Study Clinicians with Study Abstracts
Study Clinicians with Study Abstracts
Bryan Michalowicz, D.D.S., M.S.
Current Studies include:
- Diabetes and Periodontal Therapy
- Anti-CPP Antibody Prevalence in a Periodontitis Cohort
- Multi-Center Phase 3 Trial of Minocycline HC1mg Microspheres for the Use in subjects with Peri-Implantitis
Abstract for Diabetes and Periodontal Therapy Study:
The 2000 Surgeon General’s Report on Oral Health identified the relationship between improvement in periodontal health and glycemic control as an area in need of intervention studies. To date there has been no adequately powered clinical trial to address this question. The proposed Diabetes and Periodontics Trial (DPT) is a multi-center, randomized, controlled single-masked Phase III clinical trial designed to test whether non-surgical periodontal therapy (scaling and root planing) is effective in reducing HbA1c of patients with type 2 diabetes and untreated chronic periodontitis compared to a control group who will receive no initial treatment. Delayed treatment will be offered to the control group after the 6-month visit. The secondary aims will evaluate whether improvement in clinical measures of chronic periodontitis are related to changes in systemic inflammatory markers, HbA1c, and measures of insulin resistance in these patients.
Over a two and a half year period, four Clinical Centers from Schools of Medicine and Dentistry in Birmingham, AL, Philadelphia, PA, San Antonio, TX, and Minneapolis, MN will recruit a total of 600 adults (150/center) 35 years of age or older, with type 2 diabetes of at least 3 months duration, untreated moderate to severe chronic periodontitis, HbA1c between 7.5% and 9%, and who meet additional specific inclusion and exclusion criteria. Subjects will be recruited from the diabetes clinics, dental clinics and communities at each center. All eligible subjects will be examined at baseline, 3 months, and 6-months; at each visit a periodontal examination will be conducted and HbA1c values determined. Treatment will consist of scaling and root planing under local anesthetic. A standardized common protocol, and a detailed Manual of Procedures will be used at all centers. The primary study outcome will be change in HbA1c values at 6-months. Secondary outcomes are changes in periodontal clinical measures (gingival index, bleeding on probing, pocket depths, and clinical attachment levels), changes in inflammatory markers (serum C-reactive protein, plasma TNF, and serum IL-6) and changes in the Homeostasis Model Assessment (HOMA2). This study has the potential to provide a scientific basis for an improvement in the standard of care for patients with diabetes thus addressing one of the Public Health Service's Healthy People 2010 goals.
This application seeks support for the University of Minnesota Clinical Center. Separate applications have been submitted by the Study Chair, Coordinating Center, and three other Clinical Centers.
Abstract for Anti-CPP Antibody Prevalence in a Periodontitis Cohort
1. Specific Aims
Rheumatoid Arthritis (RA) is a chronic, disabling disease costing $30 billion per year in the US. Up to 70% of RA patients develop anti citrullinated peptide antibodies (ACPA, also known as anti-CCP antibodies) before the development of clinically detectable disease, creating an exciting opportunity for early detection and disease prevention. ACPA are only found in RA patients with HLA DR alleles containing a specific peptide sequence termed the shared epitope (SE). The SE is the strongest known genetic risk for the development of ACPA and RA, but environmental risks for the development of ACPA remain undiscovered. Previous data suggest that moderate to severe periodontitis confers a relative risk of 8 for development of RA, and 90% of RA cases were ACPA positive in an RA cohort enriched for periodontitis. These data suggest that periodontal pathogens may be an environmental risk for development of ACPA positive RA, but there are no published data addressing the prevalence of ACPA in periodontitis patients, per se. Thus, there is an urgent need to establish the seroprevalence of ACPA in periodontitis patients, and the risk of an ACPA+ periodontitis patient progressing to RA over time. Doing so will require the establishment of a well characterized cohort of periodontitis patients.
