Grand Rounds in Oral-Systemic Medicine

September 2007, Vol. 2, No. 3

A Peer-Reviewed Journal

Chronic Inﬂ ammation in Periodontal Diseases

Medications Inﬂ uencing Immune Response and Wound Healing (3 credits)

Dental Implications for the Immunocompromised Organ Transplant Patient

Oral Health and Chronic Kidney Disease

0709gr_c1 c1 9/14/07 4:18:49 PM What makes Colgate Total ® the #1 most recommended toothpaste?1* Proven 12-hour antibacterial, plus anti-inflammatory protection 2

The Only Toothpaste With Clinically Proven 12-Hour Antibacterial, plus Anti-inflammatory Protection

The ADA Council on Scientific Affairs’ Acceptance of Colgate Total® is based on its finding that the product is effective in helping to prevent and reduce tooth decay, gingivitis and plaque above the gum line and bad breath, when used as directed.

Better Oral Health for Better Overall Health

Visit colgateprofessional.com for free patient samples.

*#1 recommended by periodontists does not include specialty toothpastes. 1. Data on file. Colgate-Palmolive, New York, NY. 2. Panagakos FS, et al. J Clin Dent. 2005;16(suppl):S1-S19. © 2006 Colgate-Palmolive Company Printed in USA A66744 8/06

0709gr_c2 c2 9/14/07 3:33:58 PM A Peer-Reviewed Journal TABLE OF CONTENTS

VOLUME 2, NUMBER 3 — SEPTEMBER 2007 Letter from the Editors 4 Casey Hein Anthony Iacopino Charles Cobb Feature Article 6 Casey Hein Lessons Learned from The Scottsdale Project Original Article 10 Sheilesh Dave Chronic Inﬂ ammation in Periodontal Diseases: Thomas Van Dyke Immunopathogenesis and Treatment Jon Suzuki Insurance Industry Guest Editorial 18 Michael Weitzner UnitedHealthcare Dental Weighs in on Oral-Systemic Medicine The Oral Pathology-Systemic Symposia 20 James Sciubba Gingival Architectural Alterations May Provide a Clue for Diagnosing More Complex Diseases and Conditions Front Line Perspectives 24 Jonathan Levine Ensuring a Healthy Periodontium before Achieving Beautiful Teeth Front Line Perspectives 25 Michael O’Brien Implementing Clinical Procedures for Diagnosing and Treating Oral-Systemic Relationships Original Article 26 Douglas Peterson Medications Inﬂ uencing Immune Response Michael Siegel and Wound Healing Jon Suzuki Continuing Education Test 34 Original Article 36 Susan Chialastri Dental Implications for the Immunocompromised Jon Suzuki Organ Transplant Patient Original Article 45 Cheryl Thomas Oral Health and Chronic Kidney Disease: Building a Mandy Trolinger Bridge Between the Dental and Renal Communities Tools for Implementation 54

Statement of Editorial Purpose: The editorial purpose of Grand Rounds in Oral-Systemic Medicine™ is to raise awareness of the importance of the relationship between oral and systemic health, and advance the understanding of oral-systemic science and its appropriate integration into the clinical practice of mainstream dentistry and medicine by providing editorial that: • Compels members of the dental and medical communities to embrace the growing body of science called oral-systemic medicine and accept the uncertainty of its ongoing evolution. • Translates/transfers credible and relevant scientifi c fi ndings and scholarly thought related to oral-systemic medicine into authoritative editorial that is educational and engages all sectors of the healthcare professions (i.e., physicians and nurses, dentists and hygienists and allied healthcare providers). • Stimulates collaboration and innovative thinking on how to transcend professional boundaries to integrate clinical protocols that include application of oral-systemic medicine in everyday patient care. Policy on Submission of Manuscripts: The opportunity to contribute to the editorial mission of Grand Rounds in Oral-Systemic Medicine™ is offered to author candidates by honorary invitation. As such, unsolicited manuscripts are generally not accepted. Manuscripts published in Grand Rounds in Oral-Systemic Medicine™ are written by authors who are invited to contribute to this body of knowledge based upon their academic, research or clinical expertise, from both dentistry and medicine, in specifi c subject matters that pertain to oral-systemic medicine.

0709gr_1 1 9/14/07 4:00:45 PM Staff

Casey Hein, BSDH, MBA, Chief Editor, Administration Grand Rounds in Oral-Systemic Medicine™ [email protected] Frank T. Lauinger, Chairman; (ISSN #1559-6133 [1559-6141, digital version]). Anthony M. Iacopino, DMD, PhD, Associate Robert F. Biolchini, President & CEO Published quarterly by PennWell Corporation, 1421 S. Sheridan, Tulsa, OK 74112. Subscrip- Editor, [email protected] Display Sales tions for 1 year are $100 for USA, $120 for in- Charles M. Cobb, DDS, PhD, Editor Emeritus, East: Chris Page, (518) 373-0622 ternational; single-copy rates are $25 for USA, [email protected] Key Accounts: Craig Dickson, (630) 690-2472 $30 for international. POSTMASTER: Please James J. Sciubba, DMD, PhD, Columnist, Southeast: David Hurlbrink, (717) 244-3148 send change of address Form 3579 to Grand [email protected] Midwest/West: Amy Frazin, (773) 763-7680 Rounds in Oral-Systemic Medicine™, P.O. Box Lyle Hoyt, Senior Vice President, Pennsylvania, Delaware: Auggie James 3557, Northbrook, IL 60065-3557. Return undeliverable Canadian addresses to P.O. Box Group Publisher, [email protected] (847) 548-0409 122, Niagara Falls, ON L2E 6S4 ©2005 by Craig Dickson, Publisher, [email protected] Midwest/South: Marvin R. Ashworth, PennWell Corporation. All rights reserved. The Melanie Moore, MA, Technical Editor, (800) 331-4463, ext. 6266 opinions expressed in articles in this magazine [email protected] Sales Assistant: Machele Galloway, are those of the authors or sources stated and Zach Turner, Medical Illustrator, (918) 831-9756 not those of the publisher. All prices quoted in [email protected] Mailing List Sales: Kelli Berry, (800) 944-0937 advertisements are in U.S. funds. Portions of Duane DaPron, Coordinator of Editors Subscriber Customer Service: the subscriber list are made available to carefully screened companies that offer products Contributing Editors — Penny Anderson, Phone: (847) 559-7501; Fax: (847) 291-4816; and services that may be important for your Ted Anibal, Vicki Cheeseman, Mark Hartley, or visit www.omeda.com/grosm career. If readers do not wish to receive those Kevin Henry, Meg Kaiser, Kristen Wright Circulation Manager: Linda Thomas, offers and/or information, please contact list Production — Katie Blair, Production Manager [email protected] services at (847) 559-7501.

2007 Advisory Board

Salomon Amar, DDS, PhD J. Michael Gruenwald, MD David Paquette, DMD, MPH, DMSc Boston University University of Arkansas University of North Carolina at Chapel Hill for Medical Sciences Caren Barnes, RDH, MS William Reeves, DDS University of Nebraska Medical Center JoAnn Gurenlian, RDH, PhD Private Practice, Oklahoma City, OK Private Consulting, Haddonfi eld, NJ Don Callan, DDS Jonathan Richter, DDS Private Practice, Little Rock, AR Georgia Johnson, DDS, MS Private Practice, Great Neck, NY University of Iowa Christina DeBiase, BSDH, MA, EdD C. Austin Risbeck, RDH West Virginia University Lauren Kilmeade, RDH Private Practice, San Francisco, CA Private Practice, Great Neck, NY Tim Donley, DDS, MSD Louis Rose, DDS, MD Private Practice, Bowling Green, KY Barbara Kunselman, RDH, MS Private Practice, Philadelphia, PA University of Cincinnati James Ferguson II, MD Maria Ryan, DDS, PhD University of Kentucky Evanthia Lalla, DDS, MS State University of NY at Stony Brook Columbia University William Giannobile, DDS, MS, DMedSc Frank Scannapieco, DMD, PhD University of Michigan Samuel Low, DDS, MS, MEd State University of NY at Buffalo University of Florida Joan Gluch, RDH, PhD James Sciubba, DMD, PhD University of Pennsylvania Simon MacNeill, BDS, DDS Greater Baltimore Medical Center, University of Missouri-Kansas City Baltimore, MD Lorne Golub, DMD, MSc, MD (honorary) State University of NY at Stony Brook Diane McClure, RDH, MS Stanley Shanies, MD, FACP St. John’s Hospital, Springfi eld, MO Private Practice, New Hyde Park, NY Marilyn Goulding, RDH, BSc, MOS Niagara College of Canada Lenora McClean, RN, EdD Jon Suzuki, DDS, PhD, MBA State University of NY at Stony Brook Temple University Martin Greenfi eld, MD Private Practice, Great Neck, NY Brian Mealey, DDS, MS Cheryl Thomas, RDH University of Texas at San Antonio Private Consulting, Galveston, Texas Robert Greenwald, MD Long Island Jewish Medical Center, NY Sushma Nachnani, PhD Clay Walker, PhD Clinical Research, Culver City, CA University of Florida Sara Grossi, DDS, MS East Carolina University John Novak, BDS, LDS, MS, PhD Karen Williams, RDH, MS, PhD University of Kentucky University of Missouri-Kansas City

0709gr_2 2 9/14/07 4:04:16 PM lead join the perio revolution!

user-friendly software

“talking”, automated probe (no reading, no guessing) involves patient in high-tech experience

superior charting/printouts

educational movies

handouts for patients automatically trends data to track clinical endpoints

perio chart Patient Education treatment options risk assessment Patient summary

Call for Your Free 1-877-357-7623 Info Packet or Online Demo Today! www.floridaprobe.com

0709gr_3 3 9/14/07 3:34:17 PM ✍ Letter from the Editors

MOVING ORAL-SYSTEMIC SCIENCE BEYOND DENTISTRY: THE NEW IMPERATIVE Casey Hein Anthony Iacopino Charles Cobb

t is simultaneously sad and exciting to announce that with this current issue, we are stepping down as the editors of Grand Rounds in Oral-Systemic Medicine™. This was a hard decision for all 3 of us; however, we believe that without buy-in from the Imedical community, the potential of oral-systemic medicine may never be realized, and consequently the opportunity to provide optimal care to the public we serve will be signifi cantly compromised. Indeed, we can continue to preach within the dental community about the threat that oral diseases and conditions pose for systemic health, yet without strategic approaches to knowledge diffusion within the medical community, the obstacles to adoption of oral-systemic medicine will never be overcome. After carefully considering these challenges to integration, we decided that the greatest contribution we can make is to build awareness of oral- systemic science within the medical profession and provide a framework for developing collaborative, transdisciplinary models of research, education/training, and patient care. It is to this end that the 3 of us have determined to move beyond dentistry to concentrate our energy and professional goals on the medical integration of oral-systemic science.

According to a number of metrics, Grand Rounds became one of the most successful publications of its time. With its inaugural issue launched in February 2006, America’s Health Insurance Plans (AHIP), the national association that represents nearly 1,300 health insurance companies, adopted Grand Rounds as an exclusive source of credible information regarding oral-systemic health for its membership. Various articles appearing in Grand Rounds have been posted continuously on their dental portal at http://www. healthdecisions.org/Dental/. There have been countless dental schools, periodontal graduate programs and dental hygiene programs that have made Grand Rounds required reading. Grand Rounds has been widely received within the community of private practitioners, including the use of the journal for continuing education in private study clubs and large practice management organizations; the use of novel information contained in the “Tools for Implementation” section for patient education and dentist-physician communications; and the use of the journal in dentists’ and physicians’ presentations within hospital grand rounds settings. After only 6 issues, readership requests for digital subscriptions surpassed any other publication within the PennWell family.

To be sure, these are wonderful successes. However, we believe that with this issue of Grand Rounds comes an excellent opportunity for the 3 of us to continue our vision in other media. We are grateful to Lyle Hoyt, Senior Vice President and Group Publisher, and to Craig Dickson, Publisher, for understanding the importance of oral-systemic medicine, and for their vote of confi dence in our ability to create Grand Rounds. In addition, without the guidance of such a dedicated and insightful advisory board, and the very gifted authors who contributed such credible and compelling editorial, this journal would not have achieved the level of success that became a new benchmark in professional journalism. Last, but certainly not least, we want to thank our readership for such great loyalty and for sharing the vision we have to advance the understanding of oral-systemic medicine and its appropriate integration into the clinical practice of mainstream dentistry and medicine. We look forward to hearing from you.

Our thanks to Dr. Jon Suzuki for serving as the academic anchor of this issue of Grand Rounds and to all the other authors who contributed such excellent editorial.

Sincerely yours,

Casey Hein, BSDH, MBA Anthony Iacopino, DMD, PhD Charles Cobb, DDS, PhD Chief Editor Associate Editor Editor Emeritus [email protected] [email protected] [email protected]

4 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_4 4 9/14/07 4:11:47 PM 0709gr_5 5 9/14/07 3:34:35 PM Feature Article

Lessons Learned from Scottsdale By Casey Hein, BSDH, MBA†

his issue of Grand Rounds in Oral-Systemic Medi- cine™ is accompanied by a special supplement that Tfeatures a landmark document entitled the Report of the Independent Panel of Experts of ‘The Scottsdale Project’. The fi rst of its kind, this report explores the exciting new frontier of medical-dental collaboration in guidelines development for intervention of diabetes, cardiovascular disease (CVD) and periodontal disease.

Consider the promise medical-dental collaboration might hold in reversing the pandemic trends in these interrelated chronic diseases. In the past decade, there has been substantial investigation of the potential interrelationship between oral and systemic diseases. Mounting evidence suggests there is a relationship between chronic infl ammation associated with periodontal disease and increased risk for The independent panel of experts who served on The Scottsdale Proj- various systemic diseases. In spite of this evolving body of ect, and representatives from Colgate. Left to right: Walter Cohen, DDS; evidence, multiple institutional and attitudinal obstacles in- Casey Hein BSDH, MBA; Maurizio Trevisan, MD; Foti Panagakos, DMD, PhD (Colgate); Möise Desvarieux, MD, PhD; Robert Ostfeld, MD, MS; terfere with the diffusion of this body of science into con- Evanthia Lalla, DDS, MS; Louis Rose, DDS, MD; Shailesh Patel, BM, temporary healthcare. These hurdles have created a large ChB, DPhil, FRCP; Maria Ryan, DDS, PhD; Steven Offenbacher, DDS, and growing gap between what we know with reasonable PhD, MMSc; Karen Williams, RDH, PhD; Anthony Iacopino, DMD, certainty about oral-systemic connections, and what we ac- PhD; Lynnae Millar, MD; Charles Cobb, DDS, PhD; David Paquette, tually do in the clinical practice of dentistry and medicine. DDS, MPH, DMSc; Sheila Garris, MD, FACP; Sen Souvik, MD, MS, FAHA; Marsha Butler, DDS (Colgate); Carolyn Herrick, MBA (Colgate). This is precisely what the independent panel of experts from Expert not pictured: Brian Mealey, DDS, MS. The Scottsdale Project sought to address in the report.

For medical and dental practitioners who rely on the most progressive evidence-based decision making to guide their clinical practice, the Report of the Independent Panel of Experts of ‘The Scottsdale Project’ is required reading. This report discusses the scientifi c methodology, decision process, and compelling rationale for recommendations born out of three days of intense proceedings which brought together the panel of 18 experts from research, academia, and clinical medicine and dentistry. Their task was to determine whether there is suffi cient evidence to recommend the development of guidelines for the clinical practice of dentistry and medicine to assist practitioners in identifying and cross-referring patients who either have or who may be at risk for having periodontal disease, CVD, and diabetes.

The Scottsdale Project was modeled after effective public policy think tanks, and as such, it was not anticipated that the proceedings would generate a single answer to any single question. The hope was that the proceedings would elicit expert opinion that was not constrained by conventionality, social pressure of majority opinion, or determination to stand by a professional opinion previously expressed which may no longer be supported by science. In recognizing that opinions that are less accepted or more controversial today often become crystallized as accepted science at some point in the future, we sought and promoted a spread of opinion. The fi rst day of the proceedings began as somewhat of a debate, which mimicked the schism that has historically divided medicine and dentistry. Experts were urged to look upon differences of opinion as natural, and to view initial agreements as suspect. Interestingly, by the third day, minority opinions seemed to blend into more homogeneous thinking relative to the conclusions of the panel. † Chief Editor, Grand Rounds in Oral-Systemic Medicine™

6 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_6 6 9/14/07 3:51:35 PM Smooth Scaling Ahead™ with Needle-free Oraqix®! Comfort for my patients and comfort for me. What else do I need?

Why do clinicians rely on FDA approved, Needle-free Oraqix® for ultrasonic scaling and/or root planing? Because it works…easily and efficiently.

• In clinical studies, 70% of patients preferred Oraqix® vs. an injectable.* • 45% of patients stated that they would be more likely to return if Oraqix® was offered.* Needle-free Oraqix® can enable greater compliance and enhance your ability to implement full-mouth scaling. This can make the procedure—and the entire appointment—run more smoothly. When you think scaling and/or root planing, think Needle-free Oraqix®. It’s the easy way to achieve enhanced comfort, for you and your patients.

• Do not inject. • For adults who require localized anesthesia in periodontal pockets during scaling and/or root planing. • Can be used for a single tooth, quadrant, or the entire mouth. • Quick 30-second onset ® • Oraqix® should not be used in those patients with congenital or idiopathic (lidocaine and prilocaine methemoglobinemia. periodontal gel) 2.5% / 2.5% • Can be reapplied if needed to a maximum of 5 cartridges.

