systematic Review of Stress and Psychological Factors as Possible Risk Factors for Periodontal Disease Peruzzo DC, Benatti BB, Ambrosano GM, Nogueira-Filho GR, Sallum A, Casati C, Nociti FH. J Periodontol. 2007 Aug;78(8):1491-504.

Background Clinical observations and epidemiologic studies suggest that some negative life events and psychological factors may contribute to an increased susceptibility to periodontal disease. The aim of the present study was to systematically review the evidence from case-control studies, cross-sectional studies, and prospective clinical trials reporting on the influence of stress and psychological factors on periodontal disease. The focused question addressed in this systematic review was whether the scientific evidence is enough to consider stress and psychological factors as risk factors for periodontal disease.

Conclusion Within the limitations of this systematic review, the majority of studies showed a positive relationship between stress/ psychological factors and periodontal disease. However, in the future, well-designed and more representative studies should be considered to confirm these factors as a risk for periodontal disease.

Relationship of Clinical Depression to Periodontal Treatment Outcome Elter JR, White BA, Gaynes BN, Bader JD. J Periodontol. 2002 Apr;73(4):441-9.

Conclusion Clinical depression may have a negative effect on periodontal treatment outcome in this group model HMO population.

Dental Plaque, Gingival Inflammation, and Elevated Levels of Interleukin-6 and Cortisol in Gingival Crevicular Fluid From Women with Stress-Related Depression and Exhaustion Johannsen A, Rylander G, Soder B, Asberg M. J Periodontol. 2006 Aug;77(8):1403-9.

Background The aim of the present study was to investigate the importance of stress for the development of periodontitis by comparing oral health status, proinflammatory markers, and cortisol in gingival crevicular fluid (GCF) and saliva in patients with stress- related mental depression and controls.scientific evidence is enough to consider stress and psychological factors asrisk factors for periodontal disease.

Conclusion Women with stress-related depression and exhaustion had more plaque accumulation, GI, and increased levels of IL-6 and cortisol in GCF compared to normal controls, suggesting that depression might affect immune function, which could lead to impaired periodontal health.

Sarcoidosis

Sarcoidosis Affecting the Periodontium: A Long-Term Follow-Up Case Moretti AJ, Fiocchi MF, Flaitz CM. J Periodontol. 2007 Nov;78(11):2209-15.

Conclusion Patients with a medical history of sarcoidosis who present with unusual periodontal findings, such as pain, rapidly progressive gingival recession, and changes in alveolar bone density, should prompt the clinician to consider the diagnosis of intraoral sarcoidosis. Furthermore, when the diagnosis is supported by laboratory studies and microscopic examination of affected oral tissues, collaboration with a rheumatologist is FIGURE 1.39 FIGURE 1.40 necessary for case management. Because there is an unpredictable pattern of progression of these lesions, close monitoring of intraoral conditions and, at times, repeat biopsies are critical when caring for patients with a history of sarcoidosis.

BACKSTORY Link Between Rheumatoid Arthritis and Periodontitis

Rheumatoid arthritis (RA) is a systemic autoimmune disease that afflicts 0.5% to 1% of the population worldwide. The prevalence of RA in women is about three times that in men.1 RA is characterized by the accumulation of proinflammatory cell infiltration in the synovial membrane, leading to synovitis, destruction of the cartilage and bone tissue of the joints, and eventually physical impairment and disabilities.2 Rheumatoid factor provides a serologic indicator for RA, but its sensitivity and specificity are relatively low compared with anticitrullinated protein antibody (APCA), a specific marker of RA with a 99% specificity. APCA can also be used to predict the severity of the disease.3 The exact pathogenesis of RA remains unknown. Recent studies have suggested an association between periodontitis and RA.4-6

References: 1. Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: What have we learned? Immunogenetics 2011;63-459–466. 2. Pischon N, Pischon T, Kroger J et al. Association among rheumatoid arthritis, oral hygiene, and periodontitis. J Periodontal 2008;79:979–986. 3. van Venrooij WJ, Hazes JM, Visser H. Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med 2002;60:383–388. 4. de Pablo P, Chapple IL, Buckley CD, Dietrich T. Periodontitis in systemic rheumatic diseases. Nat Rev Rheumatol 2009;5:218–224. 5. Potikuri D, Dannaana KC, Kanchinadam S, et al. Periodontal disease is significantly higher in non-smoking treatment-naive rheumatoid arthritis patients: Results from a case-control study. Ann Rheum Dis 2012;71:1541–1544. 6. Farquharson D, Butcher JP, Culshaw S. Periodontitis, Porphyromonas, and the pathogenesis of rheumatoid arthritis. Mucosal Immuno 2012;5:112–120.

Excerpted from: Tang Q, Fu H, Qin B, Hu Z, Liu Y, Liang Y, Zhou L, Yang Z, Zhong R. A Possible Link Between Rheumatoid Arthritis and Periodontitis: A Systematic Review and Meta-analysis. Int J Periodontics Restorative Dent. 2017 Jan/Feb;37(1):79-86.

Periodontitis and Rheumatoid Arthritis: A Review Bartold PM, Marshall RI, Haynes DR. J Periodontol. 2005 Nov;76(11 Suppl):2066-74.

Conclusion Periodontitis and rheumatoid arthritis (RA) appear to share many pathologic features. In this review, the common pathologic mechanisms of these two common chronic conditions are explored. Emerging evidence now suggests a strong relationship between the extent and severity of periodontal disease and RA.

Anti–TNF-alpha Immunotherapy Is Associated with Increased Gingival Inflammation without Clinical Attachment Loss in Subjects with Rheumatoid Arthritis Pers JO, Saraux A, Pierre R, Youinou P. J Periodontol. 2008 Sep;79(9):1645-51.

Background Current therapies for the treatment of RA are targeted at neutralizing TNF-α with drugs such as etanercept, its recombinant soluble receptor, or infliximab, a neutralizing antibody. The combination of infliximab and methotrexate (MTX; a folate analog with inhibitory effects on IL-1 and TNF-a production) successfully delays the progressive joint destruction characteristic of RA by restricting and, possibly, reversing bone destruction. Therefore, not surprisingly, blockade of TNF- α and IL-1 was effective in treating primates with periodontitis, thus confirming that a significant component of the periodontal process results from excessive TNF- α. However, MTX used alone seemed to have no effect on alveolar bone loss in periodontitis. Because chronic periodontitis has been used as a surrogate model for controlled long-term trials of RA, therefore the preset study examined the possibility that treatment of RA with infliximab offers an opportunity to determine its effects on coexisting periodontitis.

Conclusion 1. Infliximab tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between group I (subject who had received infliximab every 6 weeks for >22 months at the time of periodontal evaluation) and group II (subjects who had received their first infusion with infliximab) with coexisting periodontitis before and after treatment. Methotrexate had no effect on periodontal status. 2. Although the plaque index revealed that bacterial infection persisted, the probing depth was equal in both groups and equivalent before and after treatment in subjects with periodontitis, whereas attachment loss was decreased after infliximab treatment. 3. Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients withRA. Therefore, TNF-a blockade could be beneficial in the treatment of periodontitis.