Our central hypothesis is that periodontal pathogens incite an immune response that breaks immunologic tolerance to self proteins common to periodontal and synovial tissues, resulting in production of ACPA in genetically susceptible HLA-DR “shared epitope” positive individuals prior to the onset of clinical RA. The long-term goals of this research are to screen individuals at high risk of RA, allowing early detection and intervention to prevent clinical disease. Population-wide screening is impractical, given the low incidence of RA, the lack of well-established environmental risks, and cost. Successful early screening and prevention of this chronic disabling disease may be possible if periodontitis is established as a major risk factor, with an enormous potential public health and economic benefit. The objective of this proposal is to establish the ACPA, RF, and clinical RA prevalence in a well-characterized periodontitis cohort, and measure association of ACPA and rheumatoid factor with family history, SE alleles, and the development of clinical RA. The rationale for this proposal is to guide longitudinal follow-up studies that determine the immunologic basis for progression of asymptomatic periodontitis patients to clinical RA, the rate of that progression, and to design interventions to halt disease progression. The proposal will use the University of Minnesota School of Dentistry clinic population of nearly 2000 well-characterized periodontitis patients and the RA clinical and translational research experience of Dr. Molitor.
Specific AIM 1: Measure prevalence of clinical RA in a well-established cohort of moderate-severe adult periodontitis, compared to age, gender, and smoking-matched controls. We expect an approximately 8-fold increased risk of clinical RA in the periodontitis cohort, compared to controls.
Specific AIM 2: Measure prevalence of ACPA, rheumatoid factor, shared-epitope HLA alleles, and family history of RA in the cohort, compared to age, gender and smoking-matched controls. We hypothesize a 7-fold or greater increase in ACPA+ individuals (many of whom will not have RA) in the periodontitis cohort, compared to controls.
Successful determination of clinical RA prevalence, ACPA titers and family history of RA in this case cohort will allow us to design follow-up studies to determine the rate of progression of asymptomatic, ACPA+ periodontitis patients to RA. This in turn will aid us in determining the feasibility of screening for RA in individuals with periodontitis and a family history of RA, a critical first step in the study of the pathogenic steps in the progression to RA, and in the design of early intervention trials to attempt prevention of clinical RA. Prior studies have compared periodontitis severity between patients with and without RA. Such a design cannot be used to examine the development of early pre-disease immunologic biomarkers of RA that may be due to periodontitis, however. The strength of this project is that we will study early biomarkers for development of RA in periodontitis patients compared to controls without periodontitis. The University of Minnesota dental school clinic provides an outstanding resource to accomplish this goal, and will allow us to establish a highly useful cohort of subjects that will facilitate our obtaining NIH funding for further research on our long-term goals.
Multi-Center Phase 3 Trial of Minocycline HC1mg Microspheres for the Use in Subjects with Peri-Implantitis
In recent years, dental implants have become increasingly popular in the United States. This popularity is due in part to high success rates, which is well documented in the literature. Implant failures, when they occur, can be attributed to excessive mechanical loading or a variety of biological complications, such as peri-implant disease or, more specifically, peri-implantitis.
The term “peri-implantitis” refers to an “inflammatory process affecting the tissues around an already osseointegrated implant, resulting in loss of supporting bone”, as stated in a review. Specifically, peri-implantitis manifests when an osseointegrated dental implant has at least one peri-implant probing depth ≥5 mm that exhibits bleeding on probing and displays radiographic evidence of peri-implant bone loss. Typically, this condition is accompanied by an underlying infection produced by the same bacteria that also are associated with periodontitis.
The most common treatment for peri-implantitis is debridement with implant-safe hand instruments and reinforcement of strict home-care regimens (brushing and flossing). More severe cases of peri-implantitis are typically treated surgically, using techniques similar to those used for periodontal surgery, in addition to thorough local therapeutic drug treatment of the exposed implant. ARESTIN® (minocycline 1 mg HCl microspheres) is currently indicated as an adjunct to scaling and root planing (SRP) procedures for reduction of pocket depth in patients with adult periodontitis.
The intention of this study is to demonstrate that clinical parameters of periimplantitis can be improved through the application of adjunctive Minocycline HCl Microspheres, 1mg following mechanical debridement, when compared to debridement alone.
The objective of this study is to evaluate the safety and efficacy of a locally delivered antibiotic, Minocycline HCl Microspheres, for the treatment of peri-implantitis, when used as an adjunct to mechanical debridement. Efficacy will be determined using clinical measurements of reduction of probing depth (PD) at Day 180 of qualifying implant sites as the primary criterion. Secondary criteria for efficacy will be reduction in bleeding on probing (BOP) from Baseline to Day 180 and the reduction of PD and BOP at Day 90 and of qualifying implant sites.
This is a multi-center, randomized, examiner-blind, parallel, two-arm, 180 day, controlled clinical trial. Approximately 215 generally healthy male and female subjects meeting the inclusion/exclusion criteria will be accepted for the trial. Subjects must be diagnosed with peri-implantitis. Peri-implantitis is defined as a condition around an osseointegrated dental implant having at least one peri-implant site with probing depth (PD) ≥5 mm that exhibits bleeding on probing and displays radiographic evidence of peri-implant bone loss.
Raj Gopalakrishnan, B.D.S., Ph.D.
Abstract for Bisphosphonate-Associated Osteonecrosis Study:
A. SPECIFIC AIMS
Osteonecrosis of the jaw (ONJ) is a significant and serious oral complication of long-term intravenous bisphosphonate (BP) treatment. The most common presentation of ONJ is painful, exposed bone that occurs in either or both jaws and simulates “tooth-ache” or bone infection. Although over 800 cases have been reported in the literature to date, a major limitation is a lack of knowledge of risk factors and their significance in development of ONJ. Moreover, the epidemiology and pathogenesis of ONJ remains unknown. This is primarily because there have been almost no prospective or matched case-control studies, with the vast majority of reports being either case series or reviews. The resulting information gap significantly impairs the development of preventative and therapeutic modalities for ONJ.
The current project will test the hypothesis that periodontal disease and periodontal pathogens are risk factors for ONJ in cancer patients receiving intravenous bisphosphonates. Our long term goal, which will be tested in a future R01 application, is to characterize key risk factors, and to understand their role in the epidemiology and pathophysiology of ONJ development. The work will be performed in a collaborative research environment. The investigators are skilled in current knowledge and theories of oral and maxillofacial pathology and bone biology (Raj Gopalakrishnan), clinical research and periodontology (Bryan Michalowicz), molecular microbiological analyses of oral samples (Dr. Joel Rudney), and biostatistics (Dr. James Hodges).
To test our hypothesis, the following specific aims will be pursued:
- To determine the association between clinical and microbiological measures of periodontitis and risk of ONJ development. Although several reports have speculated that periodontal disease is a major predisposing factor for ONJ development, no studies have been conducted to verify this association. We will perform a thorough periodontal exam in ONJ patients and matched controls to test if periodontitis is associated with ONJ development. Using quantitative PCR, we will also examine the association between ONJ risk and the presence and levels of putative periodontal pathogens – Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, and Treponema denticola - in subgingival plaque samples collected from these same cases and controls.
- To determine whether ONJ is associated with increased mucosal invasion of putative periodontal pathogens and Actinomyces species. Putative periodontal pathogens and Actinomyces species have been isolated from ONJ lesions. However, no systematic study using a case-control design has been done to test if these species are more prevalent in ONJ lesions than unaffected intra-oral sites. Previously, we showed that periodontal pathogens (A. actinomycetemcomitans, P. gingivalis, T. forsythia, P. intermedia and T. denticola) can colonize buccal epithelial cells. In a subsequent study of aggressive periodontitis patients, we found that invaded cells provided reservoirs for these pathogens that protected the pathogensfrom elimination following treatment. In the current study, we will use fluorescent in situ hybridization to evaluate the prevalence of these pathogens and Actinomyces species in oral mucosa samples obtained from near the ONJ lesion and from unaffected sites in cases, and from at-risk sites in matched controls.
The expectations from this exploratory case-control study are two-fold: 1) to determine if periodontal disease and periodontal pathogens are risk factors in ONJ development; and 2) identify ONJ patient and control populations that can participate in a prospective study as part of an R01 application to further explore relationships between periodontal disease and ONJ. The results obtained from this application will be significant because they will provide insight into the pathogenesis of a serious oral complication of BP therapy.
In addition, these results will also help us to understand the mechanism of action of BPs and the interaction with identified risk factors.
Donald Nixdorf, D.D.S., M.S.
Current Studies Include:
- Functional Imaging of Trigeminal Pair
- Quantitative Sensory Testing: Reliability Assessment & Mapping
- Understanding the Impacts of, and Screening for, Atypical Odontalgia (AO)
Eric Schiffman, D.D.S., M.S.