* vanSteenberge D et al: Patient evaluation of a novel non-injectable anesthetic gel: a multicenter crossover study comparing the gel to infiltration anesthesia during scaling and/or root planing. J Periodontol 2004; 75(11): 1471-1478. Please see the accompanying brief summary of the prescribing information.

| 1301 Smile Way | York, PA 17404 | www.professional.dentsply.com | 800.225.2787

0709gr_7 7 9/14/07 3:34:53 PM 0709gr_8 8 9/14/07 3:35:10 PM Hein. Lessons learned from Scottsdale

On the fi nal day of the proceedings, the panel of experts ➠ The credibility associated with an independent panel was asked to refl ect on whether they had any precon- of experts in formulating recommendations for guide- ceived expectations of the process, and to offer their line development is essential to ensure that there are general observations of the unique challenges inherent no biases, and that the outcome is optimal. It is critical to bringing together medical and dental experts to de- that the independent panel be comprised of experts bate the level of evidence to support oral-systemic re- who are not infl uenced by political affi liation. Diver- lationships for the fi rst time. Their comments proved to sity of opinion is also key and best accomplished by be invaluable in providing insight relative to the hurdles recruiting a depth and breadth of experts from varied that must be addressed in order for the medical commu- experiences in academia, research and clinical prac- nity to adopt and embrace this evolving body of science. I tice. This creates an environment that fosters cross call their comments, “lessons learned from Scottsdale”: education and interprofessional insights which may be forfeited unless these conditions are met. ➠ Periodontal disease’s contribution to systemic diseases will undoubtedly be challenged by the medi- ➠ Experts from the research community may be more cal profession. In order for the medical profession concerned with substantiating evidence; experts from to accept that periodontal disease may pose a threat clinical practice may be more concerned with translat- to systemic health, scientifi c evidence of such a rela- ing research into clinical care. Bringing both the re- tionship must reach a high threshold, a level of evi- searcher and private practitioner communities together dence that is fairly rigorous according to commonly increases the likelihood that guidelines are substantiat- accepted criteria for grading evidence, e.g., the Ox- ed by scientifi c rationale while simultaneously ensuring ford criteria. that the guidelines are grounded in realistic and effective strategies that can be widely implemented into pri- ➠ In considering whether it is appropriate to develop vate practice medicine and dentistry at a primary care clinical guidelines that would be useful in diagnosis level and public health setting. The Scottsdale Project and treatment, it may be counterproductive to insist is an exemplar of the balance that can be achieved by on Level 1 evidence to support guideline development. joining research and practitioner communities. Although the best evidence to support recommendations for guidelines is Oxford Level 1a, (e.g., system- ➠ To bring about the depth of discussion necessary to atic reviews of randomized clinical trials), it is impor- formulate recommendations on guideline develop- tant to consider other evidence that may not meet ment, it is critical that a high quality review of the this top threshold. Numerous organizations such as literature and evidence summaries be conducted and the American Diabetes Association and the American distributed to experts in enough time that the experts Stroke Association have developed certain guidelines are properly prepared to participate in specifi c dis- which are supported by lower levels of evidence such cussions. The literature review conducted for The as consensus opinion of experts and evidence that Scottsdale Project was considered by the participat- is confl icting albeit with the weight of evidence sup- ing experts to be of high scientifi c quality, an excellent porting the recommendation. The level of evidence to framework for discussions during the conference, and support certain periodontal-systemic relationships suffi cient to formulate recommendations for certain actually exceeds the level of evidence used to support guidelines for clinical medicine and dentistry which many guidelines formulated by various professional are worthy of adoption by professional organizations. organizations. ➠ Assuming the medical community adopts the recom- ➠ Regardless of its growing acceptance within the den- mendations coming out of the Report of the Indepen- tal community, it cannot be assumed that the medi- dent Panel of Experts of ‘The Scottsdale Project’, it is cal community is aware of the research to support vital that the dental community be prepared to work the effect of periodontal disease on local and systemic in collaboration with medical providers. infl ammation. If early studies (classic literature) are excluded from the literature search, there is a great I gratefully acknowledge the generous educational grant likelihood that medical professionals will not be ex- Colgate provided to fund The Scottsdale Project, includ- posed to some of the most important groundbreaking ing the pre-conference planning committee meeting, the research, and that medical professionals will not have extensive literature search and summaries of evidence, the opportunity to learn about fundamental concepts the conference proceedings which took place in April in related to oral-systemic medicine which were origi- Scottsdale, and fi nally, the long awaited publication of nally established in the late 1980s and early 1990s the Report of the Independent Panel of Experts of ‘The and are requisite to understanding. Scottsdale Project’.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 9

0709gr_9 9 9/14/07 3:52:07 PM Original Article

CHRONIC INFLAMMATION IN PERIODONTAL DISEASES: Sheilesh Dave, DDS, MSD† IMMUNOPATHOGENESIS AND Thomas Van Dyke, DDS, PhD‡ TREATMENT Jon B. Suzuki, DDS, PhD, MBA§

Abstract Periodontal diseases generally progress as plaque biofi lm and infl ammation-associated destruction of the attachment apparatus. Certain host factors can predispose individuals to these diseases. This paper explores the host immunologic response to periodontal pathogens, which begins with an acute phase of infl ammation, and includes an infl ux of neutrophils and plasma fl uid proteins. Chronic infl ammation appears to develop when this host response fails to properly resolve. Neutrophil production of excessive oxygen free radicals, as well as impaired neutrophil chemotaxis and phagocytosis, may play a role in the pathogenesis of various forms of periodontal disease (as well as in the pathogenesis of common risk factors such as diabetes and smoking). The genetic etiology of certain immune cell defi ciencies may also play a role. Current treatment planning for periodontal disease recognizes the destructive role of chronic infl ammatory conditions; resolvins and lipoxins may be a benefi cial adjunctive approach to modulating the immune response at the cellular and molecular levels. Concomitant management of plaque biofi lm and chronic infl ammation may prove to be critical in optimum control of many forms of periodontal disease.

Citation: Dave S, Van Dyke T, Suzuki J. Chronic infl ammation in periodontal diseases: immunopathogenesis and treatment. Grand Rounds Oral-Sys Med. 2007;3:10-17. (Digital version Grand Rounds Oral-Sys Med. 2007;3:10-17a.) (A complimentary copy of this article may be downloaded at www.thesystemiclink.com.)

Key Words: Chronic infl ammation, periodontal disease, immune mechanism, resolvin, lipoxin

Introduction eriodontal disease refers to any disease of the supporting structures of the teeth, including the interface of epithelium, connective tissue, and mineralized tissue. Very briefl y, the relationship of these supporting structures Pbegins with the tooth, which is made up of a crown (visible in the mouth) and a root (embedded in the jaw bone, also known as alveolar bone or the alveolus). The tooth root is covered in cementum, an avascular mineralized bone-like tissue. Between the root and the alveolus is the periodontal ligament, comprised of parallel collagen fi bers embedded in the cementum on one end, in the opposing alveolus on the other end. Thus the tooth is actually suspended within the alveolar bone. Where the tooth transitions from the bone to the oral cavity, the periodontal ligament ends and there is a narrow epithelial cuff attached to the cementum by hemidesmosomes. This epithelial cuff, known as the junctional epithelium, provides both a mechanical and biological barrier

between the external environment of the oral cavity and the † Private Practice Periodontics, Calgary AB, Canada internal environment of the body. Near the crown, the cuff sur- ‡ Professor, Department of Periodontology and Oral Biology, rounds the tooth but is not attached; the space between the cuff Boston University Goldman School of Dental Medicine; and the tooth is called the sulcus. A deepening sulcus indicates Program Director, Postdoctoral Periodontology; Director, conversion from health to disease; however, the hallmark of Clinical Research Center, and Associate Director Boston University School of Medicine General Clinical Research periodontal disease is the destruction of the periodontal liga- Center, Boston, MA ment and subsequent loss of alveolar bone. § Professor of Microbiology-Immunology, School of Medicine; Professor of Periodontology and Oral Implantology, School of Periodontal diseases can be broadly classifi ed as being plaque Dentistry; Associate Dean for Graduate Education, Research, induced or non-plaque induced. The incidence and severity of and International Affairs; Director, Graduate Periodontology and Oral Implantology; Temple University, Philadelphia, PA plaque-induced periodontal diseases can be modifi ed by an in-

10 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_10 10 9/14/07 4:01:15 PM A single paste for your patients?* We have it down to a science.

The most advanced Crest® toothpaste formula available

Stabilized stannous fluoride • Fights sensitivity, gingivitis, caries, and plaque • Provides long-lasting antibacterial action Sodium hexametaphosphate • Whitens through stain removal • Inhibits calculus

Recommend Crest® PRO-HEALTH™ so your patients get the widest range of benefits from Crest every time they brush.

For more information, including clinical resources, visit dentalcare.com.

“The ADA Council on Scientific Affairs’ Acceptance of Crest PRO-HEALTH Toothpaste is based on its finding that the product is effective in helping to prevent and reduce tooth decay, gingivitis and plaque above the gumline, to relieve sensitivity in otherwise normal teeth, and to whiten teeth by removing surface stains, when used as directed.”

* For patients 12 years of age and older.

0709gr_11 11 9/14/07 3:35:28 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

dividual’s infl ammatory response, systemic health, and vari- biofi lm can be considered a single organism. Biofi lms ous local factors that predispose to plaque accumulation. are characterized by impermeability and therefore resistance to host molecular and cellular defenses as well Treatment strategies for periodontal disease currently as to chemotherapeutics.7 For example, the production include control of plaque biofi lm and management of of penicillinase by one organism benefi ts all susceptible chronic infl ammation with non-steroidal anti-infl amma- organisms within the biofi lm. In this environment, known tory medications (NSAIDs). Novel classes of molecules periodontal pathogens are able to thrive and proliferate, may also promote resolution of infl ammation; examples and the disease progresses. Clinically, this correlates with include resolvins and lipoxins, which have shown benefi - increased clinical signs of infl ammation and increased cial effects in animal models of periodontitis. pocket depths.7 At a microscopic level, this is characterized by an increase in certain infl ammatory markers, cel- Immunopathogenesis of periodontal disease lular breakdown products, and sulcular fl uid fl ow. In good health, the sulcus is colonized by mostly aerobic, non-motile, bacterial fl ora. The sulcular environment is Clinical inconsistencies to plaque biofilm etiology. bathed in a continuous fl ow of plasma that passes through Historically, it was assumed that plaque-induced peri- the junctional epithelium. Contained within this sulcular odontal disease was a single disease caused by a non- fl uid are neutrophils, which are drawn to the region by specifi c accumulation of plaque whose destructive effects

host and bacterial chemotaxins such as leukotriene B4 over time resulted in the progressive loss of periodontal 1 (LTB4) and f-Met-Leu-Phe (fMLP). Once in the sulcus, the attachment at a relatively constant rate. Thus, emphasis neutrophils kill bacteria in two ways: through phagocy- was placed on maintaining high standards of oral hygiene tosis and degranulation. Also contained within sulcular in all patients and the presence of disease was generally fl uid are various infl ammatory molecules, including pros- attributed to poor oral hygiene measures. However, several β taglandin E2 (PGE2), interleukin-1 beta (IL-1 ), tumor ne- observations have challenged this view. Baer noted that in crosis factor-alpha (TNF-α),2 and gammaglobulin (IgG).3 a small percentage of juveniles, periodontal destruction progressed very rapidly and was characterized by a rela- Transition from health to disease. Regular oral hygiene tive absence of bacterial deposits.8 This disease came to measures mechanically disrupt the bacterial fl ora, sup- be known as juvenile periodontitis, and is characterized porting bacterial control by helping to maintain a rela- by specifi c bacterial infection and an altered immune re- tively constant composition of healthy bacteria.4 Clinically, sponse. Löe and colleagues conducted a long-term study this bacterial control correlates with an absence of vis- in a community characterized by poor oral hygiene and a ible infl ammation, and healthy sulcus depths of 1-3 mm.5 lack of access to professional dental care.9-11 They found However, the hallmark of periodontal disease — the de- that despite similar accumulations of bacterial deposits, struction of the periodontal ligament and subsequent loss not all individuals suffered periodontal destruction at the of alveolar bone — is mediated primarily by osteoclasts same rate. Furthermore, a small subset suffered destruc- 6 and triggered by the proinfl ammatory molecule PGE2. At tion very quickly compared with the rest of the group. this point, the attachment of the periodontal ligament to the tooth is lost, and the epithelial attachment migrates Contemporary concepts clearly recognize that periodon- into the space the periodontal ligament previously occu- tal disease is caused by the presence of specifi c patho- pied, resulting in a deepening of the sulcus beyond 3 mm. gens, but that the loss of periodontal tissues is the result A sulcus measuring greater than 3 mm is termed a peri- of a destructive host response to pathogenic bacteria. odontal pocket, and indicates a conversion from health to disease. Clinically this correlates with bleeding when Infl ammatory molecules in periodontal tissue. Within pocket depths are measured by mechanical probing.2 the periodontal tissue, at the cellular level, are neutrophils, T-Cells, B-cells, and osteoclasts.12 Also present,

Development of (plaque) biofi lm. As the pocket deepens, at the molecular level, are complement, LTB4, IL-1 and it becomes increasingly anaerobic and less accessible to interleukin-6 (IL-6), matrix metalloproteinases, prosta- mechanical disruption by routine oral hygiene methods, glandins, TNF-α, and immunoglobulins.5 These cells and e.g., brushing and fl ossing. When this occurs, a biofi lm molecules are found in greater numbers in disease than (plaque) forms. The biofi lm is characterized by greater in health, and can generally be regarded as infl amma- numbers of anaerobes, spirochetes and motile bacterial tory molecules. Directly and indirectly they initiate and species.4 Biofi lms are bacterial communities composed of mediate destruction of both the periodontal ligament many different organisms existing in a communal state. and surrounding alveolar bone.12 An extracellular environment is created with an identifi able structured organization of bacteria, in which nu- Role of infl ammation. Infl ammation is defi ned as “a com- trients and defenses become shared. In this sense, the plex reaction to injurious agents such as microbes and

12 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_12 12 9/14/07 4:01:40 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

damaged, usually necrotic, cells that consists of vascular and can lead to diseases such as periodontitis. However, it responses, migration and activation of leukocytes, and is well recognized that not all individuals are equally sus- systemic reactions.”13 The function of infl ammation is to ceptible to developing periodontal disease, and that there defend the body against microbial infection, and to repair are several forms of the disease. injured tissues. Nonetheless, infl ammation does have the potential to cause harm. Infl ammation is now believed to Periodontal disease classifi cations, characterization, play a causative or contributory role in the pathogenesis and etiology of diseases such as atherosclerosis,14 rheumatoid arthri- The American Academy of Periodontology (AAP) cur- tis,15 and gastric cancer.16 It is increasingly evident that rently recognizes two distinct forms of plaque-induced chronic infl ammatory conditions in one organ or tissue of periodontal disease: aggressive and chronic. Each form the body may produce systemic effects with deleterious can affect only a few teeth or most teeth, and hence each consequences. For example, an increased level of C-reac- form can be subclassifi ed as either localized or general- tive protein is a risk factor for atherosclerosis, and is cor- ized. A third classifi cation recognizes periodontal disease related with levels of periodontal infl ammation.17 Some induced by systemic conditions.20 evidence now points to a contributory or causative role for periodontitis in the pathogenesis of atherosclerosis.18 Aggressive periodontitis. Localized aggressive periodontitis (LAP) (Figure 1) and generalized aggressive periodontitis Infl ammation generally begins with an acute phase char- (GAP) (Figure 2) are distinct diseases of the periodontium. acterized by extravasations of plasma fl uid proteins and LAP is well characterized and affects 0.2% of individuals.21 cells, in particular neutrophils. The function of these However, its distinct profi le has made it an ideal model various factors includes the killing and elimination of for studying the underlying features and pathogenesis of microbes, debridement of necrotic tissue and eventually periodontal disease. LAP is characterized by early onset, repair and possibly regeneration of damaged tissue. As rapid progression, familial aggregation, relatively little the infl ammation persists, changing from an acute to a plaque accumulation and infection with Aggregatibacter chronic state, additional cellular players become in- (Actinobacillus) actinomycetemcomitans (Aa).22 volved, notably macrophages, mast cells, T-cells, B-cells, plasma cells, and eosinophils. Ideally, when the microbial In general, the incisor and fi rst molar teeth are affected in insult is controlled or damaged, infl ammation will subside LAP. GAP shares these features, although the entire denti- and tissue is repaired. The resolution of infl ammation re- tion is at risk, and the bacteria Porphyromonas gingivalis quires leukocytes in the area of infl ammation to undergo (Pg) and Tannerella forsythia (Tf) may also be detected apoptosis, and then be cleared from the area (without ad- in signifi cantly higher proportions than is found in the ditional leukocytes being drawn to the region during the plaque of periodontally healthy individuals.7 In addition resolution process).19 When these conditions are not met, to familial aggregation, African Americans, Hispanics, infl ammation persists in a self-sustaining chronic state, and Asians seem to be disproportionately affected.23

Figure 1: Full-mouth radiographs of a 15-year-old Hispanic female with localized aggressive periodontitis

Incisor and ﬁ rst molar osseous defects are noted. (Figure courtesy of Jon B. Suzuki, DDS, PhD, MBA)

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 13

0709gr_13 13 9/14/07 4:02:04 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

An underlying genetic etiology for LAP has been pro- Chronic periodontal disease. Chronic periodontal disease posed, although no defi nitive genetic profi le has been occurs mostly in adults, but also in younger individuals identifi ed.24 There is some debate whether the general- who are susceptible. From a clinical perspective, it ap- ized form (GAP) is simply a continuation of the localized pears to progress at a relatively constant rate over a form (LAP), or a distinct disease. To the extent that they person’s lifetime. However, a more accurate description may be different diseases, it has been observed that lo- suggests short periods of intense disease activity followed calized cases may “burn out”, i.e., the destruction stops.25 by longer periods of relative quiescence. Chronic peri- However, precise mechanisms or triggering events have odontitis is characterized by chronic plaque and calculus not been elucidated. The reason for loss of attachment at accumulation, gingival infl ammation, and loss of attach- the incisors and molars may correlate more with early ment. At a microbial level, the bacteria most commonly age of disease onset, and dentition present at that time, associated with chronic periodontitis are Pg, Treponema than with any specifi c characteristics of those individual denticola (Td), and Tf.28 With an increase in plaque ac- teeth.25 cumulation, attachment loss, and pocket depth, anaerobic bacteria increase as a component of plaque biofi lm. The host response associated with LAP is well studied. LAP is characterized by neutrophils that exist in a primed Although the incidence and severity of chronic periodon- state, and prone to degranulation and production of ex- titis is correlated with composition and duration of plaque cessive oxygen free radicals.26 At the same time, defi cien- accumulation, individuals are not equally susceptible to cies of chemotaxis and phagocytosis are also observed. chronic periodontitis. Michalowicz and colleagues, char- Oxidative stress (the increased production of free radical acterizing identical twins raised together and apart, have oxygen species) has been shown to result from excessive suggested that 50% of the susceptibility to periodontitis production by hyperresponsive neutrophils.27 Oxygen free can be attributed to genetic factors.29 To date there are radicals are injurious to all classes of biologically impor- no well-defi ned genetic determinants of periodontal distant molecules and are associated with chronic infl amma- ease. Although polymorphisms of Il-1A have been cor- tory conditions including periodontitis, atherosclerosis, related with the progression of periodontal disease in and diabetes. northern Europeans and particularly in smokers, this

Figure 2: Full-mouth radiographs of a 34-year-old Caucasian female with generalized aggressive periodontitis

Osseous defects are noted throughout the dentition. (Figure courtesy of Jon B. Suzuki, DDS, PhD, MBA)