Clinical Evaluation of Periodontal Disease in Patients with Rheumatoid Arthritis: A Cross-Sectional Study Pons-Fuster A, Rodríguez Agudo C, Galvez Muñoz P, Saiz Cuenca E, Pina Perez FM, Lopez-Jornet P. Quintessence Int. 2015 Oct;46(9):817-22.

Results Bleeding on probing was significantly greater in the rheumatoid arthritis (RA) group (0.9 ± 0.36) than the control. The Plaque Index was significantly higher in the RA group (0.76 ± 0.34) versus the control group (0.55 ± 0.2). RA patients showed a 0.13 increased risk of periodontal disease (95% confidence interval, 0.05-0.37).

Conclusion

FIGURE 1.41 — Severe periodontitis in a Patients with RA suffered a higher risk of periodontal disease and for this reason patient with rheumatoid arthritis. these patients must be instructed to intensify their oral hygiene regimes.

Periodontitis and Rheumatoid Arthritis: What Do We Know? de Smit MJ, Westra J, Brouwer E, Janssen KM, Vissink A, van Winkelhoff AJ. J Periodontol. 2015 Sep;86(9):1013-9.

Conclusion 1. From an epidemiologic point of view, patients with rheumatoid arthritis (RA) have a higher incidence of periodontal disease than individuals without RA. In addition, there is a dose-response pattern in the association between the severity of periodontitis and RA disease activity. 2. There are indications that periodontitis precedes RA, but there is no evidence yet available to show that Porphyromonas gingivalis (Pg) plays a direct role in this temporal relationship. The role of the unique characteristic of citrullination by Pg remains unexplained. 3. However, in animal models, citrullination by Pg plays a distinct role in the development and aggravation of experimental arthritis. Although the role of Pg in RA remains speculative, a causative role for periodontitis as a chronic inflammatory disease caused by infectious agents in RA seems biologically plausible.

Exploring the Possible Link: Periodontal Disease and Rheumatoid Arthritis Bartold PM. Decisions in Dent. 2015 Nov-Dec;46-49.

Conclusion 1. A recent systematic review analyzed the published intervention studies investigating the effect of nonsurgical periodontal treatment on clinical parameters for rheumatoid arthritis in patients experiencing both periodontitis and rheumatoid arthritis. This review concluded there is emerging evidence to indicate that periodontal treatment can influence a number of biochemical and clinical markers of rheumatoid arthritis disease activity, including erthryocyte sedimentation rate, levels of tumor necrosis factor-alpha, disease activity score, and anticitrullinated protein antibody levels. 2. The weaknesses of these studies, however, include low subject numbers and short duration (6-month follow-up or less). Therefore, larger population studies with longer follow-up periods are needed to further investigate whether nonsurgical periodontal treatment has any significant effect on clinical indicators of rheumatoid arthritis. 3. Research demonstrates an association between periodontal disease and rheumatoid arthritis in that they share many of the same manifestations. While causality does not seem to exist between the two diseases, there is a relationship between disease severity and the potential for periodontal infection to either initiate or modulate rheumatoid arthritis. As much remains unknown about this association, more research is needed to explore the possible connection between rheumatoid arthritis and periodontal disease, and what these data may suggest when it comes to prevention and treatment.

Periodontitis and Rheumatoid Arthritis: Epidemiologic, Clinical, and Immunologic Associations Smolik I, Robinson D, El-Gabalawy HS. Compend Contin Educ Dent. 2009 May;30(4):188-90, 192, 194.

Conclusion Rheumatoid Arthritis (RA) and Periodontal Disease (PD) share many similarities in their pathogenesis. The chronic inflammatory lesion that characterizes both of these disorders leads to strikingly similar consequences to the surrounding calcified and soft tissue.The clinical association between these two disorders, now demonstrated in several populations, is complex and may relate to a number of biologic factors, particularly shared genetic risk. An emerging understanding of the preclinical immune mechanisms that are involved in the development of the autoimmunity that leads to RA may be pointing toward the oral cavity as a major battleground. If PD proves to be a key element in breaking immune tolerance to citrullinated antigens, this offers important opportunities for intervention, both in terms of dental procedures and tolerance-inducing immunologic FIGURE 1.42 — Erosions and deformity of manipulations. These interventions ultimately may lead to the prevention of RA hands. in susceptible individuals.

Rheumatoid Arthritis and Salivary Biomarkers of Periodontal Disease Mirrielees J, Crofford LJ, Lin Y Kryscio RJ, Dawson DR, Ebersole JL, Miller CS. J Clin Periodontol. 2010 Dec;37(12):1068-74.

Conclusion RA patients have higher levels of periodontal inflammation than healthy controls, i.e., an increased BOP. Systemic inflammation appears to influence levels of select salivary biomarkers of periodontal disease, and anti-TNF-α antibody-based disease- modifying therapy significantly lowers salivary IL-1β and TNF- α levels in RA.

Clinical Periodontal and Microbiologic Parameters in Patients with Rheumatoid Arthritis Ziebolz D, Pabel SO, Lange K, krohn-Grimberghe B, Hornecker E, Mausberg RF. J Periodontol. 2011 Oct;82(10):1424-32.

Results No patients were periodontally healthy: 24 patients were classified as having gingivitis; 18 patients had moderate periodontitis; 23 patients had severe periodontitis; and one patient was toothless.

Conclusion Most patients with RA in this study showed moderate-to-severe periodontitis and the presence of periodontal pathogens. No association was found between rheumatic factor on periodontal classification and microbiologic parameters.

PRINCIPLES Rheumatoid Arthritis / Implants

• Patients have higher levels of periodontal inflammation. • Patients have altered levels of biomarkers. • Patients have increased risk for Peri-implantitis.

A Possible Link between Rheumatoid Arthritis and Periodontitis: A Systematic Review and Meta-Analysis Tang Q, Fu H, Qin B, Hu Z, Liu Y, Liang Y, Zhou L, Yang Z, Zhong R. Int J Periodontics Restorative Dent. 2017 Jan/Feb;37(1):79-86.

Results Study size ranged from 104 to 151,569 participants. The prevalence of periodontitis in rheumatoid arthritis (RA) patients ranged from 15.5% to 100%, compared with 10.0% to 82.1% in controls. In group 1 (control) and group 2, the heterogeneity was 38% and 11%, respectively. Using fixed-effects analysis, the overall pooled estimates of the odd ratios for periodontitis were 4.68 (95% confidence intervals: 3.11-7.05) and 1.28 (95% confidence intervals: 1.24-1.33) in groups 1 and 2, respectively.

Conclusion This study evaluated the prevalence of periodontitis in rheumatoid arthritis (RA) patients by systematically reviewing the relevant articles, suggesting a possible association between RA and periodontitis. Knowledge about such an association may be important because treatment of periodontitis may decrease the risk of RA development. Clinical rheumatologists and dentists should work collaboratively for the sake of reducing the occurrence of RA and/or periodonitis.

Cross-Sectional Evaluation of Periodontal Status and Microbiologic and Rheumatoid Parameters in a Large Cohort of Patients With Rheumatoid Arthritis Schmickler J, Rupprecht A, Patschan S, Patschan D, Müller GA, Haak R, Mausberg RF, Schmalz G, Kottmann T, Ziebolz D. J Periodontol. 2017 Apr;88(4):368-79.

Results Moderate to severe periodontitis was noted in 98% of patients with RA and 82% of the healthy control group. Rheumatic factor (RH)- positive patients with RA suffered from worse periodontal conditions than RF-negative patients. Age, papillary bleeding index, and presence of T. denticola are related to periodontal condition in patients with RA. Although not statistically significant, P. gingivalis and F. nucleatum occur in higher concentrations more often in anti-cyclic citrullinated peptide positive patients with RA.

Conclusion 1. In the present study, assumed causal relationships between periodontitis and RA were further substantiated. 2. Patients with rheumatoid arthritis should be routinely referred to dentists with vast experience in the field of periodontology to create the most favorable conditions for rheumatologic drug therapy by implementing (mostly uncomplicated) periodontitis therapy.

Association Between Periodontal Disease, Bacterial Vaginosis, and Sexual Risk Behaviors Zabor EC, Klebanoff M, Yu K, Zhang J, Nansel T, Andrews W, Schwebke J, Jeffcoat M. J Clin Periodontol. 2010 Oct;37(10):888-93.

Conclusion In this population, there is a small but significant association between periodontal disease and bacterial vaginosis and a possible trend between receptive oral sex with an uncircumcised partner and periodontal disease.

Association Between Chronic Periodontitis and Vasculogenic Erectile Dysfunction Sharma A, Pradeep AR, Raju P A. J Periodontol. 2011 Dec;82(12):1665-9.

Results Among the selected vasculogenic patients with ED, mild-to-moderate vasculogenic ED showed the highest prevalence, whereas prevalence for CP among all vasculogenic patients with ED was highest among severe ED (81.8%). Association of CP and vasculogenic ED was found to be correlated positively, but it showed no statistical significance. Two of five patients were found to have vascular insufficiency.

Conclusion It can be hypothesized that an association exists between vasculogenic ED and CP in young males. However, a large-scale study with confounder analysis and a longitudinal follow-up is warranted.

Clinical and Serologic Markers of Periodontal Infection and Chronic Kidney Disease Fisher MA, Taylor GW, Papapanou PN, Rahman M, Debanne SM. J Periodontol. 2008 Sep;79(9):1670-8.

Background Chronic kidney disease and its concomitant serious sequelae (i.e., end-stage kidney failure, cardiovascular disease, and premature death) represent a major public health problem in the United States. Chronic inflammatory burden has been suggested as a risk factor for chronic kidney disease and atherosclerotic cardiovascular disease. Recent data suggest that high periodontal pathogen antibody titers, periodontal disease incorporating bleeding as an indicator of active inflammation, and markers of chronic inflammatory burden contribute to chronic kidney disease. Systemic dissemination of bacterial pathogens, antigens, endotoxins, and inflammatory cytokines is related to the chronic inflammatory burden of periodontal disease.

Conclusion 1. This findings support the conclusion that edentulous adults are more likely to have chronic kidney disease, and those with a high level of systemic antibody response to one of the major periodontal pathogens (A. actinomycetemcomitans) are less likely to have chronic kidney disease after controlling for other risk factors. 2. Further research is needed to evaluate the causal inferences regarding the role of periodontal pathogen burden and its contribution to systemic inflammatory burden in longitudinal studies of chronic kidney disease with dentate and edentulous adults. 3. In addition, periodontal therapy may be considered as a means to contribute to reducing the chronic inflammatory burden in multifactorial interventions that might include counseling to modify patients’ behavior (e.g., smoking cessation counseling, diet modification, and exercise initiation) and antihypertensive drug therapy directed toward reducing the incidence, progression, and complications of chronic kidney disease.

Association between Periodontitis and Mortality in Stages 3-5 Chronic Kidney Disease: NHANES III and Linked Mortality Study Sharma P, Dietrich T, Ferro CJ, Cockwell P, Chapple IL. J Clin Periodontol. 2016 Feb;43(2):104-13.

Conclusion There is a strong association between periodontitis and increased mortality in individuals with chronic kidney disease. Sources of chronic systemic inflammation (including periodontitis) may be important contributors to mortality in patients with chronic kidney disease.

Can Oral Infection be a Risk Factor for Alzheimer’s Disease? Olsen I, Singhrao SK. J Oral Microbiol. 2015 Sep 17;7:29143.

Conclusion 1. Even among microorganisms, cooperation may occur since the brain can hardly differentiate between different microbial insults which collectively contribute capacity for enhancing inflammation. Irrespective of the cause, systemic inflammation may predict the onset of dementia. Organisms such as spirochetes, P. gingivalis, C. pneumoniae, H. pylori, Herpes simplex type I virus, and Candida are among the prime candidate pathogens in Alzheimer’s disease (AD) brains. 2. In the cascade of events causing AD, oral microorganisms may play a role, particularly anaerobic bacteria such as treponemes, P. gingivalis, Prevotella spp., Fusobacterium and Actinomyces, but also facultative anaerobic Candida species. It is important to recognize that infection can occur decades before the manifestation of dementia. 3. The most convincing evidence for a causal relationship between oral bacteria and AD is noted for spirochetes which are both neurotropic and motile. It is likely that oral infection can be a risk factor for AD but it is not the only one. 4. Experiments in humans may require long exposure time to disclose key events and mechanisms of AD. There is, as yet, no cure for AD despite concerted efforts and investment by industry. 5. Prevention of AD through long-term use of antibiotics may be impractical and could select for resistant bacteria. This is worrisome as the prevalence of AD and the public expenses related to its management are expected to increase greatly in the next decade. 6. If anaerobes of periodontitis play a major role in AD, dental hygiene and treatment will provide the AD prophylaxis from an early age as periodontitis is modifiable. However, improving oral hygiene and treating periodontal disease in the AD patient can be challenging since patients are often uncooperative. There is also need for training caregivers to assist with oral care in such patients.

Biology and Pathogenesis of Cytomegalovirus in Periodontal Disease Contreras A, Botero JE, Slots J. Periodontol 2000. 2014 Feb;64(1):40-56.

Materials and Methods This review presents evidence for a role of herpes viruses in the pathogenesis of destructive periodontal disease, and because human cytomegalovirus shows a particularly strong association with disease-active periodontitis, its pathobiology is evaluated in greater detail.

FIGURE 1.43 — Proposed model linking cytomegalovirus to periodontal breakdown. Cytomegalovirus-infected cells reach periodontal connective tissues, and reactivation or latency occur within the connective tissues. Virions infect other cells (gingival fibroblasts and inflammatory cells), which results in the release of proinflammatory cytokines and increased susceptibility to tissue breakdown, including loss of aveolar bone and periodontal attachment. GCF, gingival crevicular fluid; IL, interleukin; MHC-I, major histocompatibility complex class I; MMP, matrix metalloproteinase; TNF-, tumor necrosis factor-.

FIGURE 1.44 — Indirect immunofluorescence staining of cytomegalovirus-infected gingival fibroblasts with the primary antibody against the immediate-early pp72 protein.

Conclusion 1. Cytomegalovirus infections of the periodontium may explain several features of periodontitis, such as the insidious disease onset, the site-specificity of the periodontal attachment loss, the mirror-like disease pattern of localized aggressive periodontitis, and the overgrowth of specific bacterial species in the periodontal pocket. The dynamic interaction between infectious cytomegalovirus and host immune responses may partly account for the discontinuous pattern of periodontal disease progression and for the refractory state of disease in the case of inadequate immunity. 2. Cytomegalovirus may participate in the development of periodontitis by causing macrophages and T-cells to release osteoclast-inducing interleukin-1β and tumor necrosis factor-α. Also, gingival fibroblasts infected with cytomegalovirus exhibit diminished production of collagens I and III and enhanced generation of matrix metalloproteinases 1 and 2. 3. However, although biologically plausible, the extent to which cytomegalovirus participates in the destruction of the human periodontium is still a matter of research. Studies are needed to identify the environmental events and pathogenic pathways that trigger activation of cytomegalovirus in the periodontium, the possible link between cytomegalovirus reactivation and periodontitis disease activity, and the importance of anti-cytomegalovirus immunity in controlling periodontal disease. 4. Such information may help to explain why cytomegalovirus and other ubiquitous herpesviruses may cause periodontitis only in a relatively small subset of individuals and teeth. Hopefully, increased knowledge of the immunovirology of cytomegalovirus and other herpesviruses in periodontitis may lead to a greater understanding of periodontal host responses and to more effective preventive and therapeutic interventions, including future vaccination against periodontopathic herpesviruses.

PRODUCTS Antiviral Medication

Antiviral Medication • Valtrex (Valacyclovir) (Glaxo Smith Kline) 500 mg –– Sig. 1 tab b.i.d. for 10 days (20 tabs)

SUMMARY KEY Nutrition

• Most of the information regarding nutrition and periodontal disease is dated material primarily based on animal studies that involved severe nutritional deficiencies. • Minor nutritional deficiencies or imbalances failed to demonstrate an effect on periodontal disease in these animal models. • There is a real lack of longitudinal studies, controlling for possible confounders that meet stated criteria for evaluation of nutrition as a risk factor.

Potential Mechanisms Underpinning the Nutritional Modulation of Periodontal Inflammation Chapple IL. J Am Dent Assoc. 2009 Feb;140(2):178-84.

Conclusion Hyperinflammation characterizes the periodontitis phenotype, and oxidative stress is a key orchestration point for the diverse signaling pathways, which control inflammation. Oxidative stress is modulated by diet, as well as by infection. Recent research has demonstrated that subtle shifts in nutritional status are associated independently with the prevalence of periodontitis. Moreover, the results of contemporary animal and human studies have demonstrated the role of specific micronutrients in the modulation of the host’s inflammatory response by reducing inflammatory biomarkers and bone loss.

Periodontal Disease and Nutrition: Separating the Evidence from Current Fads Schifferle RE. Periodontol 2000. 2009;50:78-89.

Summary It is reasonable to consume a nutritionally adequate diet to help maintain host resistance and to maintain the integrity of the periodontal tissues. A good diet contributes to both good general health and good oral health. We should try to eat, and also recommend to our patients, a diet that focuses on reducing our intake of refined carbohydrates and includes eating more whole grains, fruits, vegetables and dietary sources of calcium. There is, however, insufficient evidence to justify treatment with vitamin mineral supplementation in the adequately nourished individual.

Probiotic Effects of Orally Administered Lactobacillus Salivarius WB21-Containing Tablets on Periodontopathic Bacteria: A Double-Blinded, Placebo-Controlled, Randomized Clinical Trial Mayanagi G, Kimura M, Nakaya S, Hirata H, Sakamoto M, Benno Y, Shimauchi H. J Clin Periodontol. 2009 Jun;36(6):506-13.

COMMENTARY Nutrition

The scientific community is starting to realize the health benefits of diets containing foods naturally rich in antioxidants and omega-3 polyunsaturated fatty acids, as well as the dangers of diets that are high in refined carbohydrates. Nutritional intervention studies in patients with inflammatory periodontitis are needed to evaluate the effect of nutritional approaches to periodontal management.

PRODUCTS Probiotic Support?

Consider with systemic antibiotics • Opti Probiotic (PharmaDent) Reference: Hempl S. Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R. Johnsen B, Shekelle PG. Probiotics for the Prevention and Treatment of Antibiotic-Associated Diarrhea: A Systemic Review and Meta-Analysis JAMA 2012; 9:307(18); 1959-69.

Cross-Sectional Study of Vitamin D and Calcium Supplementation Effects on Chronic Periodontitis Miley DD, Garcia MN, Hildebolt CF, Shannon WD, Couture RA, Anderson Spearie CL, Dixon DA, Lan- genwalter EM, Mueller C, Civitelli R. J Periodontol. 2009 Sep;80(9):1433-9.

Conclusion In these subjects receiving periodontal maintenance therapy, there was a trend for better periodontal health with vitamin D and calcium supplementation.

Dietary Modulation of the Inflammatory Cascade Dawson DR 3rd, Branch-Mays G, Gonzalez OA, Ebersole JL. Periodontol 2000. 2014 Feb;64(1):161-97.

Conclusion 1. This review has focused on the capacity of various dietary manipulations, regarding both the quality of ingested biomolecules and the quantity of calories, to affect the inflammatory, innate and immune responses. In particular we focused on trying to provide an overview of how these different strategies could be engaged as preventive and therapeutic approaches for the management of an array of chronic inflammatory diseases. 2. The review attempted to identify more concrete linkages of how individual dietary components alter host-cell functions at the molecular level that could translate into improvement in clinical presentation of the host. We noted many commonalities in the underlying mechanisms of chronic inflammatory diseases and similarities in how these dietary host-modulating approaches could alter the disease progression. In particular, the review provides a snapshot of the somewhat limited literature available suggesting the potential to modify chronic adult periodontitis using dietary manipulation, and, as importantly, cross-related literature that provides insights into the future management of periodontitis using biological therapeutics that have been shown to be effective in other mucosal and systemic inflammatory diseases.

Effects of Probiotics in Periodontal Diseases: A Systematic Review Yanine N, Araya I, Brignardello-Petersen R, Carrasco-Labra A, González A, Preciado A, Villanueva J, Sanz M, Martin C. Clin Oral Investig. 2013 Sep;17(7):1627-34.

Results Four randomized clinical trials were analyzed in the final review process. For the primary outcome, probing pocket depth, there would be no clinical beneficial effect of probiotics. For secondary outcomes, probiotics have shown small benefits on plaque index and gingival inflammation.

Conclusion Based on the results of this review, the effectiveness ofprobiotics on the prevention and treatment of periodontal diseases is questionable. There is currently insufficient evidence demonstrating the benefits of systematic preventative use of probiotics in patients with periodontal diseases.

COMMENTARY Nutrition

1. The use of probiotics are described to prevent or treat periodontal diseases in some clinical trials; therefore, more systematic reviews of the evidence for the effect of periodontal diseases are needed. 2. Periodontitis is an inflammatory disease. 3. Gluten is pro-inflammatory, as well as other foods like dairy. There's no reason to think that changing diets won't affect our bodies' response to inflammatory disease, such as periodontal disease or Rheumatoid Arthritis. Attention to diet should be part of our armamentarium in treatment.

Probiotics in the Dental Practice: A Review Laleman I, Teughels W. Quintessence Int. 2015 Mar;46(3):255-64.

Summary During the last decade an increased interest in alternative, preventive, and therapeutic strategies in dentistry has arisen. Probiotics are living microorganisms which, if administered in sufficient amounts, provide a health benefit to the host. Their precise mechanisms of action have not been identified, but they are able to interfere with the imbalance occurring in biofilm- associated infections. In other fields of medicine, mainly in gastroenterology, their usefulness is already proven. Concerning oral threats, probiotic bacteria may reduce the numbers of pathogens associated with dental caries (mutans streptococci). Clinically, results are encouraging, but further research is needed to demonstrate apparent effects of certain probiotic strains on oral health as well as their desired concentration and vehicle. The use of probiotics in prevention and treatment of caries, periodontal diseases, halitosis, and other oral diseases needs to be further investigated.

TABLE 1.16

Clinical Probiotic Studies included in this Review with Caries as Outcome

Study No. of participants Age range (years) Strain Vehicle, time Authors’ conclusion

Hasslof et al 179 9 L paracasei F19 Cereals, 9 mo An early probiotic intervention did not affect frequency of dental caries at the age of 9 years.

Näse et al 594 1–7 L rhamnosus GG Milk, 7 mo Probiotic intervention reduced the risk of caries significantly, particularly in the 3- to 4-year-olds.

Petersson et al 52 58–84 L rhamnosus LB21 Milk, 15 mo Daily intake of milk supplemented with fluoride and/or probiotic bacteria may reverse soft and leathery primary root caries lesions in older adults.

Stecksén- 248 1–5 L rhamnosus LB21 Milk, 21 mo The daily consumption of milk containing Blicks et al fluoride and probiotics reduced the caries activity compared to the control group (preventive fraction: 75%).

Stensson et al 113 9 L reuteri ATCC 55730 Drop, 1 y Less approximal caries and fewer sites with gingivitis in 9-year-olds when probiotics were administered during the last month of gestation and first year of life.

Taipale et al 106 4 Bifidobacterium animalis Slow releasing In 4-year-olds, the administration of BB- subspecies lactis BB-12 pacifier, 2 y 12 in infancy does not influence the caries occurrence.

TABLE 1.17 Clinical Periodontitis Studies included in this Review with Clinical Periodontal Parameters as Outcome

Study No. of participants Age range (years) Strain Vehicle, time Authors’ conclusion

Burton et al 23 18–69 S salivarius K12 Lozenge, 1 wk Significantly lower VSC values for the probiotic group when compared to the placebo group.

Iwamoto et al 20 30–66 L salivarius WB21 Tablet, 4 wk Oral administration of probiotic lactobacilli primarily improved organoleptic and VSC scores in genuine halitosis patients.

Keller et al 25 19–25 L reuteri DSM 17938 Gum, 2 wk Probiotic chewing gums may have some and L reuteri ATCC PTA beneficial effect on oral malodor assessed by 5289 OLS in patients with morning bad breath. No significant differences on VSC measurements could be shown.

Sutula et al 21 – L casei strain Shirota Milk drink, 4 wk Morning breath VSC scores were not significantly affected throughout the trial.

Suzuki et al 23 22–67 L salivarius WB21 Tablet, 2 wk VSC were significantly reduced in the probiotic period compared with the placebo period.

–, not reported/ only mean age reported; OLS, organoleptic scoring; VSC: volatile sulfur compounds.

TABLE 1.18

Clinical Periodontitis Studies included in this Review with Clinical Periodontal Parameters as Outcome

Study No. of participants Age range (years) Strain Vehicle, time Authors’ conclusion

Hallstrom 18 – L reuteri ATC 55730 Tablets, 3 wk During experimental gingivitis, daily intake of et al and L reuteri ATC PTA probiotic lozenges did not significantly affect the 5289 PI, GI, and BOP measurements.

Iniesta et al 40 20–24 L reuteri DSM 17938 Tablets, 8 wk No clinical impact of the probiotic use in and L reuteri ATC PTA gingivitis patients could be demonstrated 5289 concerning PI and GI.

Krasse et al 59 – L reuteri (2 formulas) Chewing gums, In patients with moderate to severe gingivitis 2 wk a significant reduction in PI for both probiotic groups was shown in contrast to no reduction in the placebo group. In one of the probiotic groups a significantly higher reduction of the GI compared with the placebo group was shown.

Riccia et al 26 24–51 L brevis Lozenges, 4 d With the use of the probiotic lozenges all clinical parameters (GI, PI, BOP, calculus, and temperature sensitivity) decreased significantly in periodontitis patients.

Shah et al 30 14–35 L brevis Lozenges, 2 wk The administration of a probiotic tended to lead to a significant decrease in PI, GI, PPD, and CAL at 2 mo in aggressive periodontitis patients.

Shimauchi 66 – L salivarius WB21 Tablets, 8 wk GI, PI, and BOP scores were improved after et al intervention, but no significant differences between placebo and probiotic group could be shown.

Slawik et al 28 20–33 L casei strain Shirota Milk drink, 4 Daily consumption of a milk drink reduces the wk effect of plaque-induced gingival inflammation associated with a higher plaque score due to the high carbohydrate content of the probiotic milk drink.

Staab et al 50 – L casei strain Shirota Milk drink, 8 Beneficial effect of the probiotic milk drink on wk gingival inflammation in experimental gingivitis patients.

Szkaradkiewicz 38 31–46 L reuteri ATC PTA 5289 Tablets, 2 wk Improved clinical parameters (GI, PPD, CAL) after et al probiotic use in chronic periodontitis patients. The measurements in the probiotic group were significantly lower than in the control group.

Teughels et al 30 – L reuteri DSM 17938 Tablets, 12 wk Significantly more pocket depth reduction and and L reuteri ATC PTA attachment gain in the moderate and deep 5289 pockets in the probiotic group when compared with the control group.

Twetman 38 – L reuteri ATC 55730 Chewing gums, BOP improved statistically significantly after et al and L reuteri ATC PTA 2 wk probiotic usage. 5289

Vicario et al 20 44–65 L reuteri ATC 55730 Tablets, 4 wk Probiotic usage improved PI, BOP, and PPD in and L reuteri ATC PTA non-smoking patients with initial-to-moderate 5289 chronic periodontitis. In the control group no statistically significant changes could be shown.

Vivekananda 30 35–50 L reuteri DSM 17938 Lozenges, 3 wk In chronic periodontitis patients PI, GI, GBI, PPD, et al and L reuteri ATC PTA and CAL were significantly more reduced in the 5289 patients where scaling and root planing were supplemented with a probiotic compared with scaling and root planing alone.

–, not reported/only mean age reported; BOP, bleeding on probing; CAL, clinical attachment level; GBI, gingival bleeding index; GI, Gingival Index; PI, Plaque Index; PPD: probing pocket depth.

Clinical and Biochemical Evaluation of Lozenges Containing Lactobacillus reuteri as an Adjunct to Non-Surgical Periodontal Therapy in Chronic Periodontitis İnce G, Gürsoy H, İpçi ŞD, Cakar G, Emekli-Alturfan E, Yılmaz S. J Periodontol. 2015 Jun;86(6):746-54.

Materials and Methods Thirty patients with chronic periodontitis were included and divided into two groups. Every patient had, in each quadrant, ≥2 teeth each with approximal sites with a probing depth of 5 to 7 mm and gingival index of ≥2. The test group received scaling and root planing and probiotic-containing lozenges. The control group received SRP and placebo lozenges. Plaque index, gingival index, bleeding on probing, probing depth, and attachment gain were measured. Gingival crevicular fluid was sampled for the analysis of matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 by enzyme-linked immunosorbent assay. All evaluations were performed at baseline and on days 21, 90, 180, and 360.

Conclusion Lozenges containing L. reuteri may be a useful supplement in moderately deep pockets of patients with chronic periodontitis. Low matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 levels may indicate the role of the lozenges in reduction of inflammation-associated markers up to day 180.

Clinical and Microbiological Effects of Probiotic Lozenges in the Treatment of Chronic Periodontitis: A 1-Year Follow-Up Study Tekce M, Ince G, Gursoy H, Dirikan Ipci S, Cakar G, Kadir T, Yılmaz S. J Clin Periodontol. 2015 Apr;42(4):363-72.

Materials and Methods A total of 40 patients were selected and randomly divided into two groups. Each patient had at least two teeth with one approximal site each with a probing depth of 5-7 mm and gingival index of ≥2 in each quadrant. Group I received scaling and root planing plus L. reuteri-containing lozenges, and Group II received SRP plus placebo. The plaque index, gingival index, bleeding on probing, PD and relative attachment level were measured. Microbiological sampling was performed at baseline and on days 21, 90, 180 and 360 and were analyzed by culturing. The Bonferroni-corrected paired sample t-test, Bonferroni- corrected Wilcoxon signed rank test and paired sample t-test were used to evaluate intra-group differences. Results After treatment, the measured plaque index, gingival index, bleeding on probing and probing depth were significantly lower in Group I compared with Group II at all time points. Similar observations were made for the total viable cell counts and the proportions of obligate anaerobes with the exception of day 360. In Group I, significantly fewer patients required surgery on ≥3 sites.

Conclusion L. reuteri-containing lozenges may be a useful adjuvant agent to slow re-colonization and improve clinical outcomes of chronic periodontitis. Further studies are required to clarify the optimal dose of the lozenges.

Effects of Probiotic Therapy on Metabolic and Inflammatory Parameters of Rats with Ligature-Induced Periodontitis Associated with Restraint Stress Foureaux Rde C, Messora MR, de Oliveira LF, Napimoga MH, Pereira AN, Ferreira MS, Pereira LJ. J Periodontol. 2014 Jul;85(7):975-83.

Materials and Methods 1. Sixty-four rats were divided into control, stress (STR), probiotic (PROB), periodontal disease (PD), STR-PROB, STR-PD, STR- PROB-PD, and PROB-PD groups. 2. The probiotic (Bacillus subtilis) was added to the drinking water for 44 days. PD was induced by a ligature. 3. In STR groups, the animals were subjected to restraint stress for 2.5 hours per day for 30 days. Results 1. Rats with PD exhibited increased alveolar bone loss, as well as increased levels of cyclooxygenase-2, serum C-terminal telopeptide (CTX), p38 mitogen-activated protein kinase (p38), and receptor activator of nuclear factor-κB ligand and decreased levels of osteoprotegerin (OPG). Stressed rats presented high levels of C-peptide, corticosterone, and glucose. 2. In general, the presence of stress reduced the expression of CTX and p38. PT reduced alveolar bone loss in unstressed animals. It also decreased expression of CTX and induced increased expression of OPG in unstressed animals with PD. 3. However, PT was not effective in preventing bone loss or altering the expression of inflammatory markers in stressed animals. PT decreased the number of inflammatory cells in the periodontal tissue. Groups with stress and PD showed decreased villous height and crypt depth. Stress seemed to prevent part of the probiotic beneficial effects on the small intestine.

Conclusion Based on the methodology used, PT may reduce tissue breakdown resulting from PD in unstressed rats. The protocol used for restraint stress influenced the immunomodulatory effects of PT in intestinal and periodontal tissues.

Psychosocial Impact of Periodontal Disease and Its Treatment with 24-h Root Surface Debridement Jowett AK, Orr MTS, Rawlinson A, Robinson PG. J Clin Periodontol. 2009 May;36(5):413-8.

Conclusion Patients with periodontal disease have worse OHQoL than healthy patients, but this impact can be partly ameliorated by periodontal treatment. This implies that periodontal disease is not “silent” and that conventional non-surgical treatment provided in a secondary referral centre can be effective from patients’ perspectives.

Physical Activity, Inflammatory Biomarkers in Gingival Crevicular Fluid and Periodontitis Sanders AE, Slade GD, Fitzsimmons TR, Bartold PM. J Clin Periodontol. 2009 May;36(5):388-95.

Conclusion Leisure-time physical activity may protect against an excessive inflammatory response in periodontitis.

L3 Override Oral Malodor: Causes, Assessment, and Treatment Nachnani S. Compend Contin Educ Dent. 2011 Jan-Feb;32(1):22-4, 26-8, 30-1.

FIGURE 1.45 — Nine Point Hedonic Scale for Oral Malodor Assessment FIGURE 1.46 — Graphic representation of results from oral malodor reduction with 3-week use of 0.454%SnF2 dentifrice.

TABLE 1.19 TABLE 1.20

Types of Bacteria Found on the Lingual Dorsum Types of Bacteria Found on the Tongue

Treponema denticola Peptostreptococcus Porphyromonas gingivalis Collinsella aerofaciens Panerobius Eubacterium group Peptostreptococcus micros Actinomyces species Eikenella corrodens Veillonella species F nucleatum E corrodens Veillonella Fusobacterium nucleatum Selenomonas flueggei Pigmented Prevotalla species Proteus mirabilis Selenomonas species

Abstract Oral malodor is caused mainly by facultative bacteria on the tongue that produce volatile organic compounds. Traditional assessment methods include organoleptic measurements and gas chromatography. Newer techniques make diagnosis more convenient, and the electronic nose is in the early stages of development. After assessment, active practices of using proper oral hygiene products and making small lifestyle changes can reduce the amount of oral malodor significantly for an individual.

Efficacy of a Chlorine Dioxide Containing Mouthrinse in Oral Malodor Frascella J, Gilbert RD, Fernandez P, Hendler MA. Compend Contin Educ Dent. 2000 Mar;21(3):241-4, 246, 248.

Conclusion This study demonstrates that a one-minute use of a chlorine dioxide containing mouthrinse significantly improves mouth odor pleasantness, reduces mouth odor intensity, and reduces volatile sulfur compound concentrations in mouth air for at least 8 hours after use.

Chlorine Dioxide and Chlorhexidine Mouthrinses Compared in a 3-Day Plaque Accumulation Model Paraskevas S, Rosema NA, Versteeg P, Van der Velden U, Van der Weijden GA. J Periodontol. 2008 Aug;79(8):1395-400.

Background

The aim of this study was to investigate the inhibiting effect of a chlorine dioxide (ClO2) mouthrinse as opposed to a mouthrinse containing chlorhexidine (0.20%) during 3 days of plaque accumulation. Results Chlorhexidine inhibited plaque growth significantly more than the mouthrinse containing chlorine dioxide (plaque index = 1.39 versus 1.96, respectively). The results of the questionnaire showed that the panelists found chlorhexidine easier to use and more effective. However, they preferred the taste of the chlorine dioxide mouthrinse and experienced less taste alterations.

Conclusion

ClO2 mouthrinse was a less potent plaque inhibitor than CHX. However, subjects preferred the taste of the ClO2 mouthrinse and experienced less taste alterations compared to CHX.

Genuine Halitosis, Pseudo-Halitosis, and Halitophobia: Classification, Diagnosis, and Treatment Yaegaki K, Coil JM. Compend Contin Educ Dent. 2000 Oct;21(10A):880-6, 888-9.

Conclusion 1. Although tongue brushing and appropriate mouthrinses are both important and basic treatment measures for halitosis, other dental treatments are sometimes required. 2. The treatment of genuine halitosis caused by oral conditions is not complex.

Comparative Effects of Various Commercially Available Mouthrinse Formulations on Oral Malodor Saad S, Greenman J, Shaw H. Oral Dis. 2011 Mar;17(2):180-6.

Objectives The primary aim of this study was to compare a new mouthwash (SB12®) containing 0.025% chlorhexidine and 0.3% zinc for oral malodor reduction against four commercially available mouthwashes and negative control. A secondary aim was to compare the two methods for measuring volatile sulphur compounds (VSC) by halimetry and OralChroma.

FIGURE 1.47 — Log10 halimeter changes for five products plus control (*SB12, ♦ Listerine, BreathRX, ▲ SmartMouth, ■ LacerFresh, ● Control)

Conclusion SB12 shows a consistent and reproducible inhibitory effect on oral malodor parameters, which in turn correlate well with each other.

Clinical Efficacy of a New Tooth and Tongue Gel Applied with a Tongue Cleaner in Reducing Oral Halitosis Wilhelm D, Himmelmann A, Axmann EM, Wilhelm KP. Quintessence Int. 2012 Sep;43(8):709-18.

FIGURE 1.48 — Tongue cleaning with two strokes FIGURE 1.49 — Tongue cleaner spreading FIGURE 1.50 — Application of tooth and each from the posterior to the anterior part of the the (a) tooth-and-tongue gel and (b) cleaning tongue gel (treatment C) tongue (treatments B and C) the tongue

Conclusion 1. This study evaluated three treatment approaches: (1) tooth brushing with reference toothpaste and no tongue cleaning, (2) tooth brushing with reference toothpaste and mechanical tongue cleaning, and (3) tooth brushing and tongue cleaning with tooth-and-tongue gel. 2. All three treatments showed short-term efficacy in reducing malodor as well as an additional overnight benefit after 7 days of use. 3. The combination of toothbrushing and tongue cleaning with the tooth and tongue gel provided the best results at all assessment times.

Halitosis: Measurement in Daily Practice Schmidt J, Krause F, Haak R. Quintessence Int. 2015 Jul-Aug;46(7):633-41.

Forms of Halitosis In general, halitosis can be divided into three forms: endogenous, exogenous, and psychogenic halitosis. Whereas transient bad breath caused by specific food compounds like garlic and onions is called endogenous halitosis, exogenous halitosis is induced by oral causes, systemic diseases, or medication. In psychogenic halitosis, the examiner can neither subjectively nor instrumentally confirm the presence of halitosis, although the patient is convinced of actually having bad breath. If it is possible to convince the patient of the contrary, he or she suffers from pseudohalitosis. If the patient cannot be convinced in several extensive explanation attempts, however, he or she suffers from halitophobia. In this context, the importance of the halitosis measurement for supporting the education of the patient becomes obvious. In addition to the search for the cause, the measurement of halitosis is especially relevant in psychogenic halitosis, where the patient has to be convinced of not suffering from halitosis using an “objective” examination method which is independent of the practitioner. What Causes the Smell If halitosis is diagnosed objectively, the underlying cause is most often to be found within the oral cavity. Primarily, reservoirs such as the back of the tongue, the saliva, and periodontal pockets are the locations where anaerobic bacteria degrade sulfurous amino acids, releasing foul smelling volatile sulfur compounds

(VSC), in particular hydrogen sulfide (H2S)

and methyl mercaptan (CH3SH). A brief summary of the amino acids degraded by the bacteria and the resulting products is included in this figure. Other odor- intensive metabolism products, such as aromatic amines (indole, skatole) and organic acids, are contained within the exhaled air of healthy patients only in FIGURE 1.51 — Schematic illustration of the development of volatile sulfur compounds (VSC). Bacteria metabolize proteins from saliva, gingival crevicular fluid, blood (particularly in periodontitis), very low concentrations that cannot and food residue. Thereby amino acids, such as cysteine and cystine, are generated. These can be detected by smelling. This indicates be catalyzed within further enzymatic degradation processes caused by serine dehydratase or that these substances are irrelevant for methioninase (METase), for example, in VSC or other malodorous end products. intraoral halitosis. Not all the microorganisms contribute equally to the development of halitosis. A link with halitosis has been established for some bacteria that are primarily associated with periodontitis, such as Treponema denticola, Porphyromonas gingivalis, Prevotella intermedia, Haemophilus species, Veillonella species, and Fusobacterium species, as they produce not only hydrogen sulfide but also the VSC primarily associated with periodontitis, methyl mercaptan. The concentrations of hydrogen sulfide and diamines are increased in inflamed and deep periodontal pockets, and a positive correlation between VSC and the severity of the periodontal disease has been demonstrated. In this context, methyl mercaptan is attributed a higher pathogenic potential than hydrogen sulfide. The ratio of methyl mercaptan to hydrogen sulfide is significantly higher in patients with intraoral halitosis. FIGURE 1.52 — Tongue of a halitosis patient without periodontitis. Dimethyl sulfide, which is very stable as a neutral molecule and Clearly recognizable are the fissured surface at the right margin of the tongue and the yellowish-brownish tongue coating. is emitted by the blood into the alveolar air, can be considered a systemic VSC. Therefore, it is also detectable in small quantities in patients with intraoral halitosis. With regard to halitosis, however, it only plays a secondary role besides the two key VSC methyl mercaptan and hydrogen sulfide.

TABLE 1.21 Causes for Halitosis. There are a variety of causes for halitosis which are characterized by the release of different odor- intensive gases (VSC, sulfide, ammonia, etc). Apart from intraoral causes, a number of systemic diseases can also cause halitosis. Dimethyl sulfide is a compound from the VSC group that can be measured with the OralChroma and has been linked to systemic causes for halitosis.

Cause Causative gas(es)

Intraoral halitosis Gingivitis/periodontitis Methyl mercaptan, dimethyl sulfide, hydrogen sulfide Tongue coating Combination of both above-mentioned causes

Extraoral halitosis – Pharyngeal infections: tonsillitis Unknown not “blood-borne” Nasal infections: sinusitis, postnasal drip Unknown Respiratory infections, e.g., pneumonia Unknown Pulmonary diseases: lung tumor, tuberculosis Unknown Gastric symptoms: rarely Unknown

Extraoral halitosis – Systemic diseases Liver failure/liver cirrhosis Dimethyl sulfide “blood-borne” Uremia/kidney failure Ammonia, dimethylamine, trimethylamine Diabetic ketoacidosis, diabetes mellitus Acetone Metabolic syndrome Dimethyl sulfide Food Garlic Allyl methyl sulfide Onions Methyl propyl sulfide Medication Disulfiram Carbon disulfide Dimethyl sulfoxide Dimethyl sulfide Cysteamine Dimethyl sulfide

What Causes Perceptible Halitosis As already mentioned, intraoral factors most often lead to the development of halitosis. Extraoral or systemic causes for halitosis are only rarely found in generally healthy patients. Investigations of several scientific teams demonstrate that halitosis is mainly due to the presence of tongue coating in younger patients, whereas there is a cumulative effect described with regards to periodontitis in older patients. It should be noted, however, that progressive and untreated periodontitis TABLE 1.22 promotes the development of unpleasantly smelling tongue coatings. Thus the treatment of periodontitis can eventually Production of VSC by periodontopathogens. Taking into account the statements of Bollen and Beikler, a number of reduce the development rate of new tongue coatings. periodontopathogens and the VSC produced by them are listed In this context, it should also be noted that inadequate oral hygiene here. The correlation between the bacteria associated with severe forms of periodontitis is apparent. can promote the development of halitosis. This also applies to poorly cleaned removable dentures as well as to permanently Periodontopathogenic Bacteria VSC Produced worn splints. Oral hygiene measures have been proven to Porphyromonas gingivalis and Hydrogen sulfide from serum reduce the concentrations of VSC within the oral cavity. It was Treponema denticola Methyl mercaptan from serum demonstrated, however, that halitosis cannot be detected in Prevotella intermedia Hydrogen sulfide from serum every patient with poor oral hygiene. On the other hand, patients Tannerella forsythia Several other VSC with excellent oral hygiene also suffer from halitosis. Accordingly, on the basis of halitosis measurements it is impossible to draw Micros prevotii Hydrogen sulfide from cysteine general conclusions about the oral hygiene of a patient. Besides insufficient restoration, another possible intraoral factor contributing to the development of halitosis is a reduced salivary flow rate. The reduced rinsing effect, the lack of antimicrobial activity, and the desiccation of the oral cavity can not only cause an increased release of VSC, but also an increased release of gases not containing sulfur, such as cadaverine, putrescine, skatole, indole, butyric acid, and isovaleric acid. Xerostomia can be caused by diseases of the salivary glands (e.g., tumors, salivary gland stones), systemic diseases (Sjögren’s syndrome), or medication. Especially anticholinergic antihypertensive drugs, cardiac drugs, and antidepressants have been mentioned in the literature in connection with reduced salivary flow. Similarly, continuous emotional stress and anxiety influence the rate of salivary secretion and the composition of the saliva, as they lead to a continuously increased sympathetic tone that causes the parasympathetically innervated salivary glands to show secretion changes. If oral causes are to be ruled out, rhinopharyngeal, oropharyngeal, and gastrointestinal factors have to be taken into consideration, and a specialist in the respective field should be consulted. In the field of ear, nose, and throat medicine, common causes for halitosis are found in the nose area, the paranasal sinus system, and the nasopharynx. Possible causes can also be located in the hypopharynx and the larynx. The cause of halitosis is most often located in the pharynx. Patients with pathologic findings in the ear, nose, and throat area will not always suffer from halitosis, even if they are diagnosed with periodontitis at the same time.

The Effect of Periodontal Therapy on Intra-Oral Halitosis: A Case Series Erovic Ademovski S, Mårtensson C, Persson GR, Renvert S. J Clin Periodontol. 2016 May;43(5):445-452.

Materials and Methods Sixty-eight adults with intra-oral halitosis were included in a case series. Intra-oral halitosis was evaluated at baseline, and at 3 months after treatment using the organoleptic scores (OLS), Halimeter®, and a gas chromatograph. Results Significant reductions for OLS, total sum of volatile sulphur compounds (T-VSC) and methyl mercaptan probing pockets 4 mm, 5 mm and 6 mm were significantly reduced as a result of therapy. Bleeding on probing (BOP) and plaque indices were also significantly reduced. For the 34 individuals with successful periodontal treatment (BOP<20% and a ≥50% reduction of total pocket depth) reductions in OLS and T-VSC scores were found. Eleven individuals were considered effectively treated for intra-oral halitosis presenting with a T-VSC value <160 ppb, a H2 S value <112 ppb and a MM value <26 ppb.

Conclusion Non-surgical periodontal therapy resulted in reduction of OLS, MM and T-VSC values 3 months after therapy. Few individuals were considered as effectively treated for intra-oral halitosis

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