Current Study Includes:
- Reliability Study for – TMJ/Intra-Articular Disorders: Impact on Pain, Functioning & Disability and
- Recall Study or IMPACT for TMJ/Intra-Articular Disorders: Impact on Pain Functioning & Disability
Temporomandibular muscle and joint disorders (TMJD) are common conditions with a substantial public health burden. Although TMJD patients commonly have temporomandibular joint (TMJ) intra- articular disorders, including disc displacement (DD) and osteoarthritis (OA), the clinical significance of these disorders and their causal relationship to persistent jaw pain and dysfunction are poorly understood. The recently completed Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Validation Project (U01 DEO13331) demonstrated that 1) TMJ imaging is required to diagnose TMJ intra-articular disorders; and 2) cross-sectional data show that radiographically diagnosed DD and OA are significantly associated with jaw pain, jaw functional limitations and disability. It is therefore critical that we assess longitudinally whether these cross-sectional findings can be supported. Given that the available Validation Project cohort was assembled at a cost of $8.2 million, it is unlikely that there will be another similar cohort in the future to investigate the question, one of great significance to the public health: Are TMJ intra-articular disorders causally related to patient-reported outcomes of jaw pain intensity, jaw function and disability? Study participants will be recalled from the Validation Project cohort 9 years after their initial comprehensive examination was completed. Their physical status will be re-assessed, and progression of their intra-articular joint diagnoses will be measured by comparing bilateral TMJ MRI and CT at follow-up to baseline imaging. The subjects' psychosocial status will also be re-assessed along with the primary outcome measures of pain intensity, jaw functional limitations, and disability that are core domains recommended for assessment by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT). The study will assess when, and under what circumstances, intra-articular disorders progress and whether this progression is associated with increased jaw pain, jaw limitations and disability. We will also determine, as a secondary aim, which baseline biological and psychosocial factors are predictors for progression of TMJ DD and OA at follow-up. The ultimate goal is to determine the degree to which progressive change in intra-articular disorders contributes to pain and dysfunction outcomes, within the context of the biopsychosocial model. This project will provide knowledge necessary for development of evidence-based guidelines for TMJD diagnosis and management, as well as contribute to cost effective imaging and elimination of unnecessary diagnostic radiation.
Wook-Jin Seong, D.D.S, M.S., Ph.D.
Current Study Includes:
- Comparison of Initial Implant Stability of Posterior Maxillary Implants with Bicortical Fixation to Implants Engaging Only the Alveolar Crest
Historically, implant success rates have been very high (>90%). However, posterior maxillary implants still have lower success rates compared to implants placed in other areas of jawbone. In the Sinus Consensus Conference of 1996, Jensen (1998) reported an incidence of implant loss in posterior maxilla of 15%. After 8 years, Buser (1997) had a cumulative success rate of 87% and 95% for posterior maxilla and overall mandible respectively. More recently, the systematic review by Wallace and Froum (2003) had variable implant survival rate of 61.7% to 100% (average 91.8%) for implants placed in maxillary sinuses augmented through a lateral window (direct sinus lift technique) while Emmerich (2005) review on osteotome elevation of the sinus floor (indirect sinus lift technique) showed 96% survival rate at 36 months. Low success rates in the posterior maxilla have been related to the low quality of bone and subsequent low initial implant stability as measured immediately after placement surgery. Therefore, lack of initial implant stability has been well correlated to the early or late failure of the implants. (Esposito 1998; Truhlar 1997)
Primary objectives of this study is to do followings in patients with 7 – 11 mm of residual bone height below the sinus floor in posterior maxilla.
- Determine whether dental implant engaging both the alveolar crest cortical bone and sinus floor using stopper drill and self-threading concept (bi-cortical fixation) increases initial implant stability compared to the short implants engaging only alveolar crest cortical bone (uni-cortical fixation) and/or ones engaging both crest and sinus floor but with green stick fracture from osteotome and mallet (indirect sinus lift technique);
- Study whether different surgical techniques used, residual bone height, bone density, and length and width of the implants used affect initial implant stability in posterior maxilla;
- Compare secondary implant stability (after healing implant stability) of implants fixed bi-cortically, uni-cortically and with indirect sinus lift technique at 2nd stage surgery/6 month healing and 1 year follow-up;
- Measure amount of endo-sinus bone formation from 1 year follow-up CT scan and evaluate safety and post-operative complications of bi-cortical fixation and indirect sinus lift techniques reported throughout the follow-up periods.