14 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_14 14 9/14/07 4:02:33 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

does not seem to extend to all population groups.30 In a tosis are characterized by reduced numbers of circulat- recent study of patients with severe chronic periodonti- ing neutrophils and increased susceptibility to infection tis, candidate genes were identifi ed that may be mark- including periodontal diseases. These conditions under- ers or determinants of susceptibility to periodontitis, but line the importance of neutrophil function to periodontal these results are preliminary and additional studies are health. They are characterized by diminished neutrophil required.31 function, and in contrast to hyperfunction, they illustrate the complexity of the infl ammatory response. Periodontal disease induced by systemic conditions. Neutrophil disorders with systemic manifestations are Additional risk factors for periodontal disease: diabetes known to result in periodontal destruction. Most of these and smoking. Diabetes is a defi ned risk factor for chronic conditions are very rare and because of their severe sys- periodontal disease, and, in turn, periodontal infections temic manifestation, the periodontal aspects are not al- may compromise glycemic control.35 Possible mechanisms ways well studied. Much of the information regarding the for this relationship have been investigated. Altered neu- periodontal aspects of the diseases and periodontal man- trophil and monocyte function in patients with diabetes are agement comes from case reports. characterized by increased oxidative stress and impaired chemotactic and phagocytic capability.23 In this respect, Neutrophil activity is characterized by migration, adher- the profi le of phagocytes in these patients is very simi- ence, phagocytosis, and intracellular or extracellular lar to that seen in patients with aggressive periodontitis. microbicidal activity. Selectins are expressed on the sur- The stimulus for priming of neutrophils and monocytes in face of the endothelial (e-selectin) and neutrophil cells people with diabetes seems to be mediated by advanced (p-selectin) and the interaction of these molecules with glycation end products (AGEs) binding to an extracellu- one another causes the neutrophil to adhere to the blood lar receptor for advanced glycation end products (RAGE). vessel wall. Once adherence is initiated, tighter binding This, in turn, initiates an intracellular cascade involving a occurs through the expression of intracellular adhesion protein kinase C (PKC) intracellular pathway whose fi nal molecule 1 (ICAM-1) on the neutrophil, as well as through product is O2–. This effect can be stopped by blocking the beta 2 integrins on the endothelial cell surface. Migration receptor for advanced glycation end products. The primed

to the site of injury is in response to LTB4 and the infl am- neutrophil state is characterized by several additional ab- matory peptide C5a, as well as to molecules of bacterial normalities: up-regulation of oxygen free radical species origin. Once at the site of injury, phagocytosis may occur production; diminished phagocytic and chemotactic capa- and is mediated by the presence of opsonins C3b and im- bility; and an increased predisposition to degranulation of munoglobulin. catabolic and proinfl ammatory molecules.27

Following phagocytosis, intracellular microbicidal activ- Smoking is also a well-defi ned risk factor for periodontal ity occurs via non-oxidative and oxidative pathways. The disease.30 While there is no genetic component, the non-oxidative pathway involves the fusion of the intercel- impact of smoking on neutrophils and monocytes affects lular non-specifi c granules containing lytic enzymes with periodontal health. Neutrophils taken from smokers, as phagosome. The oxidative pathway involves the produc- with patients suffering from LAP or diabetes, demonstrate tion of reactive oxygen species within the specifi c gran- an increased oxidative burst but impaired phagocytosis α ules of the macrophage or monocyte, and subsequent fu- and chemotaxis. Levels of both PGE2, TNF- , neutrophil sion of these granules with the phagosome. Alternatively, collagenase and elastase are increased in the gingival bacteria may not be phagocytosed but killed instead by crevicular fl uid. Furthermore, monocytes taken from

extracellular degranulation of specifi c and non-specifi c smokers demonstrate an increase in production of PGE2 in granules. The reactive oxygen species O2– and OH– are response to stimulation with lipopolysaccharide. In many microbicidal; when formed within the phagocyte vacuole, respects, the neutrophils of smokers appear primed.33 they are potent mechanisms for killing bacteria. However, when these oxygen species are released into the extracel- Treatment strategies lular environment, signifi cant tissue damage may result. Management of aggressive periodontal diseases. Current management of aggressive periodontal diseases is focused Abnormalities and dysfunction at any step of the neutro- primarily on eliminating the bacterial load and shifting phil response to infection can result in serious disease. the subgingival fl ora to a more favorable aerobic profi le. Disorders of chemotaxis, phagocytosis, myeloperoxidase This has been accomplished mainly with aggressive me- function, defective opsonization, and adherence are all chanical debridement with or without surgery, and often observable. These diseases, while relatively rare, result in with the use of adjunctive antibiotic therapy. Protocols susceptibility to infection including periodontal infection. for antibiotic treatment vary widely but often involve the Furthermore, cyclic neutropenia and chronic agranulocy- concomitant use of amoxicillin and metronidazole. Other

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 15

0709gr_15 15 9/14/07 4:02:58 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

chemotherapeutics that have been studied include the to its effects; and conversely, that resolvins down regulate tetracyclines, clindamycin, and the quinolones. Each has the production of superoxide by neutrophils from both its relative advantages and disadvantages. healthy and LAP individuals.

Management of chronic periodontal diseases. Current Other recent studies are revealing new information therapeutics recognize the destructive role of chronic in- about the impact of lipoxins and resolvins on periodontal fl ammatory conditions. Therefore, contemporary treat- disease. The authors have demonstrated that Pg-induced ment planning should also address management of infl am- experimental periodontitis in rabbits can be arrested by mation.34 The proinfl ammatory role of lipids is well known, topical application of synthetic lipoxins on the gingiva.19 and current NSAIDs target lipids specifi cally by inhibiting Briefl y, periodontal disease was initiated in rabbits by the the conversion of cyclooxygenase 1 and 2 (COX-1 and COX- local application of Pg-soaked ligatures around the necks 2) into prostaglandin; these medications have been shown of the teeth. This destruction can be largely attenuated to slow or halt periodontal destruction.34 (See fi gure entitled by the topical application of lipoxins or resolvins at the Role of lipid mediators in infl ammation, which may be ac- necks of the teeth.36 Lipoxins and resolvins possess no cessed and downloaded from the Clinical Decision-Making antibacterial properties. The most logical explanation for Tools section at www.thesystemiclink.com). Unfortunately their effect is that they inhibit the progression of infl am- NSAIDs have undesirable side effects that can be severe mation. It should be noted that although tissue destruc- in nature, and include gastric bleeding or gastrointestinal tion was largely mitigated, there was no evidence that irritation; their safety in long-term use is debatable. Many the rabbits suffered from uncontrolled local or systemic of their negative effects stem from the fact they could be bacterial infection. Thus, Van Dyke and Dave30 reported considered relatively blunt instruments, being used to that, while lipoxins and resolvins modulate the infl am- modulate the very complex process of infl ammation. In the matory response, they do not interrupt it completely. Vital process, these medications interrupt both the harmful and protective mechanisms remained largely intact in this benefi cial effects of infl ammatory molecules. More recently, model, though some of the rabbits in this study were sus- the role of lipid mediators in the resolution of infl ammation ceptible to periodontal destruction consistent with cur- has been elucidated. Two endogenously produced classes rent concepts regarding differences in human variation of molecules that promote the resolution of infl ammation in susceptibility. Currently, lipoxins and resolvins are not are lipoxins and resolvins. available for clinical use. The results described suggest that they have the potential to fundamentally change fu- Lipoxins are produced through cell-cell transmembrane ture treatment strategies for periodontal disease. interactions. It is known that aspirin triggered lipoxins (ATL) are produced through acetylation of the cyclooxy- Limited clinical impact has resulted from our under- genase molecule. Indeed it was the discovery of ATL that, standing that the host response is the primary destructive in turn, lead to the discovery of endogenous lipoxins. agent in periodontal disease. Alternatives to mechanical These were the fi rst class of lipid molecules known to pro- debridement with or without antibiotic therapy have in- mote the resolution of infl ammation. Lipoxins are known cluded the administration of sub-antimicrobial doses of

to inhibit neutrophil chemotaxis in response to both LTB4 doxycycline (SDD), which have been shown to inhibit the and fMLP, to inhibit angiogenesis, promote macrophage activity of collagenase but have no signifi cant effect on phagocytosis of apoptotic leukocytes, regulate cellular microbes.30 The SDD dose of 20 mg twice a day in con- function of fi broblasts and endothelial cells and to inhibit junction with scaling and root planing has been shown to the activity of TNF-α.19 The benefi cial effects of local and result in a statistically signifi cant reduction in periodontal systemic application of these agents have been demon- destruction over a one-year period.37 However, the clini- strated in murine and rabbit models of periodontitis.7 cal signifi cance of this effect is debatable, and to date this protocol has not achieved widespread utilization in the Resolvins are a second recently described class of mole- periodontal community. cules derived from omega-3 fatty acids whose production is also triggered by aspirin. A recent study19 demonstrated Conclusion the benefi cial effect of topical application of resolvins in a Our present understanding of periodontal disease leads rabbit periodontitis model. It was shown that neutrophils us to believe that while bacterial pathogens colonizing the from individuals with LAP produce as much as 10-15 times sulcular environment are the primary etiologic agents, it more superoxide than neutrophils from healthy individu- is the destruction by the host response that plays a primary als; this excess superoxide is damaging to the host. One role in determining the extent of tissue destruction ob- study35 reported that while lipoxins abrogate as much as served. On the basis of the recent studies of lipoxins and 90% of superoxide production from healthy individuals, resolvins, as well as evidence from the successful use of neutrophils from LAP healthy individuals are refractory NSAIDs for the treatment of periodontitis, we believe that

16 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_16 16 9/14/07 4:03:22 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

the observed destruction is primarily caused by an ex- 10. Schatzle M, Löe H, Burgin W, et al. Clinical course of chro- cessive host infl ammatory response to periodontal patho- nic periodontitis. I. Role of gingivitis. J Clin Periodontol. gens, and a failure of that response to properly resolve. 2003;30(10):887-901. 11. Schatzle M, Löe H, Lang NP, et al. Clinical course of chronic Regarding the current availability of effective and safe host periodontitis. III. Patterns, variations and risks of attachment immune modulation for treatment of periodontitis, while loss. J Clin Periodontol. 2003;30(10):909-918. NSAIDs are effective, they have clear and signifi cant risks. 12. Taubman MA, Kawai T, Han X. The new concept of periodon- The sub-antimicrobial dose of doxycycline has been shown tal disease pathogenesis requires new and novel therapeutic to be quite safe and clinically signifi cant in clinical trials; strategies. J Clin Periodontol. 2007;34(5):367-369. however, this treatment modality has not gained wide- 13. Kumar V, Abbas AK, Fausto N, et al. Robbins Basic Pathology, spread adoption. In the future, novel classes of molecules 8th edition. Philadelphia, PA: WB Saunders; 2007:(in press). that promote the resolution of infl ammation, including re- 14. Libby P. Inflammation in atherosclerosis [review]. Nature. solvins and lipoxins, may become clinically available, with 2002;420(6917):868-874. the potential for tremendous impact on clinical manage- 15. Chung CP, Avalos I, Raggi P, et al. Atherosclerosis and inflam- ment of periodontitis and other infl ammatory conditions. mation: insights from rheumatoid arthritis. Clin Rheumatol. 2007;26(8):1228-1233. Disclosures 16. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. Thomas Van Dyke, DDS, PhD is a professor at Boston J Clin Invest. 2007;117(1):60-69. University, which is assigned patents on resolvins that are 17. Moutsopoulos NM, Madianos PN. Low-grade inflammation in licensed for clinical development and are subject to con- chronic infectious diseases: paradigm of periodontal infec- sultant agreements. tions. Ann N Y Acad Sci. 2006;1088: 251-264. Jon B. Suzuki, DDS, PhD, MBA serves on the scientifi c advi- 18. Dave S, Batista EL Jr., Van Dyke TE. Cardiovascular disease sory boards of Biohorizons and Philips Oral HealthCare. and periodontal diseases: commonality and causation [review]. Compend Contin Educ Dent. 2004;25(7 Suppl 1):26- References 37. 1. Offenbacher S, Scott SS, Odle BM, et al. Depressed leukotriene 19. Van Dyke TE, Serhan CN. Resolution of inflammation: a new B4 chemotactic response of neutrophils from localized paradigm for the pathogenesis of periodontal diseases. J juvenile periodontitis patients. J Periodontol. 1987;58(9):602- Dent Res. 2003;82(2):82-90. 606. 20. Armitage GC. Development of a classification system for perio- 2. Lamster IB, Ahlo JK. Analysis of gingival crevicular fluid as dontal diseases and conditions [review]. Ann Periodontol. applied to the diagnosis of oral and systemic diseases [re- 1999;4(1):1-6. view]. Ann N Y Acad Sci. 2007;1098:216-229. 21. Löe H, Brown LJ. Early onset periodontitis in the United ` ` 3. Stefanovic G, Markovic D, Ilic V,` et al. Hypogalactosylation of States of America. J Periodontol. 1991;62(10):608-618. salivary and gingival fluid immunoglobulin G in patients with 22. Saxen L. Juvenile periodontitis [review]. J Clin Periodontol. advanced periodontitis. J Periodontol. 2006;77(11):1887- 1980;7(1):1-19. 1893. 23. Long JC, Nance WE, Waring P, et al. Early onset periodonti- 4. Haffajee AD, Teles RP, Socransky SS. The effect of periodon- tis: a comparison and evaluation of two proposed modes of tal therapy on the composition of the subgingival microbiota. inheritance. Genet Epidem. 1987;4(1):13-23. Periodontol 2000. 2006;42:219-258. 24. Diehl SR, Wang YF, Brooks CN, et al. Linkage disequilibrium 5. Newman MG, Takei HH, Carranza FA (eds). Carranza’s of interleukin-1 genetic polymorphisms with early onset Clinical Periodontology. 10th edition. Philadelphia, PA: W.B. periodontitis. J Periodontol. 1999;70(4):418-430. Saunders Company, 2006;242-262, 432-453. 25. Tonetti MS, Mombelli A. Early onset periodontitis. Ann 6. Choi BK, Moon SY, Cha JH, et al. Prostaglandin E(2) is a Periodontol. 1999;4(1): 39-53. main mediator in receptor activator of nuclear factor- 26. Kantarci A, Van Dyke TE. Resolution of inflammation in kappa B ligand-dependent osteoclastogenesis induced periodontitis [review]. J Periodontol. 2005;76(11 Suppl):2168- by Porphyromonas gingivalis, Treponema denticola, and 2174. Treponema socranskii. J Periodontol. 2005;76(5):813-820. 27. Nassar H, Kantarci A, Van Dyke TE. Diabetic periodontitis: a 7. Socransky SS, Haffajee AD. Dental biofilms: difficult thera- model for activated innate immunity and impaired resolution peutic targets. Periodontol 2000. 2002;28:12-55. of inflammation. Periodontol 2000. 2007;43: 233-44. 8. Baer PN. The case for periodontosis as a clinical entity. J 28. Socransky SS, Haffajee AD. Evidence of bacterial etiology: a hi- Periodontol. 1971;42(8):516-520. storical perspective [review]. Periodontol 2000. 1994;5:7-25. 9. Heitz-Mayfield LJ, Schatzle M, Löe H, et al. Clinical course of chronic periodontitis. II. Incidence, characteristics and For additional references to this article, please consult the Grand Rounds in Oral-Systemic Medicine™ time of occurrence of the initial periodontal lesion. J Clin digital version of at www.thesystemiclink.com. Periodontol. 2003;30(10):902-908.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 17

0709gr_17 17 9/14/07 4:03:45 PM Dave, Van Dyke, Suzuki. Chronic inﬂ ammation in periodontal diseases: immunopathogenesis and treatment

29. Michalowicz BS, Aeppli DP, Kuba RK, et al. A twin study of 2002;73(9):1030-1036. genetic variation in proportional radiographic alveolar bone 34. Jeffcoat MK, Reddy MS, Haigh S, et al. A comparison of height. J Dent Res. 1991;70(11):1431-1435. topical ketorolac, systemic flurbiprofen, and placebo for the 30. Van Dyke TE, Dave S. Risk factors for periodontitis [review]. J inhibition of bone loss in adult periodontitis. J Periodontol. Int Acad Periodontol. 2005;7(1):3-7. 1995;66(5):329-338. 31. Kim DM, Ramoni MF, Nevins M, et al. The gene expression 35. Hasturk H, Kantarci A, Ohira T, et al. RvE1 protects from lo- profile in refractory periodontitis patients. J Periodontol. cal inflammation and osteoclast-mediated bone destruction 2006;77(6):1043-1050. in periodontitis. FASEB J. 2006;20(2): 401-403. 32. Mealey BL, Oates TW; American Academy of Periodontology. 36. Jain A, Batista EL Jr., Serhan C, et al. Role for periodontitis in Diabetes mellitus and periodontal diseases. J Periodontol. the progression of lipid deposition in an animal model. Infect 2006;77(8):1289-1303. Immun. 2003;71(10): 6012-6018. 33. Holzhausen M, Rossa Júnior C, Marcantonio Júnior E, et al. 37. Ashley RA. Clinical trials of a matrix metalloproteinase inhibi- Effect of selective cyclooxygenase-2 inhibition on the develop- tor in human periodontal disease. SDD Clinical Research Team. ment of ligature-induced periodontitis in rats. J Periodontol. Ann N Y Acad Sci. 1999;878: 335-346.

17A G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_17 a17 9/14/07 10:00:08 AM Need CE? www.ineedce.com

“Easy as 1, 2, 3” Courses: 1. Log on to www.ineedce.com

2. Select and review course Cosmetic Oral-Body Connection Endodontics Orthodontics 3. Enter answers & payment information Ergonomics Pathology Hygiene Periodontology Graded Instantly! Implants/Surgery Pharmacology Infection Control Prevention Lasers Prosthodontics Print oﬀ veriﬁ cation forms immediately Latex Allergy Radiology Legal Tooth Whitening New courses added every month Medical TMD/TMJ

If you would like to subscribe to our monthly e-mail newsletter, please send an e-mail with SUBSCRIBE in the subject line to [email protected]

The Academy of Dental Therapeutics and 1-888-INEEDCE PennWell Corp is an American Academy Stomatology is an ADA CERP Recognized Provider of Dental Hygiene Recognized Provider

0709gr_b17 b17 9/14/07 10:41:15 AM Guest Editorial

UNITEDHEALTHCARE Michael D. Weitzner, DMD, DENTAL WEIGHS IN ON MS, Vice President, Clinical Product Development, ORAL-SYSTEMIC MEDICINE UnitedHealthcare Dental

he editorial vision of Grand Rounds in Oral-Systemic Medicine™ notes that “scientific study that is not translated and used in daily practice ultimately is wasted”, and cites as one of its goals the stimulation T of “collaboration and innovative thinking on how to transcend professional boundaries to integrate clinical protocols that include application of oral-systemic medicine in everyday patient care”. The dental insurance industry shares this vision, as we seek to develop products and services that are clinically efficacious, cost effective, and value-added for members and payers. In two previous editorials, my colleagues at other leading dental insurance companies did a fine job of sharing their organization’s growing efforts in the area of oral-systemic health. While continuing in the same spirit, this editorial will shift the focus somewhat to the principles and considerations that underlie UnitedHealthcare Dental’s current and future efforts in oral-systemic medicine.

We will be seeing a variety of dental carriers offering increased levels of programs and products, including stand-alone dental plans; however, integrated medical-dental systems are likely to be at an advantage. This is due to the growing evidence that access to dental benefi ts helps reduce morbidity and mortality. UnitedHealthcare Dental works closely with other UnitedHealth Group companies to develop programs and products to impact populations across company lines. Examples include UnitedHealthcare, which offers consumer directed health benefi t plans and services for individuals, and small and mid-sized employers; Uniprise, a leading provider of benefi t delivery and service solutions for large employers; AmeriChoice, which organizes healthcare benefi ts and services for benefi ciaries of Medicaid and other government-sponsored healthcare programs; Ovations, which provides health and well-being services to Ameri- cans age 50 and older; and Optum, which delivers integrated, cohesive personal health management solutions such as consumer health information, education, and decision support services. Through these different companies, United- Healthcare Dental can tailor oral health solutions, for various systemic conditions, to different markets.

In the future, we believe dental benefi ts will be seen as an “essential” benefi t for total health. As the evidence supporting a relationship between periodontal disease and various systemic conditions — such as pregnancy, cardiovascular disease, diabetes, and more recently osteoporosis — continues to grow, dental benefi ts, particularly preventive and periodontal benefi ts, will be seen as essential components in managing these conditions. As an example of our own efforts, UnitedHealthcare Dental recently launched its Prenatal Dental Care program, offering pregnant women increased levels of preventive and periodontal services. Indeed, as the evidence of linkages grow, it is likely that dental liability will increase, as the failure to diagnose and treat periodontal needs will be perceived as having catastrophic consequences.

Consumers will expect exchange of information among medical and dental providers. Through UnitedHealth Group’s technology company, Ingenix, we maintain common databases and data management to help employers, dentists, physicians, and other healthcare providers improve healthcare delivery and operations. Using personal health management solutions offered through Optum, including services noted above, individuals have access to information to educate themselves about their condition so they can make informed choices about their care. Employers who self- insure will have the growing expectation that plans will be able to manage dental claims initiated by physicians, and be able to provide data linked to disease management processes.

Government programs will need to be included in any oral-systemic solution. Patients eligible for Medicaid may be at

18 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_18 18 9/14/07 3:50:31 PM UnitedHealthcare dental weighs in on...

odontal and other oral origins.” Indeed, the challenges Figure 1: UnitedHealthcare Dental summary of principles and cited here are also refl ected in the outcomes noted in the considerations for developing oral-systemic products and literature (particularly at the moment, in the literature services on periodontology and pregnancy), which often appear to contradict each other. This makes it diffi cult to defi ne Integrated an approach that is consistent with published scientifi c “Essential” medical-dental Larger research. In fact, in the case of periodontal disease and benefit systems medical-dental pregnancy, specialty societies in dentistry appear to have package integration taken a stronger stand than they have in medicine.

Programs in oral-systemic medicine should be aligned Coupled with with overall efforts in disease and risk management. These Information Oral-systemic disease and risk include management of dental caries in children, man- exchange products and services management agement of high-risk adults and seniors, screening and management for oral cancer, and oral care for patients with cancer and other conditions associated with immune suppression. These programs will not only involve mem- Inclusion in Balancing the ber education, outreach, and tracking, but also formation government literature of partnerships with physicians, nurses and disease man- programs agement professionals who will be working with these patients; such partnerships can include UnitedHealthcare Dental in efforts to coordinate and manage care. higher risk for diabetes, cardiovascular disease, or pregnancy resulting in low birth weight infants and/or pre- Oral-systemic medicine is the centerpiece of a larger ef- term deliveries. As evidence grows for the link between fort to integrate medical and dental care. Other facets periodontal disease and other health conditions, dental of this effort include educating and involving dentists in benefi ts will increasingly be seen as essential to improv- helping patients better manage their medical care; edu- ing affordability and quality of care. Through AmeriChoice cating and involving physicians in helping patients better and our private label Medicaid managed care partners, manage their dental care; and coordinating those areas UnitedHealthcare Dental can offer programs that will that fall between medical and dental care, such as tem- reach this vulnerable population. poromandibular joint and oral care for cancer patients. These opportunities extend to Medicaid, where Ameri- Products and services in the area of oral-systemic health Choice has already been a leading advocate for involving will need to balance the seeming contradictions in the dentists in helping patients manage their overall health. literature. With the growing interest in this burgeoning area comes a risk that the hype will outpace the science. We are clearly in the early stages of research and devel- The vision statement of Grand Rounds in Oral-Systemic opment in oral-systemic medicine, and much work is yet Medicine™, shared at the beginning of this editorial, also to be done. Based on these principles, and others that will notes that “Unlike past epidemiological eras, when sci- emerge as the science evolves, UnitedHealthcare Dental entists were able to uncover a direct cause and effect will continue to look for opportunities to expand its port- relationship ..., the chronic infl ammatory disease states folio of products and to work closely with others in the ... that defi ne this era are interconnected within a com- UnitedHealth Group family of companies, to provide ac- plicated web of multiple infl ammatory and genetic fac- cess to high quality, affordable care that empowers indi- tors which include infections and pathologies of peri- viduals to better manage their own overall health.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 19

0709gr_19 19 9/14/07 3:50:54 PM The Oral Pathology-Systemic Symposia

GINGIVAL ARCHITECTURAL Dr. James Sciubba ALTERATIONS MAY PROVIDE A CLUE FOR DIAGNOSING MORE COMPLEX DISEASES AND CONDITIONS

By James J. Sciubba, DMD, PhD

Case 3-2007 This is the case of a 2½-year-old boy with persistent and progressive gingival hypertrophy.

Case Presentation This child was referred by his pediatrician for an oral evaluation. The parents of this healthy 2½-year-old male noted the presence of a painless and gradual overgrowth of the attached gingiva, which was initially noted shortly after the primary dentition had erupted. There was associated interference with function, oral hygiene, and eruption pattern. Concurrently the parents noted the formation of painless, fi rm, subcutaneous masses over the forehead that may have arisen in association with trauma, but have been persistent and painless with slow growth evident.

History revealed no systemic disease, seizure disorder, ocular abnormality, or organomegaly. The usual developmental milestones had been met.

Physical examination revealed a well developed, well nour- ished child with appropriate motor and mental develop- Figure 1: Painless masses over the forehead ment. The facial skin was slightly eczematous, with no sign of a 2½-year-old boy at initial presentation of papular or eruptive diseases elsewhere. Overall hair pattern and pinna morphology were normal. The head and neck examination further revealed the presence of multiple fi rm and painless masses over the forehead; these masses were surfaced by intact and normal-appearing skin (Figure 1). Each of the masses measured approximately 2.5 cm in diameter and essentially fi xed to the epidermis, but was not attached to the periosteum. Further examination revealed the presence of similar scalp masses over the occipital region and left postero-lateral region.

Careful intraoral examination revealed a fully erupted normal primary dentition without caries, mobility or mal- position. Markedly bulbous and multinodular gingival ar- chitecture dominated the oral examination with no sign Photo courtesy of James J. Sciubba, DMD, PhD of tissue friability, tenderness or bleeding (Figure 2). The level of the attached gingiva approached the incisal edges in both arches, with pseudopocketing evident but without

20 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_20 20 9/14/07 4:05:33 PM Sciubba. Gingival architectural alterations may provide a clue ...

seen (Figure 3). Cytologic details were benign in nature. Figure 2: Gingival hypertrophy at the Of note, however, was an abundance of acellular hyaline initial presentation of a 2½-year-old eosinophilic zones containing narrow irregular collagen boy with bulbous, non-tender features with absence of friability and bleeding bundles between separated plump spindle-shaped and on manipulation stellate fi broblasts. Fibroblast morphology was further characterized by an expanded cytoplasm, while the area surrounding these cells demonstrated a lacunar quality in some regions. There was no sign of a signifi cant infl ammatory component within the stroma.

The diagnosis was gingival fi bromatosis with prominent hyaline alteration within the stroma. Several weeks following the gingival resection, the forehead lesions were removed by a plastic surgeon. The microscopic qualities present in the resected tissue were essentially identical to the gingival tissues, with the fi nal pathology report noting the hyaline quality of the stromal component.

Differential diagnosis Photograph courtesy of James J. Sciubba, DMD, PhD Gingival architectural alterations characterized by diffuse and symmetric enlargement are noted over a wide periodontal attachment loss, though there was a slightly spectrum of conditions. These conditions may be reactive, lesser degree of posterior gingival overgrowth. A normal hereditary, or medication-related, and may be isolated radiographic survey was noted, with appropriate devel- and restricted to the oral cavity, or as a component of a opment of secondary dentition. systemic disease process. The enlargement may involve the interdental papillae, attached gingival, and marginal In view of impending incisal and occlusal functional gingival, and include: disturbance secondary to the soft tissue proliferation, a 1. Drug-induced overgrowth (phenytoin, cyclosporine conservative gingivoplasty with exposure of the clinical A, nifedipine) crowns was performed, with tissue submitted for patho- 2. Infl ammation-based gingival enlargement logic evaluation. Microscopic analysis of the specimen 3. Neoplasia-related gingival overgrowth demonstrated a thinned but intact overlying orthokera- 4. Syndrome-associated or heredity-based gingival tinized epithelium over a uniformly well-vascularized stro- hypertrophy ma, where evenly but widely distributed fi broblasts were a. Cowden syndrome b. Prune belly syndrome Figure 3: A representative photomicrograph of c. Cross syndrome the ﬁ bro-hyaline stroma enclosing numerous d. Zimmerman-Laband syndrome ﬁ broblasts, some of which show a lacunar e. Murray-Puretic-Drescher syndrome quality obtained from the gingival mucosa f. Rutherfurd syndrome

The syndromes include many extraoral features and fi ndings, such as mental retardation, progressive sensori- neural hearing loss, seizure disorder, hypertrichosis, and cutaneous abnormalities with associated abnormalities of the distal phalanges.

Based upon the clinical fi ndings of diffuse and symmetrical gingival enlargement, the presence of evolving subcutaneous masses, and the histopathology, the diagnosis was juvenile hyaline fi bromatosis.

Future course Over the ensuing four years several other clinical ab- Histological section courtesy of James J. Sciubba, DMD, PhD normalities developed, including more widespread dis-

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 21

0709gr_21 21 9/14/07 4:06:04 PM Sciubba. Gingival architectural alterations may provide a clue ...

matosis). As with the patient in this case, the syndrome Figures 4a and 4b: Terminal phalangeal is characterized by diffuse and symmetrical gingival fi - osteolysis as a result of hyaline-ﬁ brous bromatosis, multiple cutaneous and subungual hyaline proliferation in a subungual distribution fi bromas, and fl exural contractures of the large joints of the extremities. Autosomal recessive transmission is stated, though in this case no family history was noted, nor was there consanguinity evident upon pedigree analysis. More recent studies have identifi ed mutations in the gene responsible for the encoding of capillary morphogenesis protein 2, a transmembrane protein induced during capillary development that binds laminin and type 4 collagen by way of a von Willebrand factor A do- main.1 The specifi c gene has been mapped to chromosome 4q21, with identifi cation of 15 genetic mutations encoding the stated capillary encoding protein. More recently, differences in mRNA expression of fi bronec- tin and laminin have been described where there are Photograph and radiograph courtesy of James J. Sciubba, DMD, PhD alterations in adhesion molecule and extracellular matrix mRNA expression.2,3 The related condition, infantile systemic hyalinosis, is a more severe clinical problem tribution, and an increased number of subcutaneous le- with visceral involvement and premature death. Of in- sions initially confi ned to the forehead and scalp. Hyaline terest is the fact that both conditions are members of fi bromas were noted on the pinnae, within the nose, and the same disease spectrum; gingival hypertrophy is a importantly over the hands, feet and at the digits with as- common component.4 Clinicians are reminded that gin- sociated osteolytic changes at the terminal phalanges of gival architectural alterations may point the way to a all extremities (Figures 4a and b). more complex set of diseases and conditions that may be emerging or previously undetected. Multidisciplinary In addition, the patient developed mild contracture-re- investigation and management strategies are necessary, lated functional defi cits of the extremities. His younger including strict gingival and periodontal maintenance.5 brother was examined at age 2½, and was also found to have similar mucocutaneous lesions, though slightly less References pronounced than his older brother at a similar age. The 1. Hanks S, Adams S, Douglas J, et al. Mutations in the gene patient’s older sister did not demonstrate any stigmata of encoding capillary morphogenesis protein 2 cause juvenile this condition. Genetic counseling and pedigree analysis hyaline fibromatosis and infantile systemic hyalinosis. Am J failed to reveal any other affected family members. Hum Genet. 2003;73:791-800. 2. Hakki SS, Balci B, Hakki EE, et al. Identification of the Several gingival remodeling procedures and plastic sur- difference in extracellular matrix and adhesion molecules of gical procedures (involving the ears, digits, and scalp) cultured human gingival fibroblasts versus juvenile hyaline were performed into and beyond adolescence. Genetic fibromatosis gingival fibroblasts using cDNA microarray counseling was performed with the family. analysis. J Periodontol. 2005;76(12):2244-2253. 3. Rahman N, Dunstan M, Teare MD, et al. The gene for juvenile Discussion hyaline fibromatosis maps to chromosome 4q21. Am J Hum A patient presenting with gingival overgrowth or hyper- Genet. 2002;71(4):975-980. trophy offers the clinician an opportunity to fully evalu- 4. Muniz ML, Lobo AZ, Machado MC, et al. Exuberant juvenile ate the patient’s circumstances, beyond the oral fi ndings hyaline fibromatosis in two patients. Pediatr Dermatol. and implications. 2006;23(5):458-464. 5. Uslu H, Bal N, Guzeldemir E, et al. Three siblings with juvenile The specifi c syndrome in this case is termed the Mur- hyaline fibromatosis. J Oral Pathol Med. 2007;36(2):123- ray-Puretic-Drescher syndrome (juvenile hyaline fi bro- 125.

22 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_22 22 9/14/07 4:06:38 PM Earn 4 CEUs $35 per person Seating is Limited – Register Today!

Improve your outcome. Enhance your practice.

This course offers solutions that will enhance your approach to REGISTER ONLINE non-surgical periodontal therapy and increase profi tability for OR FOR ADDITIONAL your practice. INFORMATION: At the conclusion of this program, participants should be able to: www.newperiosolutions.com Apply information linking perio and Recognize the benefi ts and limitations 888.299.8016 systemic health to maximize diagnosis of different methods of biofi lm removal and motivate patients Implement ultrasonic instrumentation Identify barriers and develop solutions techniques that enhance clinical to patient acceptance of periodontal outcomes treatment Identify practice management issues Incorporate appropriate pain control and solutions that impact the techniques improving patient comfort success and profi tability of soft and effi ciency during instrumentation tissue management EVENTS LOCATIONS:

DETROIT, MI TIMOTHY DONLEY, DDS, MSD Timothy Donley DDS MSD is currently in the private practice of Periodontics and FRIDAY Implantology in Bowling Green, KY. After graduating from the University of Notre Dame, SEPTEMBER 14, 2007 Georgetown University School of Dentistry and completing a general practice residency, 8:30 am – 12:30 pm he practiced general dentistry. He then returned to Indiana University where he received his Masters Degree in Periodontics. Dr. Donley currently serves as editor of the Journal of DoubleTree Hotel Dearborn the Kentucky Dental Association and is an adjunct professor of Periodontics at Western 5801 Southﬁ eld Expressway Kentucky University. His course is part of the ADA Seminar Series. Dentistry Today Detroit, MI 48228 recently listed him among the Leaders in Continuing Education. He lectures and publishes frequently on topics of interest to clinical dentists and hygienists. SAN DIEGO, CA

FRIDAY Brought to OCTOBER 12, 2007 you by: PennWell Corporation is an ADA CERP Recognized Provider. 8:30 am – 12:30 pm Hilton San Diego Mission Valley

Flagship Sponsors: ® Produced by: 901 Camino del Rio South RDH San Diego, CA 92108 DENTAL ECONOMICS ®

0709gr_23 23 9/14/07 3:35:47 PM Front Line Perspectives

ENSURING A HEALTHY

Jonathan B. Levine, PERIODONTIUM BEFORE DMD, PC, Private Practice Prosthodontics; ACHIEVING BEAUTIFUL TEETH GoSMILE Aesthetics, New York, NY

hile some Americans are searching for the fountain of youth, millions of other Americans are dying of cardiovascular and other chronic infl ammatory diseases. What most fail to realize is that there is a link between W periodontal disease and cardiovascular disease: the “perio-cardio link”. As healthcare providers, we have an obligation to identify periodontal diseases, educate our patients, and treat it.

I have incorporated periodontal health into my aesthetic practice by creating standard operating procedures for our entire administrative and clinical staff to ensure that our team operates with consistency and a mindset for constant learning. Our common goal is for our patients’ mouths to be disease-free, in order to support our beautiful restorations and alert our patients to risk factors that could impact their overall health and longevity. We use a methodical approach to patient care: take time to understand our patients’ needs, gather information on all levels, visualize a solution, then choose an appropriate technique to move from problem to solution.

The fi rst appointment: identify the problems Each new patient completes our standard forms, including our customized risk assessment questionnaire (with detailed questions about the patient’s family history of chronic infl ammatory diseases, risk of diabetes, cardiovascular disease and stroke). Once the new patient is seated for consultation, the doctor reviews the patient’s risk assessment questionnaire and medical history, and gains perspective on the patient’s desires for aesthetic outcomes by reviewing the patient’s customized aesthetic evaluation form and consultative dialogue.

In this information gathering phase of the appointment, we use several tools including the Florida Probe® (which helps us determine periodontal health), mounted study casts, full mouth x-ray, and our customized aesthetic evaluation form. The Florida Probe® is a computerized system that standardizes periodontal probings with both an audio read out and a visual chart showing probing readings, attachment loss, and other diagnostic information. This is an excellent tool for eliminating the subjectivity of manual probings, and engages the patient in an audio and visual process that reinforces the diagnosis.

The second appointment: visualize the solution With all of the information gathered, we look at the patient’s aesthetics, function, and overall health, to build a baseline and diagnostic wax-up. We use two different visual techniques (computer imaging and direct mock-ups) to create an opportunity for a “visual discussion”. In addition, the unique patient risk profi le, periodontal records, and radiographs, help us generate a conservative, nonsurgical “PointPerio” treatment plan. Our dental hygienists and aesthetic dentists work together as a team to assess the patient’s complete periodontal health before beginning aesthetic treatment.

With a solution in mind we can choose the appropriate technique for aesthetic treatment. Our starting point, however, is always focused on the patient’s periodontal health. After initial therapy, we reevaluate periodontal status and identify cases which require more aggressive treatment. Once our patient achieves total oral health, we can proceed to the next step: aesthetic or restorative treatment. Without a doubt, ensuring periodontal health before aesthetic procedures is essential. Beautiful teeth cannot be sustained in the long term without a healthy mouth.

Acknowledgments The author would like to acknowledge Ronni Gussin for her signifi cant contributions to this article.

24 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_24 24 9/14/07 4:04:48 PM Front Line Perspectives

IMPLEMENTING CLINICAL PROCEDURES FOR DIAGNOSING

Michael O’Brien, DMD, AND TREATING ORAL-SYSTEMIC Private Practice General Dentistry; Auburn Dental RELATIONSHIPS Associates, Auburn, AL

ardly a day goes by in the world of dentistry without some mention of the role of oral health in the overall health of patients, and the potential for poor oral health to increase risk for systemic disease. It has never been more Himportant for practitioners to diagnose and assess these risk factors, and then implement appropriate plans for prevention and treatment.

Education is paramount to successful implementation. As with all other clinical issues, the dentist and staff must be fully informed and work synergistically to develop evidence-based diagnostic and treatment protocols.

Although patients are now generally better informed about their health, we still see misinformation or misunderstand- ing regarding the oral-systemic relationship. In our offi ce, we schedule monthly in-offi ce training for both clinicians and support staff in order to stay current with new information and distinguish evidence-based research from vague suspicions. We focus on the relationship of periodontal disease to cardiovascular disease, diabetes, and pregnancy, and emphasize to patients that good oral health is important to overall health, longevity, and well-being. We have found several patient education tools to be useful, including pamphlets that explain the signifi cance of risk factors, useful links from our website, special issues of our patient newsletter, and individual letters to patients in high-risk groups. Through these educational tools, we have been effective in communicating that poor dental health does not necessarily CAUSE systemic illness, but it can contribute to the risk of developing or worsening of certain interrelated chronic conditions associated with periodontal disease.

By inviting physicians on staff at local hospitals and laboratories, we have extended our educational programs to the local medical community. We found that hosting “lunch and learn” programs and speaking at physician conferences is effective in increasing the awareness of the oral-systemic message within the medical community. This process has served to build relationships that are integral to implementing collaborative oral-systemic healthcare services.

Above all, dental professionals must lead the way in providing service that fi rst and foremost benefi ts the patient, while also considering medico-legal implications. Our offi ce is one of 40 Centers for Dental Medicine™ within the United States. As such, our offi ce is set up to screen, test, and appropriately treat patients with elevated health risks. Our protocol begins with identifying patients who are either pregnant, who have active cardiovascular disease or diabetes, or who present clinically with bleeding on dental probing. These patients are screened for DNA genotype, C-reactive protein levels, and glycated hemoglobin levels. In pregnant patients or those considering pregnancy, we determine elevated maternal IgG antibodies. Additionally, we perform a Florida Probe® exam, and then determine the category of risk from the results of all these tests. With this information, we can determine and implement an appropriate treatment protocol. Protocols range from little or no change in treatment plan (perhaps simply increasing the frequency of their home or offi ce-based preventive procedures), to 12-month programs that involve scaling and root planing, laser decontamina- tion and debridement, advanced homecare and preventive procedures, and nutrient supplements to aid in healing. This information also allows us to identify patients who need to be referred to physicians.

In summary, it is important not only to be well informed about the latest research on oral-systemic health, but also to take a leading role in educating our counterparts within the medical community. This type of collaboration may provide great promise in ensuring the overall health of our patients.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 25

0709gr_25 25 9/14/07 3:51:13 PM Original Article

MEDICATIONS INFLUENCING IMMUNE Douglas E. Peterson, DMD, PhD† RESPONSE AND Michael A. Siegel, DDS, MS‡ WOUND HEALING Jon B. Suzuki, DDS, PhD, MBA§

Abstract This paper offers an overview of the 3 primary groups of medications that have the potential to directly or indirectly infl uence the immune response: antineoplastic agents, bisphosphonates, and steroids. Antineoplastic agents in high-dose chemotherapy regimens have been a foundation of oncology management of disseminated disease for several decades. New generations of cytotoxic agents with increased capability for increased tumor cell cytotoxicity have evolved over time. Current regimens are highly specifi c for tumor cells, yet some can produce clinically signifi cant compromise in the patient’s systemic and tissue-based immune response as well as in wound healing capability. The dentist can offer a pivotal contribution to the oncology team by preventing or ameliorating these and related side effects. In particular, the literature provides compelling evidence for eliminating high-risk oral lesions of the dentition, periodontium, periradicular region, and mucosa prior to initiating myelosuppressive chemotherapy. Novel molecular approaches to cancer therapy, including monoclonal antibodies, are changing the profi le of oral and systemic toxicities. Though such agents are beginning to facilitate new successes in oncology practice, further research is needed.

Bisphosphonates, in both intravenous and oral forms, are increasingly used to improve mineral bone density in patients with osteoporosis, multiple myeloma, and other diseases and conditions. Osteoporosis is associated not only with postmenopausal women, but also with several medications used to treat breast cancer, gastric acidity, and other conditions. Bisphosphonates directly suppress osteoclast activity and angiogenesis, and, ultimately suppress wound healing and immune response.

Steroids, in both topical and systemic forms, are used to suppress undesirable immune responses and manage a wide variety of systemic and intraoral mucosal disorders, including recurrent aphthous ulcerations and lichen planus. Steroids can be a mainstay in pharmacologic immunomodulation when proper care is taken to minimize steroid- induced side effects.

Citation: Peterson D, Siegel M, Suzuki J. Medications infl uencing immune response and wound healing. Grand Rounds Oral-Sys Med. 2007;3:26-33. (Digital version Grand Rounds Oral-Sys Med. 2007;3:26-33a.) (A complimentary copy of this article may be downloaded at www.thesystemiclink.com.)

Key Words: Antineoplastic agents, bisphosphonates, steroids, periodontal diseases, dental management

Introduction he immune response is the primary host defense † Professor, Department of Oral Health and Diagnostic Sciences, against microorganisms, including bacteria, viruses, School of Dental Medicine; Chair, Head & Neck/Oral Oncology and fungi. The innate and acquired immune responses Program, Neag Comprehensive Cancer Center, University of T Connecticut Health Center; Farmington, CT are synergistic, and play a vital role in the overall host de- ‡ Professor and Chair, Department of Diagnostic Sciences, Nova fense mechanism. Southeastern University, College of Dental Medicine, Fort Lauderdale, FL Selected systemic diseases and conditions require medication § Professor of Microbiology-Immunology, School of Medicine; for optimal management. However, both the clinician and the Professor of Periodontology and Oral Implantology, School of Dentistry; Associate Dean for Graduate Education, patient must assess the risks and benefi ts before proceeding Research, and International Affairs; Director, Graduate with pharmacologic therapy. For example, anti-neoplastic Periodontology and Oral Implantology; Temple University, agents are likely to cause mild, moderate, and/or severe side Philadelphia, PA

26 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_26 26 9/14/07 3:52:29 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

effects associated with various pharmacologic classes, immune reactions. Pharmacologically, this is achieved doses, regimens, and mechanisms of action of these agents. through a number of mechanisms, including: (1) gene ex- Cancer chemotherapy should be managed by a qualifi ed pression that leads to reduction in the synthesis of impor- physician who is experienced in using such antineoplastic tant mediators of the infl ammatory process (such as pros- agents, and in a clinical facility that is appropriate to care taglandins and leukotrienes);7 (2) suppression of cyclooxy- for both the cancer and the potential medical complica- genase synthesis resulting in decreased neutrophil, mono- tions that may result from chemotherapy. cyte, and eosinophil chemotaxis, as well as inhibition of vascular and infl ammatory responses to prostaglandins;8 We address three primary groups of medicationsi that (3) inhibition of white blood cell production;8 (4) inhibition have the potential to either directly or indirectly infl uence of adhesion molecule synthesis in endothelial cells, which the immune response: impairs attachment of infl ammatory cells and hinders • Antineoplastic agents their recruitment to sites of infl ammation;8 (5) inhibition of • Bisphosphonates macrophage-driven antigen phagocytosis, which is neces- • Steroids sary for development of some immune responses;7 and, (6) Concurrent immunosupportive therapies, such as antibi- suppression of antibody production.9 Topical or systemic otics and antimicrobial rinses, are frequently used with steroid therapy is used for a wide variety of systemic and these medications. oral mucosal disorders. However, because of the profound and varied metabolic effects caused by steroids, they can Antineoplastic agents primarily function to prevent or exacerbate many systemic conditions including, but not suppress the growth, development, or metastases of neo- limited to, hypertension, diabetes mellitus, gastrointestinal plastic cells. The ideal objective of cancer treatment is to ulcers, cataracts, mental illness, tuberculosis, and fungal reduce the cancer cell population to zero.1 Many antineo- infections.10 The immune suppression that results from plastic drugs are myelosuppressive, thus resulting in dra- steroid use may also lead to infections by opportunistic or matic reduction of circulating leukocytes as measured by indigenous microorganisms. white blood cell count and/or total granulocyte count, and total platelet count. Contemporary oncology practice of- Antineoplastic agents ten uses combinations of antineoplastic agents in multiple High-dose chemotherapy can directly and indirectly re- cycles for patients collectively exhibiting a range of solid sult in oral toxicities, including impairment of both wound tumors. In addition, chemotherapy is increasingly admin- healing and immune response (Table 1).11,12 The combi- istered concurrently with high-dose head and neck radia- nation of these direct and indirect effects can compromise tion for oral malignancies that have metastasized beyond cancer patients’ quality of life.13,14 In some cases, the oral the primary initial site of occurrence. This evolution of lesions can result in the need to limit the dose of subse- pharmacologic regimens for metastatic cancer contin- quent chemotherapy to allow the lesion to heal; in the ues to produce clinically signifi cant side effects, including neutropenic patient, this can contribute to mortality.12 compromised oral, systemic, and tissue immunity, accompanied by compromised wound healing. Table 1 Oral complications of cancer chemotherapy Bisphosphonates primarily function to enhance bone mineral density (generally measured with Direct Toxicities Indirect Toxicities dual-energy x-ray absorptiometry (DEXA) and expressed as a “T score”), and reduce pathogenic frac- Oral mucositis Myelosuppression tures (e.g., as measured by hip fracture reduction). • Neutropenia Pharmacologically, these agents reduce osteoclast Neurotoxicity • Immunosuppression function.2 Bisphosphonates are associated with im- • Taste dysfunction • Anemia paired angiogenesis3 and impaired wound healing,4 • Dentinal hypersensitivity • Thrombocytopenia which impede delivery of immune cells to the site of microbial challenge, and therefore indirectly result in Temporomandibular Infection immunosuppression. Bisphosphonates are also asso- dysfunction • Viral ciated with osteonecrosis of the jaw (BIONJ).5,6 • HSV, VZV, CM V, EBV, other Dental and skeletal growth/ • Fungal Steroids primarily function to suppress undesirable development (pediatric patients) • Candida, Aspergillus, other • Bacterial i The group of medications used to permit “acceptance” of a transplanted organ is discussed in another article in this Adapted with permission from The Chemotherapy Source Book,15 copyright issue of Grand Rounds; please see “Dental Implications Lippincott Williams & Wilkins, 2007. for the Immunocompromised Organ Transplant Patient.”

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 27

0709gr_27 27 9/14/07 3:52:47 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

Severe oral mucositis is characterized by extensive, pain- Figure 1: Severe oral mucositis in a patient on ful ulcerations of non-keratinized mucosa (Figure 1). antineoplastic therapy Chemotherapy-induced alimentary tract mucosal injury in cancer patients has been the subject of increasingly sophisticated research over the past decade.11,12,16,17 This progress has included development of a pathobiologic model (Figure 2).18

Frequencies of oral mucositis vary in chemotherapy patients; estimates include 10% associated with adjuvant chemotherapy, 40% associated with primary chemotherapy, and 80% associated with hematopoietic stem cell transplant.13,14 Incidence and severity of oral and gastrointestinal mucositis can be infl uenced by multiple variables, including drug class and mechanism of action of each chemotherapeutic agent (Figure 3), as well as dose intensity The lesion is characterized by extensive, painful ulcerations of non- and frequency of administration.13,14,19 While use of chemo- keratinized mucosa. (Photo courtesy of Douglas E. Peterson, DMD, therapy regimens is based on a number of cancer disease PhD) parameters including histo- logic type of the neoplasm, Figure 2: Pathology model of progression of ulceration (mucositis) and wound healing of patients on it is the chemotherapy, not Figureantineoplastic 2: Pathology therapy model of progression of ulceration (mucositis) and wound healing of patients on antineoplastic therapy the cancer itself, that di- Phase I & III: rectly governs risk for oral Messaging, and gastrointestinal muco- Normal Phase I: Signaling, & Phase IV: Phase V: sal toxicity. Examples of this Epithelium Initiation Amplification Ulceration Healing wide variation in mucosi- Radiation tis incidence and severity have recently been reported across various cancer patient cohorts:19 • Conventional chemotherapeutic regimens for non- Hodgkin’s lymphoma are associated with 3-10% incidence of Chemotherapy severe oral mucositis. However, most (>90%) Submucosa Basal cell Blood vessel Inflammatory Fibroblast comparable patients Epithelial layer cell do not develop severe The paradigm illustrates the continuum of mucosal injury and eventual repair that involves both oral oral mucosal injury. epithelium and the underlying oral mucosal connective tissue. Phase I (“Initiation”) begins within hours • Multi-cycle platinum- of fi rst administration of high-dose cancer therapy. Phases II and III then emerge during the fi rst few based regimens, with days following this initial cancer therapy, and are characterized by a genetically-governed upregulation in proinfl ammatory cytokines, which can then further amplify mucosal injury via positive feedback loops. It or without concurrent is important to note that the infl ammatory pathways in Phases I-III are primarily or exclusively subclinical; radiotherapy, are as- clinical signs and symptoms of oral mucositis are typically absent. sociated with a low in- Phase IV is characterized by the hallmark clinical stage of oral mucositis, with overt, painful, and fre- cidence of severe oral quently extensive oral ulcerations. These lesions will usually resolve during the 2-4 weeks after high-dose mucositis in lung can- chemotherapy is discontinued, as illustrated in Phase V. cer patients. However, This current paradigm is in marked contrast with the concept held until the late 1990s that oral mucositis radiotherapy in these represents results of injury to only oral epithelial basal cells. The contemporary pathobiology modeling has patients is associated created new opportunities for development of targeted drug therapies designed to reduce severity of clinically with >15% incidence signifi cant oral mucosal toxicity. of severe esophageal Reprinted by permission from Macmillan Publishers Ltd: Sonis, Nat Rev Cancer,18 copyright 2004 (versus oral) mucositis.

28 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_28 28 9/14/07 3:53:08 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

• Figure 3: Incidence of oral mucositis in relation to type of cancer therapy Conventional chemotherapy in advanced colorectal cancer patients is not likely to be associated with producing severe oral mucositis. In contrast, however, the overall incidence of diarrhea in these patients is high (16%), increasing to approximately 25% when both irinotecan and oxaliplatin are incorporated into the cancer treatment regimens.

Current research includes pursuit of possible mechanistic-based factors that are principally responsible for this variable expression of oral and gastrointestinal Figure courtesy of Douglas E. Peterson, DMD, PhD mucositis across cancer patients.

Table 2 Management suggestions relative to invasive dental procedures in patients undergoing antineoplastic therapy

Medical Status Guideline Comments

There is no defi nitive scientifi c Patients with chronic Regimens recommended by the American evidence detailing infectious risk for indwelling venous access Heart Association20 for infective these lines following dental procedures. catheters (e.g., Hickman device) endocarditis prophylaxsis are often used. This recommendation is empiric. Neutrophils Order CBC with differential

>1,500 cells/mm3 Prophylactic antibiotics for neutropenia are Other indications for prophylaxis usually not necessary. may be present.

<1,500 cells/mm3 Antibiotic prophylaxis should be considered. If organisms are known or Regimens recommended by the American Heart suspected, appropriate adjustments Association20 for infective endocarditis prophylaxis to antibiotic regimens should be are often used. However, clinical judgment is critical: made based on sensitivities. if infection is present or neutropenia is severe, more aggressive antibiotic therapy may be indicated, based on consultation with an infectious disease specialist.

a Order platelet count and, if indicated, Platelets coagulation tests >75,000 cells/mm3

40,000 - 75,000 cells/mm3 No additional platelet support needed. Platelet Use techniques to promote establishing transfusions are optional; consider administering and maintaining control of bleeding (e.g., preoperatively and 24 hours later. Additional trans- sutures, pressure packs, minimization of fusions are based on clinical course. trauma). <40,000 cells/mm3 Platelets should be transfused 30 minutes before In addition to above, consider using surgical procedure; obtain STAT platelet count, hemostatic agents (e.g., microfi brillar transfuse regularly to maintain counts above 30,000 collagen, topical thrombin, fi brin glues). - 40,000 cells/mm3 until initial healing has occured. Monitor sites carefully.

a Assumes that all other coagulation parameters are within normal limits and that platelet counts will be maintained at or above the speciﬁ ed level until stabilization/healing has occurred. Adapted with permission from Schubert MM, Epstein JB, Peterson DE. Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Neidle EA (eds). Pharmacology and Therapeutics for Dentistry, 5th Edition, page 803.21 Copyright Elsevier (Mosby-Year Book Inc.) 2004.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 29

0709gr_29 29 9/14/07 3:53:30 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

ventions in patients scheduled to receive high- Table 3 Guidelines for dental extractions in patients scheduled to dose chemotherapy. However, procedures undergo myelosuppressive chemotherapy associated with dental extractions have been used by clinicians for many years, based on Timeframe, Parameter Guidelines historical retrospective studies.22,23 Guidelines Scheduling extraction if neutrophil Perform extraction at least 10 days prior to for dental extractions in patients scheduled to count expected to decrease <500 neutrophil count becoming <500 cells/mm3 undergo myelosuppressive chemotherapy are 3 cells/mm outlined in Table 3. Day of extraction, if absolute Consider use of a broad-spectrum neutrophil count <1,500 cells/mm3 prophylactic antibiotic regimen New trends in oncology practice based on 30 minutes prior to extraction, if Administer random donor or histocompati- “targeted” therapies. Targeted cancer thera- platelet count <40,000 cell/mm3 bility-matched platelets (as available) pies, including monoclonal antibodies, are be- During extraction Minimize surgical trauma, with alveolec- ing utilized with increasing frequency in clini- tomies as necessary to achieve primary cal oncology practice.24 For example, potential closure with multiple interrupted sutures targets of monoclonal antibodies are growth After extraction Minimize use of hemostatic packing factor receptors, signaling kinases, and tran- agents within extraction sites scription factors.24 These novel molecular Adapted with permission from The Chemotherapy Source Book,15 copyright Lippincott approaches are in turn causing a change in Williams & Wilkins, 2007 expression of toxicities among various cancer cohorts, including diarrhea and oral mucosal In some cases, oral mucositis necessitates chemotherapy ulceration.24 The potential impact on immune response dose reduction or schedule modifi cations in order to re- and wound healing relative to oral toxicities requires ad- duce severity of future oral mucosal injury. For example, ditional study. among patients undergoing chemotherapy for solid tumors or lymphomas, dose reduction was twice as common Bisphosphonates after treatment cycles for patients with mucositis than for Management of cancer patients may also include those without mucositis.16 This compromise in optimal bisphosphonates to control metastatic bone lesions dosing schedule can affect tumor response and thus pa- through impairment of osteoclast function.6 A severe tient survival. In addition, oral mu- complicating factor is BIONJ cositis can contribute to increased Figure 4. Lower left lingual area with associated osteomyelitis, al- healthcare costs associated with of peridontium in a patient on though most BIONJ patients ex- (a) extended hospital stays, (b) antineoplastic therapy hibit osteonecrosis without osteo- need for total parenteral nutri- myelitis.5,6 Maxillary, mandibular, tion, (c) infection management, and soft-tissue lesions, second- and (d) nutritional support.13 ary to long-term bisphosphonate use in patients with cancer, have Dental management of patients been increasingly reported in taking antineoplastic agents. It the literature.25-28 Over time, the is important that the oncologist accumulation of compromised and dentist maintain clear com- bone matrix can lead to pain munication in order to provide and clinically evident bone expo- maximum preventive and thera- sure that can be diffi cult to man- peutic management. Elements of age clinically (Figure 4).28 Since the health professional consul- there are currently no evidence- tation include both the patient’s Increasing compromised bone matrix can lead to pain based guidelines for treatment and clinically evident bone exposure. medical status and an integrated of BIONJ, prevention may be the 28 oncology/dental management Reprinted from Migliorati, J Clin Oncol, with permission best approach to managing this from American Society of Clinical Oncology, copyright plan (relative to oral disease be- 2003 complication.26 fore, during, and after cancer treatment).14 Management suggestions relative to invasive Steroids dental procedures in patients currently receiving antineo- Topical or systemic steroid therapy is indicated for a wide plastic therapy are outlined in Table 2. variety of systemic and oral mucosal disorders. Common uses for systemic steroids include endocrine disorders A limited number of studies address guidelines for dental (primary or secondary adrenal insuffi ciency), rheumatic extractions, endodontic management, and related inter- disorders (rheumatoid arthritis), collagen diseases (sys-

30 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_30 30 9/14/07 3:53:51 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

temic lupus erythematosus), dermatologic Table 4 diseases (pemphigus, pemphigoid, lichen Systemic equivalents for steroid medications planus, erythema multiforme), respiratory Generic Name Milligrams39 diseases (sarcoidosis, chronic obstructive pulmonary disease), hematologic diseases Cortisone 25.00 (idiopathic or secondary thrombocytopenia, Hydrocortisone 20.00 acquired hemolytic anemia), gastrointestinal Prednisone 5.00 diseases (ulcerative colitis, regional enteritis) Methylprednisone 4.00 and edematous states.10 Intraoral disorders Triamcinolone 4.00 for which steroids are indicated include re- Dexamethasone 0.75 current aphthous stomatitis,29 lichen planus,30-32 pemphigus,33 and pemphigoid.30,33 Table 5 39 Dental management of patients receiving Relative levels of potency of topical steroids steroid therapy. The mainstay of pharma- Potency Level Steroid (% Active Ingredient) cologic immunomodulation depends on the proper incorporation of steroid therapy into Ultra-potent • Clobetasterol propionate (0.05%) • Halobetasterol propionate (0.05%) the management of many intraoral mucosal disorders such as recurrent aphthous Potent • Desoximetasone (0.25%) ulcerations and lichen planus. This class • Fluocinonide (0.05%) of medications can be used either topically Moderately potent • Betamethasone dipropionate (0.05%) or systemically, but care must be exercised • Betamethasone valerate (0.10%) to minimize steroid-induced side effects. • Fluticasone propionate (0.05%) The medical history must be used to iden- • Triamcinolone acetonide (0.05%, 0.10%) tify patients on chronic steroid therapy to Mildly potent • Aclometasone dipropionate (0.05%) manage systemic illness, to ensure that they • Hydrocortisone (0.05%, 0.10%) can respond to the pain and anxiety of the dental procedure. The primary endogenously secreted temic absorption. Custom trays and adhesive vehicles can glucocorticoid is cortisol. Cortisol and its exogenous an- be used to enhance the topical effect of intraorally applied alogues are responsible for a wide variety of functions topical steroids.38 and physiologic effects, which include the inhibition of infl ammation. The anti-infl ammatory action of cortisol is There are no uniformly accepted or absolute guidelines modulated by its inhibitory action on lysosome release, for steroid supplementation in the dental setting. Current prostaglandin production, eicosanoid and cytokine re- evidence suggests that most patients who are managed lease, endothelial cell expression of intracellular and ex- with chronic corticosteroids and undergoing routine tracellular adhesion molecules that attract neutrophils dental therapy do not require supplementation as long and the function of leukocytes.34 Inappropriate manage- as pain and anxiety are well controlled (Table 6).35,40 ment of patients on chronic steroid therapy could result However, patients on chronic corticosteroid therapy may in unusual but documented acute adrenal insuffi ciency remain at risk for adrenal suppression. Medical consul- (Addisonian crisis), which is potentially life threaten- tation with the patient’s physician will assist the dental ing.35,36 Because of the profound and varied metabolic practitioner in determining if a need for steroid supple- effects caused by steroids, care must be taken in their mentation exists. administration. Conclusion Most adverse reactions to corticosteroids occur after a High-dose cytotoxic agents continue to be a key compo- 2-week period.37 Therefore, if systemic steroids are pre- nent of cancer treatment regimens directed to metastatic scribed by the dentist, whenever possible, the general cancer. Despite development of medications that have rule is to prescribe a higher dose for a short period of shown impressive clinical outcomes in recent years, many time (burst therapy) rather than a lower dose over a pro- of these products can directly impair immune function as tracted period of time. Topical steroid therapy for oral well as wound healing. In addition, novel molecularly tar- mucosal disorders has been reported to be quite safe for geted therapies are being used with increasing frequency a short-term course of therapy. Table 4 identifi es systemic in oncology practice, with associated changes in toxicity equivalent doses for steroids to assist the clinician in the profi les for many patients. Further research is needed in prescription of these medications. If ultra-potency topical order to more fully defi ne the adverse events associated steroids are used (Table 5), there is a potential for sys- with these molecules.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 31

0709gr_31 31 9/14/07 3:54:11 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

Table 6 Steroid supplementation guidelines for dental patients

Procedure Guidelines35,40

Routine dental procedures • Steroid supplementation is not usually necessary if the patient is currently taking including extractions man- steroids. Ensure effective local anesthesia and adequate postoperative pain control. aged with local anesthesia • Administer normal maintainence steroid dose on the day of the procedure if pa- where pain can be well con- tient has discontinued regular steroid usage within the previous 2-week period. trolled both intraoperatively • No supplementation is generally required if the patient has a previous his- and postoperatively. tory of regular steroid usage which has been discontinued for greater than 2 weeks or is using topical or inhalation steroids. Extremely anxious patient • Double the patient’s steroid regimen on the day of the procedure and the managed with local anesthe- day after the procedure (if signifi cant postoperative pain is anticipated) for sia only patients currently taking steroids. • Double the normal maintainence dose on the day of the procedure if the pa- Complicated or emotionally tient has discontinued regular steroid usage within the previous 2-week period. stressful procedure managed • No supplementation is generally required if the patient has a previous history of with local anesthesia only regular steroid usage which has been discontinued for greater than 2 weeks. Dental procedures requiring • Administer parenteral corticosteroids in a hospital setting using 100 mg general anesthesia (usually in hydrocortisone 1 hour before procedure and double the daily dose on the a hospital setting or outpatient following day (if postoperative pain is anticipated). surgical center Alternate day steroid regimen • Treat patient on the day they normally take their steroid medication. No change in the steroid regimen is necessary.

It is essential that the dentist collaborate with the rest medications can signifi cantly improve the morbitity of of the oncology team in order to prevent or ameliorate vesiculubullous and ulcerative oral mucosal disorders. acute and chronic oral sequelae of antineoplastic therapies. This collaboration is warranted by compelling evi- Disclosures dence in the literature, which suggests that high-risk oral Douglas E. Peterson, DMD, PhD serves as consultant lesions — of the dentition, periodontium, periradicular to Endo Pharmaceuticals, Genzyme Corporation, MGI region, and mucosa — should be eliminated prior to ini- Pharma, and Nuvelo. tiation of myelosuppressive chemotherapy. In addition, Jon B. Suzuki, DDS, PhD, MBA serves on the scientifi c advi- chemotherapy can cause acute oral complications that sory boards of Biohorizons and Philips Oral HealthCare. in selected cases require several months following cessation of the drugs for clinical resolution. Multiprofessional References approaches to management of these medically complex 1. Chabner BA. Clinical strategies for cancer treatment: The role of cancer patients can directly improve quality of life and, drugs. In: Chabner BA, Longo DL (eds.). Cancer Chemotherapy in some cases, patient survival. and Biotherapy: Principles and Practice. 4th edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:3. Bisphosphonates (intravenous and oral) are used in 2. Marx RE. Oral and intravenous bisphosphonate-induced management of osteoporosis, and osteoporosis-related osteonecrosis of the jaws. Hanover Park, IL:Quintessence sequelae of selected medications (e.g., anti-cancer, anti- Publ. Co; 2007c: pp 9-19. psychotic, antacids). Dental management should proceed 3. Santini D, Caraglia M, Vincenzi B, et al. Mechanisms of with caution in patients currently taking this family of disease: Preclinical reports of antineoplastic synergistic medications. action of bisphosphonates [review]. Nat Clin Pract Oncol. 2006;3(6):325-338. The mainstay of pharmacologic immunomodulation de- 4. Wang HL, Weber D, McCauley LK. Effect of long-term oral pends on the proper incorporation of steroid therapy into bisphosphonates on implant wound healing: literature review the management of many intraoral mucosal disorders and a case report [review]. J Periodontol. 2007;78(3):584- such as recurrent aphthous ulcerations and lichen pla- 594. nus. This class of medications can be used either topically 5. Lam DK, Sandor GK, Holmes HI, et al. A review of or systemically, but care must be exercised to minimize bisphosphonate-associated osteonecrosis of the jaws and its steroid-induced side effects. Proper use of this class of management [review]. J Can Dent Assoc. 2007;73(5):417-422.

32 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_32 32 9/14/07 3:54:30 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

6. Wade ML, Suzuki JB. Issues related to diagnosis and treat- of cancer therapy In: Yagiela JA, Dowd FJ, Neidle EA (eds). ment of bisphosphonate-induced osteonecrosis of the jaws. Pharmacology and Therapeutics for Dentistry, 5th Edition. St. Grand Rounds Oral-Sys Med. 2007;2:46-53. Louis, MO: Mosby-Year Book Inc.; 2004:803. 7. VanDyke TE, Serhan CN. Resolution of inflammation: a new 22. Overholser CD, Peterson DE, Bergman SA, et al. Dental ex- paradigm for pathogenesis of periodontal diseases. J Dent tractions in patients with acute nonlymphocytic leukemia. J Res. 2003;82(2):82-90. Oral Maxillofac Surg. 1982;40(5):296-298. 8. Trummel CL. Adrenal corticosteroids. In: Yagiela JA, Dowd 23. Williford SK, Salisbury PL 3rd, Peacock JE Jr. et al. The safety FJ, Neidle EA, et al. Pharmacology and Therapeutics for of dental extractions in patients with hematologic malignan- Dentistry, 5th Edition. St. Louis, MO: Elsevier. 2004:566-568. cies. J Clin Oncol. 1989;7(6):798-802. 9. Atkinson JC, O’Connell A, Aframian D. Oral manifesta- 24. Keefe DMK, Gibson RJ. Mucosal injury from targeted anti- tions of primary immunological diseases. J Am Dent Assoc. cancer therapy. Support Care Cancer. 2007;15(5):483-490. 2000;131(3):345-356. 25. Migliorati CA, Casiglia J, Epstein J, et al. Managing the care 10. Shimmer BP, Parker KL. Adrenocorticotropic hormone; adre- of patients with bisphosphonate-associated osteonecrosis: an nocortical steroids and their synthetic analogs; inhibitors of American Academy of Oral Medicine position paper [review]. the synthesis and actions of adrenocortical hormones. In: J Am Dent Assoc. 2005;136(12):1658-1668. [Erratum in: J Hardman JG, Limbird LE (eds). Goodman and Gillman’s The Am Dent Assoc. 2006;137(1):26.] Pharmacological Basis of Therapeutics, 10th Edition. New 26. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the York, NY: McGraw-Hill Inc.;2001:1666-1668. jaw in multiple myeloma patients: clinical features and risk 11. Sonis ST, Peterson RL, Edwards LJ, et al. Defining mecha- factors. J Clin Oncol. 2006;24(6):945-952. nisms of action of Interleukin-11 on the progression of ra- 27. Reid IR, Bolland MJ, Grey AB. Is bisphosphonate-associated diation-induced oral mucositis in hamsters. Oral Oncol. osteonecrosis of the jaw caused by soft tissue toxicity? Bone. 2000;36(4):373-381. 2007 May 10;[Epub ahead of print]. 12. Lalla RV, Peterson DE. Oral mucositis [review]. Dent Clin 28. Migliorati CA. Bisphosphonates and oral cavity avascular North Am. 2007;(in press). bone necrosis. J Clin Oncol, 2003;21(22):4253-4254. 13. Sonis ST, Elting LS, Keefe D, et al. Perspectives on cancer 29. Pinto A, Lindemeyer RG, Sollecito TP. The PFAPA syndrome in therapy-induced mucosal injury: pathogenesis, measure- oral medicine: differential diagnosis and treatment. Oral Surg ment, epidemiology, and consequences for patients. Cancer. Oral Med Oral Pathol Oral Radiol Endod. 2006;102(1):35-39. 2004;100(9 Suppl):1995-2025. 30. Gonzales-Moles MA, Morales P, Rodriguez-Archilla A, et al. 14. National Cancer Institute. Oral complications of chemotherapy Treatment of severe chronic oral erosive lesions with clo- and head/neck radiation (PDQ®). Available at: http://www.nci. betasol propionate in aqueous solution. Oral Surg Oral Med nih.gov/cancerinfo/pdq/supportivecare/oralcomplications/ Oral Pathol Oral Radiol Endod. 2002;93(3):264-270. healthprofessional/. Accessed Dec 27, 2006. 31. Plemons JM, Rees TD, Zachariah NY. Absorption of a topi- 15. Lalla RV, Peterson DE, Brennan MT, et al. Oral toxicities. In: cal steroid and evaluation of adrenal suppression in patients Perry MC (ed). The Chemotherapy Source Book. Fourth edition. with erosive lichen planus. Oral Surg Oral Med Oral Pathol. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:(in press). 1990;69(6):688-693. 16. Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer 32. Lodi G, Scully C, Carrozzo M, et al. Current controversies therapy. Clinical and economic outcomes of chemotherapy-in- in oral lichen planus: report of an international consensus duced mucositis. Cancer. 2003;98(7):1531-1539. meeting. Part 2. Clinical management and malignant trans- 17. Lalla RV, Peterson DE. Treatment of mucositis, including new formation. Oral Surg Oral Med Oral Pathol Oral Radiol medications [review]. Cancer J. 2006;12(5):348-354. Endod. 2005;100(2):164-178. 18. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 33. Lozada-Nur F, Miranda C, Miliksi R. Double blind clinical 2004;4(4)277-284. trial of 0.05% clobetasol propionate ointment in orabase and 19. Keefe DM, Schubert MM, Elting LS, et al. Updated clinical 0.05% fluocinonide ointment in orabase in the treatment of practice guidelines for the prevention and treatment of mu- patients with oral vesiculoerosive diseases. Oral Surg Oral cositis. Cancer. 2007;109(5):820-831. Med Oral Pathol. 1994;77(6):598-604. 20. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective 34. Little JW, Falace DA, Miller CS, et al. Dental Management of endocarditis: guidelines from the American Heart Association: the Medically Compromised Patient, 6th edition. St. Louis, a guideline from the American Heart Association Rheumatic MO: C.V. Mosby, Inc.; 2002:271. Fever, Endocarditis, and Kawasaki Disease Committee, 35. Miller CS, Little JW, Falace DA. Supplemental corticosteroids Council on Cardiovascular Disease in the Young, and the for dental patients with adrenal insufficiency: reconsideration Council on Clinical Cardiology, Council on Cardiovascular of the problem. J Am Dent Assoc. 2001;132(11):1570-1579. Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc. For additional references to this article, please consult the Grand Rounds in Oral-Systemic Medicine™ 2007;138(6):739-745, 747-760. digital version of at www.thesystemiclink.com. 21. Schubert MM, Epstein JB, Peterson DE. Oral complications

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 33

0709gr_33 33 9/14/07 3:54:49 PM Peterson, Siegel, Suzuki: Medications inﬂ uencing immune response and wound healing

36. Barnes NC. The properties of inhaled corticosteroids: simi- plication of clobetasol propionate in custom trays. Oral Surg larities and differences. Prim Care Respir J. 2007;16(3):149- Oral Med Oral Pathol Oral Radiol Endod. 2003;95(6):688- 154. 692. 37. Lozada F, Silverman S Jr, Migliorati C. Adverse side effects 39. Physicians Desk Reference (PDR). 61st edition. Montvale, NJ: associated with prednisone in the treatment of patients with Thompson PDR; 2007:1953. oral inflammatory ulcerative diseases. J Am Dent Assoc. 40. Gibson, Ferguson JW. Steroid cover for dental patients on 1984;109(2):269-270. long-term steroid medication: proposed clinical guidelines 38. Gonzalez-Moles MA, Ruiz-Avila I, Rodriguez-Archilla A, et al. based upon a critical review of the literature [review]. Br Treatment of severe erosive gingival lesions by topical ap- Dent J. 2004;197(11):681-685.

33A G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_33 a33 9/14/07 10:01:26 AM RDH magazine presents the ﬁ rst RDH Event Online Tradeshow and Conference.

Experience A Tradeshow From Th e Comfort Of Your Own Home At NO COST! www.rdhevent.com

October 19-20, 2007 This innovative online conference and exhibition uses leading-edge technology to bring the industry of dental hygiene decision-makers together with solution providers at the convenience of your personal computer.

• Visit the interactive exhibit fl oor • Meet vendors fi lled with top exhibitors • Get samples • Network with hygiene • Earn continuing education industry professionals • Listen to our keynote speaker • Win Prizes and fi ve conference sessions

® Flagship Media Sponsor:RDH Owned & Produced by: Platinum Event Sponsor:

0709gr_b33 b33 9/14/07 10:41:34 AM Continuing Education Test Questions for Continuing Education Test Questions for

MEDICATIONS INFLUENCING IMMUNE RESPONSE AND WOUND HEALING 3 credits

This CE course is intended for dentists and dental hygienists. The cost of this course is $45 for 3 credits. The test and personal information may be accessed and downloaded at www.thesystemiclink.com. Check the box that corre- sponds to your answer. After completing the test, fi ll in the personal information on the next page and return the form and test answers via either of two options:

1) Submit via U.S. Mail to: Grand Rounds in Oral-Systemic Medicine™ 1421 S. Sheridan Road Tulsa, OK 74112

2) Submit via fax to (918) 831-9804 For inquiries about the results of this Continuing Education Test, contact Carroll Hull at (800) 633-1681.

1. Which of the following is a class of medication that can 4. Dental management of patients taking antineoplas- impair immune responsiveness? tic medications should not include which of the follow- ❏a steroids ing? ❏b medications utilized to prevent rejection of solid organ ❏a consultation with physician transplants ❏b comprehensive oncology and dental treatment plan ❏c bisphosphonates ❏c dental treatment to minimize incidence or severity of ❏d cancer chemotherapeutic agents oral disease that may otherwise occur in association ❏e all of the above with subsequent high-dose cancer treatment ❏d delaying dental intervention until acute oral side ef- 2. Which of the following is a potential adverse side effect of fects are observed cancer chemotherapy? ❏e antibiotic prophylaxis for selected at-risk patients prior ❏a signifi cant compromise of immune response to invasive oral procedures ❏b signifi cant compromise of wound healing capacity ❏c decreased quality of life 5. Which of the following statements is correct regarding ❏d increased risk for oral mucosal infection chronic use of bisphosphonates in patients? ❏e all of the above ❏a comprehensive, evidence-based guidelines are currently available for treatment of bisphophonate-induced 3. Which of the following is correct regarding cancer chemo- osteonecrosis of the jaws therapeutic drugs? ❏b bisphosphonates can be important in controlling meta- ❏a these drugs affect only oral epithelium, but not the un- static bone lesions in cancer patients derlying oral mucosal connective tissue ❏c most patients with bisphosphonate-induced osteone- ❏b risk of and severity for oral mucositis is related to class of the crosis of the jaws also exhibit osteomyelitis at the same drug as well as its frequency and dosage of administration oral bony site ❏c severe oral mucositis does not result in subsequent re- ❏d the principal mechanism by which bisphosphonates duction of chemotherapy dosage in some patients receiving infl uence bone metabolism is by impairing function of multi-cycle regimens of the drugs osteoclasts ❏d there are no oral toxicities associated with these medica- ❏e statements “b” and “d” above tions ❏e none of the above

34 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_34 34 9/14/07 3:59:53 PM Peterson, Sigel, Suzuki. Medications inﬂ uencing immune response ... : ce test questions

6. Which of the following are oral complications of long-term 9. Topical steroid therapy for oral mucosal disorders is bisphosphonate use in cancer therapy? characterized by which of the following? ❏a rampant caries ❏a generally safe ❏b xerostomia ❏b a short-term course of treatment ❏c microfractures of the maxilla and mandible ❏c ultra-potency topical steroids can be absorbed sy- ❏d lichen planus stemically ❏e all of the above ❏d custom trays and adhesive vehicles can be used to enhance the effect of intraorally-applied topical steroids 7. Which of the following is true regarding patients on ❏e all of the above chronic steroid therapy? ❏a this type of patient is not frequently encountered in the 10. Which of the following is an effect of systemic steroid dental offi ce therapy? ❏b inappropriate management can lead to life-threatening ❏a infl ammation is reduced adrenal insuffi ciency ❏b white blood cell production is inhibited ❏c the patient’s medical history is not important ❏c prostaglandin and leukotriene production is reduced ❏d the patient should not receive dental care ❏d cyclooxygenase synthesis is suppressed, leading to de- ❏e all of the above creased neutrophil and monocyte chemotaxis ❏e all of the above 8. Which of the following is true regarding systemic steroid therapy for oral conditions? ❏a should be prescribed at high dose for a short period of time Questions are based on a manuscript by Douglas E. Peterson, DMD, ❏b should never be prescribed by a dentist PhD, Michael A. Siegel, DDS, MS, and Jon B. Suzuki, DDS, PhD, MBA, entitled, “Medications Infl uencing Immune Response and Wound ❏c does not affect any existing systemic diseases/conditions Healing”. ❏d has no associated side effects ❏e adverse reactions only occur after many years of continuous therapy

Name:______

Address:______E-mail address:______

City:______State:______Zip:______

Day Telephone:______

Cost is $45. Payment by check or credit card is acceptable. If paying by check, please make payable to: Grand Rounds in Oral-Systemic Medicine. If paying by credit card, please complete the following information:

❏ MasterCard ❏ Visa ❏ Discover ❏ American Express

Name on card: ______

Account #: ______

Exp. date:______

Participants scoring at least 70% will receive verifi cation of 3 credits.

PennWell Corporation is an ADA CERP Recognized Provider

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 35

0709gr_35 35 9/14/07 4:00:20 PM Original Article

DENTAL IMPLICATIONS FOR

THE IMMUNOCOMPROMISED Susan M. Chialastri, DMD† ORGAN TRANSPLANT PATIENT Jon B. Suzuki, DDS, PhD, MBA‡

Abstract The survival rate of patients with serious renal, liver and cardiac diseases has increased signifi cantly due to pioneering work with organ transplants, enhanced by pharmacologic advances in immunosuppressive drug therapy. However, cyclosporine, an immunosuppressant used to prevent rejection of the solid organ transplant, has serious side effects including gingival enlargement. Tacrolimus and other newer drugs offer the same immunosuppression but with fewer side effects. Adverse complications during end-stage renal disease, the pre-transplant period, and the post-transplant period represent major concerns to the health professionals caring for these patients. Periodontal disease and other oral infections may pose serious risks that may compromise the success of a solid organ transplant. Evidence related to microbiological and immunological factors suggests that there is a consistent and strong association between the presence of periodontal pathogens and complications during the post-transplant phase; these factors could lead to the eventual rejection of the solid organ transplant. This article offers a broad overview of the published scientifi c literature on a number of oral/facial complications commonly seen in patients receiving organ transplant therapies and immunosuppressive drugs. Over 90 textbook chapters and peer reviewed journal articles were reviewed. The extensive clinical experience of both authors is incorporated with recommendations from other published authors, to propose dental care recommendations in patients before and after transplant procedures.

Citation: Chialastri S, Suzuki, J. Dental implications for the immunocompromised organ transplant patient. Grand Rounds Oral- Sys Med. 2007;3:36-44. (Digital version Grand Rounds Oral-Sys Med. 2007;3:36-44c.) (A complimentary copy of this article may be downloaded at www.thesystemiclink.com.)

Key Words: Renal transplants, cyclosporine, tacrolimus, gingival hyperplasia, organ rejection

Introduction uman organ transplantation, a topic of science fi ction in past years, is now a reality. Development of various immunosuppressive agents such as cyclosporine (cyclosporine A (or CyA) and tacrolimus (FK 506) has minimized Hthe signifi cance of obtaining a perfect tissue match between donor and recipient. These advances will further increase the clinical application of human-to-human organ transplantation in coming years.1 Signifi cant clinical aspects of immunosuppressive agents used in organ transplantation are listed in the table entitled Immunosuppressive drugs: summary of indications, mechanisms, metabolism in precautions, and infl uence on dental treatment, which can be accessed and downloaded from the Clinical Decision-Making Tools section at www.thesystemiclink.com.

To ensure optimal clinical outcomes of organ transplantation, it is critical for medical, dental, and allied healthcare professionals to be familiar with prevention, identifi cation, and/or treatment of the oral complications associated with pre- and post-organ transplant therapies. Wynn and colleagues2 have described the following oral/facial complications associated with immunosuppressive drugs: † Associate Professor, Department of Periodontology and Oral • Gingival hypertrophy/enlargement Implantology, Temple University, Maurice H. Kornberg • Mouth ulcers School of Dentistry, Philadelphia, PA • Dysphasia ‡ Professor of Microbiology-Immunology, School of Medicine; Professor of Periodontology and Oral Implantology, School of • Salivary gland enlargement Dentistry; Associate Dean for Graduate Education, Research, • Gingival bleeding and International Affairs; Director, Graduate Periodontology • Gingivitis and Oral Implantology, Temple University, Philadelphia, PA

36 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_36 36 9/14/07 3:55:17 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

• Xerostomia • Glossitis Table 1 • Abnormal taste Risk factors for gingival enlargement • Mouth odor associated with cyclosporine A • Fungal (Candida) infections • Herpes simplex Risk Factor Comment • Esophagitis • Oral moniliasis Cyclosporine dose • Cyclosporine (nonmodifi ed) is • Stomatitis poorly absorbed, resulting in • Nonmelonoma skin carcinoma average trough level of 46%; • Lymphadenopathy when switching to cyclosporine A, dose adjustments need to be • Petechia made and plasma concentra- • Increased gingival hemorrhage tions monitored until desired • Anemia trough level is achieved; however, modifi ed doses >500 mg/day In addition to drug-induced gingival enlargement, other have been reported to induce prevalent yet often unrecognized threats to successful gingival overgrowth2 organ transplantation arise from the risk of developing • Drug dosage tends to be a poor other oral/facial complications, including certain types of predictor of gingival changes, de novo malignancies, as well as viral, bacterial, or fungal but dose related to body weight infections associated with periodontal disease. Therefore, may be more meaningful5,14 collaborative care is critical to the success of organ trans- • Gingival overgrowth associated plantation, as refl ected in concordant dental care recom- with higher total yearly cyclo- mendations for patients before and after organ trans- sporine A dose15 plantation. Concomitant use of • Concomitant use of cyclospo- Increased risk of gingival enlargement associated with cyclosporine A with a rine A with a calcium channel immunosuppressive drugs calcium channel blocker (often used to address Cyclosporine is a potent immunosuppressant used in blocker hypertensive effects of cyclo- organ transplant recipients, with side effects including sporine A) is associated with a nephrotoxicity, neurotoxicity, hepatoxicity, hypertrichosis, higher prevalence or severity 12,13 hypertension, and gingival overgrowth.2,3 Gingival lesions of gingival enlargement; es- 12,16 were fi rst reported in 1978 with results of the fi rst clini- pecially with nifedipine, but to a lesser degree with amlo- cal trials on cyclosporine.4 Gingival enlargement occurs dipine, verapamil17 and diltia- in approximately 8-70% of the patients taking the medi- zem18 cation, with an overall incidence of approximately 25- 30%.5-9 However, up to 97% of pediatric heart and lung Genetic • HLA-DR2 phenotype — 50% of transplant recipients demonstrate some degree of cyclo- predispositiona renal transplant recipients with 10 sporine A-induced overgrowth. Statistical reporting can this allele and cyclosporine A be confounded by other drugs taken concomitantly with treatment have gingival over- cyclosporine.5,6,11 For example, calcium channel block- growth15 ers are often given for cyclosporine-induced hyperten- • HLA-B37 phenotype — signifi - sion, and this combination is associated with gingival cantly associated with more se- 2 overgrowth. Cyclosporine is also used with adjunctive vere gingival overgrowth19 prednisolone or azathioprine for post-transplant therapy; • HLA-DR1 phenotype — protec- however, these agents have an inverse relationship with tive role against gingival over- 12 occurrence of gingival enlargement. Overall, risk factors growth induced by cyclosporine for cyclosporine A-induced gingival enlargement include A20 dose, concomitant use with calcium channel blockers, and genetic predisposition (Table 1). Clinical features of im- aHLA Class I and Class II genes, whose products are munosuppressive drug-induced gingival enlargement are critical for immunological specifi city and transplantation described in Table 2, and shown in Figures 1-3. Further histocompatibility, play a major role in susceptibility to a information from numerous authors on the risk factors, number of other autoimmune diseases; the HLA system was very clinical manifestations, and pathogenesis of drug-induced important in the development of clinical transplantation.21 gingival enlargement is summarized in the 2004 report

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 37

0709gr_37 37 9/14/07 3:55:39 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

Figure 1: Cyclosporine A-induced gingival Figure 2: Cyclosporine A- and nifed- enlargement in an 11-year-old African American ipine-induced gingival enlargement in male a 13-year-old African American male

Malocclusion due to the changes in eruption and exfoliation patterns Photo courtesy of Susan M. Chialastri, DMD can result in additional gingival inﬂ ammation and gingival enlargement creating speech, mastication, and esthetic issues. With the altered pattern of delayed exfoliation of the primary teeth and ecto- pic eruption of the permanent teeth due to the gingival enlargement; Figure 3: Cyclosporine A and nifedipine- extraction of the involved primary teeth usually results in decreased induced gingival enlargement in 13-year-old inﬂ ammation.28 African American male, 18 months after gingivectomy surgery Photo courtesy of Susan M. Chialastri, DMD Note recurrence of gingival enlargement due to poor plaque control.

of the American Academy of Periodontology on Drug Associated Gingival Enlargement.13

Tacrolimus is used as a “rescue therapy” in organ transplant cases with ongoing rejection, and for patients who have developed a ctclosporine A-induced nephrotoxicity.1- 3 It has also become an effective alternative to cyclosporine therapy for primary immunosuppression in pediatric renal transplant cases.1-3 The most common side effects of tacrolimus include anemia, renal toxicity, hyperkalemia, 2 chronic diarrhea and allergies. The gingival hyperplasia, Photo courtesy of Susan M. Chialastri, DMD hypertension, and hirsuitism observed with cyclosporine are not seen with tacrolimus.29-31 This may be related to: from cyclosporine to tacrolimus, cyclosporine-related gin- • Secreted protein acidic and rich in cystein (SPARC), gival hyperplasia and hypertrichosis resolve almost com- a glycoprotein that mediates cell-matrix interactions. pletely, mean total cholesterol is reduced, and mean sys- SPARC mRNA levels tended to increase 72 hours after tolic and mean diastolic blood pressures are reduced.31,34 cyclosporine A treatment while they are undetectable in FK 506-treated fi broblasts.32 Increased risk of developing certain types of “de novo” • Increased matrix metalloproteinase-1 (MMP-1 gene) malignancies and metalloproteinase-2mRNA (MMP-2 gene), which Transplant recipients are also at an increased risk of de- may be important for regulating collagen type I (COL- veloping the following de novo malignancies seen in the 1) homeostasis in the gingival connective tissue com- dental setting: partment of FK 506-immunosuppressed subjects.32 • Epithelial dysplasia – (3 to 7 fold increased risk)35 • A role of ECM stabilization that may be associated • Squamous oral carcinoma, especially of the lip in CsA with FK 506, and does not overdo the gingival over- treated patients36-38 growth.33 • Basal cell carcinoma39 • Lymphoma (lymphoproliferation disease), non-Hodg- Patients may be converted to tacrolimus with minimal risk kin’s lymphoma – (2 to 3 fold increased risk) 40 of allograft dysfunction or rejection.29,34 After switching • Kaposi’s sarcoma41,42

38 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_38 38 9/14/07 3:56:02 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

• Cervical carcinoma43 Table 2 • Human papilloma35,42 Clinical manifestations of gingival enlargement The incidence of these de novo malignancies increases induced by immunosuppressive drugs progressively with length of time after transplantation, ranging from 10% after 10 years, to 40% after 20 years Feature Clinical Manifestation post-transplant.36 Human papilloma virus DNA has been detected in the tumors, suggesting that immunosup- Onset • Usually develops within 1- pression may have a permissive effect on viral prolifera- 3 months after initiation of tion.35 Prior to the availability of appropriate antiviral treatment with the associated medications before the clinical drugs (e.g., acyclovir, gancyclovir and valacyclovir), ap- manifestations of the gingival proximately 50% of renal allograft recipients (who were enlargement may be noted9,22 seropositive for herpes simplex) experienced recurrent, • severe, and prolonged HSV infections.44-46 Long-term Enlargement normally begins at post-allograft immunosuppression may predispose pa- the interdental papillae and affects the marginal and papillary tients to human herpesvirus 8 (HHV-8) and associated tissue5,9,23 Kaposi’s sarcoma.42 However, anti-herpetic regimens have signifi cantly reduced the frequency of HSV infec- • Tissues in edentulous areas do not 6 tions.47 seem to be affected Appearance • Most drug-induced gingival en- Increased risk of infection associated with periodontal largement cases have a very disease in immunocompromised patients similar appearance and are dif- 5 Underlying periodontal disease can affect the successful fi cult to distinguish outcome of an organ transplant via direct and indirect • Gradually, gingival lobulations pathways. Untreated dental infections or oral mucosal le- are formed, and may appear sions can jeopardize renal function in the newly trans- infl amed or more fi brotic in na- planted kidney.48 It has been hypothesized that periodon- ture depending on degree of local factors inducing the infl am- tal disease should be viewed on the basis of the model of mation13 virus-bacteria-host immune response interaction which • may account for the gingival infl ammation episodes re- Gingival epithelium is invaded Candida 24,26 ported by several authors.28,49 Acute periodontal infec- by hyphae tions in myelosuppressed cancer patients are associated • Pebbly or papillary lesions that with high concentrations of subgingival plaque — pre- appear on the surface of larger dominantly Staphhylococcus epidermidis, Candidia albi- lobulations, sometimes with a cans, Staphylococcus aureus, and Pseudomonas aerugi- caulifl ower appearance associated with cyclosporine A24-26 (see nosa — and in some patients a concomitant bacteremia.50 Figures 1 and 2) Pathogens that are normally associated with infections in • myelosuppressed cancer patients, as well as indigenous Impact Tissues are hyperemic and bleed more readily upon probing — oral fl ora, are associated with acute periodontal infec- generally more with cyclospo- tions during granulocytopenia.50 These fi ndings highlight rine A than with phenytoin5 the mouth as a source for acute infections in immunosup- • pressed patients. The results can be disfi guring due to the alterations in tooth 9,23 Role of bacterial plaque biofi lms in cyclosporine- position and occlusion (see Figures 1-3) induced gingival enlargement • Plaque accumulation has been strongly associated with Fibrotic enlargement usually confi ned to the attached gingiva, gingival overgrowth, both in the animal model of cyclo- but when it extends, it can inter- sporine A-induced gingival enlargement51 and in a large fere with esthetics, mastication, group of cyclosporine A-treated allograft patients using a and speech24, 25 multivariate regression analysis model.52 Oral hygiene sta- Patient • More likely seen in males27 tus including bacterial plaque, calculus, and bleeding must population be assessed before administration of the drugs. Patients • More severe in younger pa- with evidence of an infl ammatory gingival overgrowth be- tients who are taking cyclospo- 11 fore initiating cyclosporine A treatment are more likely to rine develop severe gingival enlargement.53 However, a large

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 39

0709gr_39 39 9/14/07 3:56:29 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

study of cyclosporine A-treated patients failed to fully ex- and the most common infectious reason for transplant plain the distribution of gingival overgrowth based solely rejection, including bone marrow and stem cell grafts.64 on the level of plaque and gingivitis.54 Some studies have Infection can occur by transfer of virus with the allograft suggested that while plaque biofi lm can probably modify or by reactivation of latent virus remotely acquired by the the characteristics, it is not essential for the development recipient.49 Seronegative recipients who acquire organs of gingival overgrowth.55-57 The relationship between gin- from seropositive donors are at greatest risk of devel- gival infl ammation and the development of gingival over- oping infection, and these primary infections tend to be growth is still unclear, although a positive relationship has most severe. The use of antilymphocyte antibody therapy been suggested.14 There is no agreement in the literature for immunosuppression after organ transplantation also regarding the effects of home care and professional plaque enhances the likelihood and the severity of infection in control on gingival enlargement. susceptible recipients.65 HCMV infection typically emerges 1-3 months after transplantation, although onset may be Role of infl ammatory cytokines in periodontal disease delayed in patients receiving antiviral prophylaxis, which and solid organ transplant deterioration may suggest a reactivation of a latent virus.65 HCMV infec- Periodontal pathogens can potentially cause a bacteremia tion appears to enhance the overall level of host immuno- that might eventually lead to the rejection of the trans- suppression, possibly accounting for frequent emergence planted organs, and a great deal of research is focused on of other opportunistic infections and presenting strong the role of infl ammatory cytokines in the periodontal-sys- evidence for the role of herpesvirus in the pathogenesis temic connection. Interleukin (IL)1β is a pro-infl ammato- of human periodontal disease.66 Despite antiviral therapy, ry cytokine that is elevated in infl amed gingival tissues.13 renal transplant patients affected by periodontitis are at Histological examination of cyclosporineA-induced gingi- risk of viral replication within the periodontal tissues, val lesions has revealed a dramatic elevation in IL-6 ex- as the periodontal pockets may serve as a reservoir for pression by cells within the gingival connective tissue.58,59 HCMV replication.67 Infl ammation plays a role in organ transplant rejection, and levels of serum IL-6 can identify individuals who HCMV infection seems to be a signifi cant risk factor for are at greater risk for transplant rejection.60 Although the development of bacterial septic infection in liver cyclosporine A therapy does not directly increase IL-1β transplant recipients,61,68,69 and for causing colonization and IL-6 levels in the gingival fl uid, infl ammation associ- of the oropharynx by gram-negative bacilli in renal trans- ated with cyclosporine A-induced gingival lesions might plant recipients.70 A herpesvirus periodontal infection be more directly responsible for cyclosporine A-induced has the potential to increase the level and pathogenic- tissue overgrowth.58 Ioannidou and colleagues60 reported ity of specifi c periodontopathic pathogens. In a study of that transplant recipients with chronic periodontitis had 140 adults with gingivitis or periodontitis, periodontal signifi cantly higher serum IL-6 levels than those without Epstein Barr Virus (EBV-1) and HCMV were related to chronic periodontitis, that there was a positive correla- the elevated occurrence of the pathogens Porphyromonas tion between periodontal IL-6 gene expression levels and gingivalis, Porphyromonas forsythus, Prevotella interme- serum IL-6 protein levels, and that periodontal tissue de- dia, Prevotella nigrescens, and Treponema denticola.66 In struction and local IL-6 synthesis are associated with el- patients who are immunocompromised, activation of the evated IL-6 levels in transplant recipients. This may have herpesvirus may therefore play a major role as activator serious implications in solid organ transplant deteriora- of the periodontal disease process.49 tion and chronic rejection. Opportunistic infections in immunosuppressed patients Role of herpesvirus infections in systemic and Post-transplant recipients are immunocompromised and periodontal disease therefore at increased risk for opportunistic infections Herpesvirus infections affect cytokine-chemokine net- and complications that lead to signifi cant morbidity and works,49,61,62 as cytokines and chemokines play important mortality. Some infections involve more than one patho- roles in the fi rst line of defense against human herpes- gen, e.g., pneumonia may have viral, bacterial, or fungal virus infections, and also contribute signifi cantly to the etiology.2 All immunosuppressed patients are at risk from regulation of acquired immune responses. bacteremia from oral microorganisms. Daily bacteremia from chewing or tooth brushing is most likely the cause Human Cytomegalovirus (HCMV) infection induces a pro- of systemic infections, rather than dental treatment71, in infl ammatory cytokine profi le, with production of inter- light of American Heart Association (AHA) recommend- leukin (IL)-1β, IL-6, IL-12, tumor necrosis factor alpha ed premedication regimens for all dental procedures.71 (TNF-α), interferon (IFN)-α/β, IFN-γ,62 and prostaglandin In spite of the recent changes issued by the AHA in the 63 Prevention of Infective Endocarditis (IE) Guidelines E2 (PGE2). HCMV is the most common viral pathogen in encountered in all solid organ recipient populations,61,64 April 2007, numerous comorbid factors — such as older

40 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_40 40 9/14/07 3:56:50 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

age, diabetes mellitus, immunosuppressive conditions or transdisciplinary team members are more committed to therapy, and dialysis — may complicate IE, which further the patient’s total care by sharing responsibility, and each increases morbibity and mortality rates in organ trans- member is accountable for how the plan is implemented. plant recipients.72 Furthermore, in light of drug side ef- This approach requires extreme dedication by each team fects and compromised renal clearance, controversy member in order to provide optimal care; information remains in the national and international medical com- regarding the patient’s health status and progress is as- munities regarding antibiotic prophylaxis.42 In a survey of sessed, observed, recorded, and shared with all special- U.S. organ transplants, among the 294 survey responses ties involved in the patient’s care.75 (38% response rate), 85% recommended antibiotic prophylaxis prior to dental care, and 96% recommended the Concordant recommendations for dental care 1997 AHA endocarditis prevention regimen.73 It is the in pre-organ transplant recipients opinion of the authors of this article that since solid organ Many patients with end stage renal disease (ESRD) are in transplant recipients are in a drug-induced immunosup- poor health for a long time as they await potential organ pressed state, they should continue to receive antibiotic transplantation. In fact, the majority of patients with re- prophylaxis; as with any medication; however, the risk of nal disease will show oral symptoms such as changes in an adverse event associated with the antibiotic must not the teeth, bone and periodontium. Oral manifestations of exceed the benefi t. Since most cases of IE are not attrib- patients with chronic renal failure receiving hemodialysis utable to an invasive procedure, but rather to randomly include malodor ‘bad breath,’ and a metallic taste which occurring bacteremias from routine daily activities, this is due to the high urea content in saliva and its subse- is reason enough to ensure that the patient has healthy quent breakdown to ammonia.76 The patients appear to plaque-free teeth and infl ammation-free gingiva, to re- be predisposed to xerostomia.77 Patients with dry mouth duce the risk of infections associated with odontogenic are often prone to retrograde parotitis; these complica- bacteria.74 tions are believed to result from a combination of direct gland involvement, chemical infl ammation, dehydration Increased risk for Candida and Aspergillus infections and mouth breathing.48 Children with renal disease can In organ transplant recipients treated with cyclosporine have premature tooth loss and dental developmental ab- A, C. albicans is the most frequent species identifi ed in normalities such as delayed eruption, enamel hypoplasia the saliva; C. dubliniensis, C. parapsilosis, C. krusei, and and narrowing of the pulp chamber.42,77 Bone resorption C. tropicalis are also found.36 In patients treated with ta- can lead to pathologic tooth mobility and drifting.42,78 A crolimus, C. albicans and C. dublieniensis are found.36 The wide range of bone anomalies can arise in chronic renal same Candida hyphae have been seen invading the gin- disease due to defects of calcium metabolism with resul- gival epithelium.26 The presence of Candida in an immu- tant secondary hyperparathyroidism, affecting up to 92% nosuppressed patient should come as no surprise since of the patients receiving hemodialysis.79 The bony features yeasts are opportunistic organisms. Aspergillus species is that may be seen include decreased trabeculation, bone an opportunistic and endemic fungi that has also been demineralization, decreased thickness of cortical bone, reported to cause serious infections in organ transplant “ground glass appearance of bone”, radiolucent fi brocys- recipients. It is by far the most frequent and lethal fungal tic lesions and radiolucent giant cell lesions.42,78 Abnormal pathogen occurring in 5% of liver, lung, and heart trans- healing after extractions may occur.42 (For information on plant patients, and less frequently in kidney transplant dental management of patients with renal disease, please patients.65 see “Oral Health and Chronic Kidney Disease: Building a Bridge Between the Dental and Renal Communities” in Collaborative approaches to care of organ transplant this issue of Grand Rounds.) recipients Most patients are severely immunocompromised from Furthermore, because these patients are severely immu- post-transplant medications; therefore, dental profes- nocompromised, many of them are suffering from bacteri- sionals must fi rst consult with the transplant recipient’s al and fungal infections (which are often under-treated due attending physician before beginning any dental treat- to the severity of the existing kidney failure and the exten- ment. Conversely, the patient’s physician should have the sive medications they are taking for ESRD).80 Periodontal potential transplant candidate obtain a complete dental disease, dental caries and poor plaque control are often and periodontal evaluation before the patient can be ignored, and these issues can potentially be life threat- fully considered for an organ transplant. Historically, col- ening in the renal transplant patient. In the 1998 study80 laborative care for organ transplant patients has at best of 4 renal dialysis centers in Virginia, the renal dialysis taken a multidisciplinary approach, but with the grow- sample studied had 100% prevalence of periodontal dis- ing number of transplant cases, a more comprehensive ease, which is greater than the 85% seen in the general transdisciplinary approach is more appropriate. The population. The authors of that study suggested that a

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 41

0709gr_41 41 9/14/07 3:57:12 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

stringent continued care program be established to pre- ➤ Consider systemic antibiotics during scaling and root vent oral disease from progressing undetected. Bleeding planing. Use caution with certain antibiotics due to ne- tendencies in these patients were attributed to a com- phrotoxicity.78 bination of factors, including anticoagulants used with ➤ Conduct supportive periodontal maintenance while the hemodialysis therapy and vascular access maintenance. patient is on dialysis at an interval determined by the The reduction in the platelet counts and platelet adhe- patients needs; every 3-4 months may prove helpful. sion and increased capillary fragility can all lead to an ➤ Conduct dental procedures the day after dialysis.78,83 If increase in the loss of blood during dental procedures.76 a new shunt is being placed, then it is best to wait two weeks before initiating treatment. NO dental treat- The following general recommendations for dental thera- ment should be performed if there is any infection or py in prior to solid organ transplantation are based on the clotting at the site of the shunt. Complications with the work of various expert sources and the clinical experi- shunt can lead to infective endocarditis. ence of the authors of this article. ➤ Try to save teeth via endodontic therapy (preferred ➤ Obtain a medical consult from the patient’s nephrolo- over extraction). gists to discuss recent coagulation values, and medica- ➤ Analyze saliva and gingival crevicular fl uid for active tions, including steroids and administration of antibio- HCMV infection.67 tic prophylaxis.76,78 ➤ Consider hematologic conditions that most commonly ➤ Consider hematologic conditions that most commonly affect the patient with uremia and renal failure: ane- affect the patient with uremia and renal failure: anemia and excessive bleeding. Obtain white blood cell mia and excessive bleeding. Obtain white blood cell count and platelet count, and bleeding time should be count and platelet count, and bleeding time should be obtained before proceeding with surgical dental pro- obtained before proceeding with surgical dental procedures including extractions. Hematocrit, hemoglo- cedures including extractions. Hematocrit, hemoglobin and differential blood tests should be performed to bin and differential blood tests should be performed to evaluate for anemia. Note that bleeding can be a signifi - evaluate for anemia. Note that bleeding can be a signifi - cant problem in patients on dialysis because warfarin cant problem in patients on dialysis because warfarin or heparin therapy is used to prevent clotting in the or heparin therapy is used to prevent clotting in the shunt.76,78 shunt.76-78 ➤ Perform minimally invasive extractions at least 8 hours ➤ Conduct comprehensive periodontal and restorative after dialysis. Meticulous surgical technique should be examinations and develop comprehensive treatment followed. Use hemostatic agents and suturing to ensure plans before the patient receives the transplant. hemostasis. If necessary, the dialysis regimen can be ➤ Conduct a complete series of radiographs for on all modifi ed and Vitamin K therapy can be considered.42 dentate patients. A panoramic radiograph is suffi - ➤ Prescribe fl uoridated toothpaste and/or fabricate cient for edentulous patients. Caries, periodontal custom fl uoride trays for at-home fl uoride applica- disease, cysts, tumors, impacted teeth, periapical tion if decay is a problem. lesions and any pathological condition needs to be ➤ Educate patient regarding the connection of periodon- addressed.78 tal disease and their role in the success or failure of ➤ Give special attention to the head, neck and oral can- renal dialysis and renal transplantation. cer examination due to the predilection for skin can- ➤ Follow current AHA recommendations73 for premedica- cers and lymphomas.41,43 Any suspicious lesions and/or tion for all dental procedures, due to the increased risk localized or diffuse swellings should be examined fur- of infection for the uremic patient on dialysis.42,72,78,83 ther by the attending physician. ➤ Use postoperative antibiotics. Penicillin, erythromycin, ➤ Eliminate local bacterial plaque factors through me- amoxicillin, and clindamycin are preferred; these an- ticulous home care instructions and plaque control tibiotics may be used in usual doses for a short course techniques. Consider a sonic electric toothbrush,81 of therapy.78 and oral irrigator if needed. The patient must attain ➤ Manage pain. Acetaminophen, propoxyphene hydro- acceptable dental health. Parents of pediatric patients chloride, pentazocine and codeine can be used in should also receive oral hygiene instructions to bet- moderate amounts, and the dosages should be adjusted. ter assist and/or supervise their child. Avoid aspirin and meperidine hydrochloride.76,78,83 ➤ Perform mechanical debridement. ➤ Use chlorhexidine 0.12% mouth rinse which may be Concordant recommendations for dental care in benefi cial28,82 as an anti-fungal and antimicrobial. It post-organ transplant recipients should be used as a pre-operative rinse for all dental The following general recommendations for dental ther- procedures. apy in solid organ transplant recipients are based on the

42 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_42 42 9/14/07 3:57:33 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

work of various expert sources and the clinical experi- sugar-free gum to stimulate salivary fl ow, mouth ence of the authors of this article. moisturizing gel or mouth spray, synthetic saliva- ➤ After consultation with the medical team members, aqueous solution, or prescriptions for 1.1% neutral consider switching from cyclosporin to tacrolimus for sodium fl uoride toothpaste, 0.63% stannous fl uoride signifi cant resolution or complete regression of the rinse concentrate, or 0.4% stannous fl uoride gel to gingival enlargement.26 minimize the potential for root caries in the adult pa- ➤ Advise the patient to follow an oral hygiene program tient.2,76 prior to transplant surgery.84 Oral hygiene instructions ➤ Children with chronic renal failure (CRF) have signifi - should include: cantly lower isolation frequency of Streptococcus mu- √ Extra soft brush for sensitive teeth tans,94 but it signifi cantly increases 3 months post √ Chlorhexidine 0.12% mouth rinse BID78,85,86 transplant.94 Caries may become more signifi cant in √ Mild toothpastes with low abrasive qualities children post-transplant. Use fl uoride rinses or at- and no added whitening or tartar control products home fl uoride application trays if necessary. which can be irritating in a dry mouth ➤ For gingival enlargement, scalpel or laser excision is √ Non-alcohol containing mouthwashes necessary if the excess tissue is unsightly and/or in- ➤ Conduct quadrant scaling and root planing56 to possi- terferes with mastication, speech or oral care.26 The bly help resolve the infl ammation, which may elimi- classical surgical approach has been gingivectomy, nate the need for surgery;87 at least 12 months of oral however an alternative periodontal fl ap approach has hygiene, subgingival scaling, and periodontal main- also been suggested,11 to limit the large denuded con- tenance therapy is most effective in resolving the in- nective tissue wound seen in the gingivectomy. This al- fl ammation.88 ternative approach minimizes post operative pain and ➤ Perform microbial culture and antibiotic sensitivity bleeding, permits healing by primary intention,95 and test to best determine that the etiology is bacterial and possibly prevents or limits the overzealous healing not fungal, since Candida hyphae have been found in or faster cell proliferation of the injured connective the gingival lesions as previously pointed out. tissue especially when plaque control is diffi cult after ➤ Freqeuntly monitor saliva and gingival crevicular fl uid surgeries and the tissue regrowth may easily recur. for active HCMV infection; this may reduce the risk of Recurrence rate of severe cyclosporine A-induced gin- transplant complications due to HCMV infection.67 gival enlargement after surgery is about 40% within 18 ➤ Use caution when prescribing an antibiotic due to po- months.95 (Figure 3.) The recurrence rate was found tential nephrotoxicity.2,78 to be higher in younger patients with greater existing ➤ For slight to moderate gingival enlargement, use sy- gingival infl ammation and who are poorly compliant stemic antibiotics. If treated early, condition responds well to the recommended maintenance visit schedule.95 to azithromycin 250-500 mg/per day for 3-5 days.89-91 Regular re-motivation and professional care at fre- Azithromycin may lead to amelioration or complete re- quent recalls after periodontal surgery is important.96 gression of the gingival overgrowth and the duration of ➤ To minimize the risk of adrenal crisis in individuals the effects may be 3 months to 2 years.90 Another stu- who have taken large doses of corticosteroids (10 mg dy contradicted the fi ndings stating that azithromycin prednisolone daily during the preceding 3 months) and/or metronidazole do not really cause regression of and are undergoing surgical procedures (including the overgrowth but act on the concomitant bacterial extractions of more than one tooth), appropriate corti- infection and gingival infl ammation.92 costeroid cover should be administered.42,78 ➤ For bleeding on probing or cyclosporine A-induced ➤ Biopsy of the excised tissues is recommended due to gingival overgrowth, use azithromycin-containing the risk of epithelial dysplasias, lymphoproliferative toothpaste (85 mg of azithromycin per gram of diseases and carcinomas reported in organ transplant toothpaste).93 recipients.97 ➤ If Candida is identifi ed, use topical antifungal medications. Regimens include clotrimazole troche 10 mg Conclusion (1 troche slowly dissolved in mouth fi ve times a day Although advances in immunosuppressive regimens, sur- for 14 consecutive days), and nystatin oral suspension gical techniques, organ preservation, and overall man- 5 ml (1 teaspoon — hold in mouth for 2 minutes and agement of transplant recipients have improved graft swallow) QID.2 and patient survival, infectious complications remain ➤ For angular cheilitis, use nystatin ointment (applied to a major obstacle. Bacterial, fungal, and viral infections the lesion) QID until healing occurs.2 are implicated after transplant surgery as causes for or- ➤ For xerostomia, use over-the-counter (OTC) moisturizing gan rejection. Recognition of infection as a serious com- toothpaste, alcohol-free, anti-bacterial mouthwash, plication following solid organ transplantation supports

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 43

0709gr_43 43 9/14/07 3:57:55 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

the need for pre-transplant screening, early diagnosis of 7. Palestine AG, Nussenblatt RB, Chan CC. Side effects of systemic active infection, and modalities for prevention and treat- cyclosporin in patients not undergoing transplantation. Am J ment of various infections. Proper prophylactic and treat- Med. 1984;77(4):652-656. ment strategies are imperative when dealing with chron- 8. Boltchi FE, Rees TD, Iacopino AM. Cyclosporine A-induced ic immunosuppression, nosocomial and host pathogens, gingival overgrowth: a comprehensive review. Quintessence emerging drug resistance, multiple drug interactions and Int. 1999;30(11):775-783. medication toxicities. 9. Daley TD, Wysocki GP. Cyclosporin therapy — its significance to the periodontist. J Periodontol. 1984;55(12):708-712. The interrelationship between periodontal infl ammation 10. Kilpatrick, NM, Weintraub RG, Lucas JO, et al. Gingival over- and systemic diseases has been established, and infl am- growth in pediatric heart-lung transplant recipients. J Heart mation plays a critical role in organ transplant rejection. Lung Transplant. 1997;16:1231-1237. Periodontal disease can have serious detrimental effects 11. Seymour RA. Calcium Channel blocker and gingival over- on the successful long-term outcome of patients receiving growth [review]. Br Dent J. 1991;170(10):376-379. organ transplants. Long term transplant survival in these 12. Wilson RF, Morel A, Smith D, et al. Contribution of individual patients may depend on eliminating the negative effects drugs to gingival overgrowth in adult and juvenile renal of periodontal disease, through careful consideration of transplant patients treated with multiple therapies. J Clin the use of localized and systemic antibiotics, antimicrobi- Periodontol. 1998; 25(6):457-464. al rinses, frequent recalls, and good daily plaque control. 13. Dongari-Bagtzoglou A. Research, Science and Therapy Committee, American Academy of Periodontology. Drug- Collaborative care integrates various disciplines and team associated gingival enlargement [review]. J Periodontol. members responsible for the patient’s health, and the 2004;75(10):1424-1431. dentist and dental hygienist can play an integral role on 14. Seymour RA, Ellis JS, Thomason JM. Risk factors for drug- the transplant team in establishing a clinical protocol that induced gingival overgrowth [review]. J Clin Periodontol. assists the organ transplant recipient in maintaining op- 2000;27(4):217-223. timal oral health. The transdisciplinary approach is ideal, 15. Radwan-Oczko M, Boratynska M, Klinger M, et al. Risk factors but may be diffi cult to achieve in the private practice set- of gingival overgrowth in kidney transplant recipients treating where the lines of communication are more diffi cult ted with cyclosporin A. Ann Transplant. 2003;8(4):57-62. to maintain. In the hospital/medical center setting, each 16. Thomason JM, Ellis JS, Kelly PJ, et al. Nifedipine pharma- team member would more likely be able to commit to cological variables as risk factors for gingival overgrowth meeting regularly to share information and to teach and in organ-transplant patients. Clin Oral Invest. 1997;1(1):35- learn across disciplines. 39. 17. James JA, Marley JJ, Jamal S, et al. The calcium channel Disclosures blocker used with cyclosporin has an effect on gingival over- Jon B. Suzuki, DDS, PhD, MBA serves on the scientifi c ad- growth. J Clin Periodontol. 2000;27(2):109-115. visory boards of Biohorizons and Philips Oral HealthCare. 18. Morisaki I, Fukui N, Fujimori Y, et al. