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Clinical Innovations in Managing Inﬂammation and Periodontal Diseases: The Workshop on Inﬂammation and Periodontal Diseases
Robert J. Genco*
his summary will highlight the clinical implications of the Workshop on Inﬂammation and Periodontal Diseases reported in this supplement of the Journal of Periodontology. In selecting clinical innovations, the objective criteria of present or potential clinical utility have been applied, as well as the context of these innovations in light of recent and past literature. However, in any such endeavor, there is likely to be unintentional selectivity based upon judgment about future developments and relevance. Clinical innovations will be discussed relative to a timeline of implementation with three categories discussed: those that may be applied in the short term (1 to 2 years), medium term (5 to 10 years), and long term (‡10 years). The medium-term innovations will require further research and development, whereas the long-term innovations will likely require extensive translation of science and technology to apply them to useful clinical practice. The risk/beneﬁt ratios and cost/beneﬁt ratios will be important considerations in ﬁnal decisions to implement these innovations. INNOVATIONS THAT APPEAR TO BE READY FOR SHORT -TERM APPLICATION (1 TO 2 YEARS) 1) Development and use of risk proﬁles for periodontal disease and for diabetes that can be self-reported and used in dental and medical practices (King, p. 1527). 2) Assessment of risk for future atherothrombotic vascular events in dental patients, especially those with periodontal disease using the traditional markers of risk as well as C-reactive protein (CRP) in the Reynolds Risk Score (Ridker and Silvertown, p. 1544). 3) Management of periodontal disease in patients with diabetes and cardiovascular disease to improve oral health as well as overall health (King, p. 1527). 4) Use of nutraceutical and drug combinations such as omega-3 fatty acid and aspirin to control inﬂammation associated with periodontal infections (Van Dyke, p. 1601).
5) Use of inhibitors of matrix metalloproteinase (MMP)-2, -8 and -9 for adjunctive management of periodontal disease to assist in surgical and non-surgical therapy (Giannobile, p. 1592). INITIATIVES FOR APPLICATION IN THE MEDIUM TERM (5 TO 10 YEARS) 1) Diagnosis of active bone loss by measuring the ratio of receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) (Cochran, p. 1569). 2) Use of diet rich in omega-3-fatty acids to reduce genetic predilection to metabolic syndrome; application of nutragenomics (Ordovas and Shen, p. 1508). 3) Use of a new class of anti-inﬂammatory agents, the endogenous resolvins and protectins. These molecules possess potent anti-inﬂammatory, proresolving, and anti-ﬁbrotic activity to moderate excessive inﬂammation in chronic diseases such as inﬂammatory bowel disease and periodontitis (Serhan, p. 1520 and Van Dyke, p. 1601). Resolvins will resolve inﬂammation by an active, well-orchestrated, agonist-mediated return to tissue homeostasis (Van Dyke, p. 1601). 4) Use of tests for MMP-8 in saliva, and fragments of bone collagen in tissue ﬂuids for monitoring periodontal disease (Giannobile, p. 1592). 5) Use of bone sparing agents such as bisphosphonates that inhibit osteoclast recruitment and limit bone loss while minimizing osteonecrosis of the jaw (Giannobile, p. 1592). 6) Use of statins and targeted anti-inﬂammatory therapies in patients with periodontal disease to modulate inﬂammation and, hence, lower risk for systemic conditions such as atherosclerosis (Ridker and Silvertown, p. 1544). 7) New classiﬁcation system for periodontal disease deﬁning ‘‘disease resistant,’’ ‘‘disease aggressive,’’ and ‘‘treatment resistant subjects.’’ This will likely be based on subgingival microbial composition, clinical features, systemic risk factors such as diabetes and smoking, inﬂammatory molecule proﬁles, and genetic background including classic genetic features
* Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo, Amherst, NY.
Summary of Workshop on Inﬂammation and Periodontal Disease
Volume 79 • Number 8 (Suppl.)
based upon DNA sequences and epigenetic and micro-RNA features (Offenbacher et al., p. 1577). INITIATIVES FOR APPLICATION IN THE LONG TERM ( >10 YEARS) 1) Regulation of RANK/RANKL/OPG axis to prevent bone loss (Cochran, p. 1569). 2) Regulation of apoptosis to minimize bone loss (Cochran, p. 1569). 3) Application of knowledge of dietary modulation of genetic inﬂuence on phenotype in pathogenic pathways, e.g., cholesterol levels and obesity, likely leading to personalized genetic-based approaches for prevention and treatment of cardiovascular diseases and other complex inﬂammatory disease such as periodontal disease (Ordovas and Shen, p. 1508). 4) Determination of genetic risk proﬁles for periodontal disease based upon: a) genome-wide association studies of genetic changes encoded in DNA (SNPs, insertion, deletion, and inversions); and/or b) epigenetics (changes in meiotic or mitotic inherited change in gene expression not included in DNA itself). These epigenetic changes involve posttranslational methylation of DNA or modiﬁcation of histone proteins in the chromatin. They are inﬂuenced by environmental factors including diet, infection and inﬂammation, aging, and other factors (Wilson, p. 1514 and Offenbacher et al., p. 1577); and/or c) based on micro-RNAs, the small non-coding RNAs that regulate expression of many genes (Wilson, p. 1514). 5) Use of tests for genetic links between CRP or other inﬂammatory mediators, periodontal disease, diabetes, and premature atherothrombosis to assess risk for development of these conditions (Ridker and Silvertown, p. 1544). 6) New understanding of periodontal disease where disease pathogenesis may be modeled by incorporating gene, protein, and metabolite data into dynamic biologic networks. The key nodal points in these networks may be targets for disease management (Kornman, p. 1560). 7) Vaccination with periodontal pathogens to protect against periodontal infection. For example, vaccination against periodontal pathogens such as Porphyromonas gingivalis may protect against periodontal bone loss based on experiments in rats and monkeys. Also, vaccines for dogs and cats are already on the market directed to canine and feline Porphyromonas species including P. gulae. 8) Strategies to prevent uncoupling of bone deposition and bone resorption, possibly by inhibiting tumor necrosis factor-alpha (Graves, p. 1585). THE ROLE OF ANTI-INFLAMMATORY THERAPY IN MANAGING PERIODONTAL DISEASES: AN OVERARCHING THEME? In addition to the short-, medium-, and long-term initiatives described above, there was an overarching in1610
terest regarding the role of anti-inﬂammatory therapy in managing periodontal disease. It is well accepted that periodontal tissue destruction is a result of infection with oral bioﬁlm organisms, setting into motion a wide variety of inﬂammatory reactions that result in epithelial, connective tissue, and bony tissue destruction. There are key questions that remain to be answered: What is the long-term effect of this inﬂammatory response? Does it persist? Does it alter the tissue’s susceptibility to secondary infection, or is it merely transient with no long-term effects on host susceptibility and subsequent infection? There are at least four possibilities: 1. The inﬂammation is self-perpetuating. Somehow the inﬂammatory response persists after an initiating event. This appears to be the case in many autoimmune diseases where there is an adaptive or innate immune response to altered tissue antigens which perpetuates the disease, even for a lifetime. So far, studies have not found clear evidence for an autoimmune response in periodontal disease; however, antibodies to bacterial antigens which cross-react with tissues have been found in patients who have periodontal disease. The role of these antibodies remains unclear. The inﬂammation may also be self-perpetuating because of a persistent antigen, such as intracellular organisms, or an antigen that is not effectively removed. Clearly, there is a persistence of the infecting agents and the antigens in untreated periodontal disease; however, rigorous study of this is also needed. Why do the pathogens emerge and persist in some individuals, but others who harbor the same organisms seem to be resistant to pathogen emergence? If the inﬂammation were truly self-perpetuating, long-term anti-inﬂammatory therapy may be indicated. There is no evidence that this is the case because signiﬁcant resolution of periodontal inﬂammation most often occurs after removing the causative microﬂora, but recurrence of disease is high unless there is regular control of the microﬂora, and not all gingivitis progresses to periodontitis. Is variation in individual inﬂammatory response the key? 2. It is possible that inﬂammatory changes alter susceptibility of the periodontium to reinfection. That is, changes do not lead to persistence of an inﬂammatory response in the periodontium after removing the infectious insult but do alter susceptibility to reinfection. The inﬂammation resulting from periodontal infection changes the tissue in some way so that it is more susceptible to another bout of infection with oral bioﬁlm. The possibility raised in this symposium is that this occurs through epigenetic changes in DNA or histones by methylation. It is hypothesized that these changes then persist in the tissue and increase the susceptibility to reinfection (Offenbacher et al., p. 1577); in this instance, long-term tissue changes that might increase
J Periodontol • August 2008 (Suppl.)
susceptibility to reinfection but directly do not cause inﬂammation. If this were the case, an approach to therapy would be to not only remove the infection but also to treat the tissue somehow to mitigate, modulate, or eliminate the posttranscriptionally altered DNA and histones resulting from epigenetic changes. 3. It is possible that inﬂammation is transient and exists only during active periodontal infection. Once this infection is resolved, the tissue goes back to the original state of homeostasis. In this case, the inﬂammation is not perpetuated and is not long lasting, and the tissue shows no increased susceptibility to reinfection. The therapeutic approach would be to remove the infecting organism and prevent their recurrence. Anti-inﬂammatory agents may assist in the initial resolution of inﬂammation but may not be essential for long-term therapy or prevention of recurrence of periodontal disease. 4. It is possible that the individual inﬂammatory response is genetically programmed to be hyperreactive or resolution deﬁcient. The initial inﬂammatory response to the bioﬁlm sets up the environment for overgrowth of pathogens and development of periodontitis. This would require long-term therapeutic management of the inﬂammatory response, either continuous or intermittent. Based on present evidence, a strong case can be made for the third and perhaps the fourth possibility,
i.e., resolution of inﬂammation after effective removal of the periodontal infection. However, it remains to be investigated to what extent prior periodontal disease increases the susceptibility of the host to subsequent bouts of infection and whether, once diseased, it is possible to restore tissue homeostasis. There is ample evidence that the anatomic changes resulting from periodontal disease, such as residual periodontal pockets and angular bony defects, predispose individuals to further periodontal infection and destruction. The old adage is still extant: the best predictor of future periodontal breakdown is past periodontal breakdown. The conference speakers, moderators, and those in the audience who asked critical questions challenged our thinking on the role of inﬂammation in periodontal diseases and those systemic conditions linked to periodontal disease. From this constructive confrontation comes new insight into these complex relationships and hopefully innovations that will beneﬁt our patients.
Correspondence: Dr. Robert J. Genco, School of Dental Medicine, State University of New York at Buffalo, Baird Research Park, 1576 Sweet Home Rd., Suite 103, Amherst, NY 14228. Fax: 716/636-5921; e-mail: firstname.lastname@example.org. Submitted June 4, 2008; accepted for publication June 19, 2008.
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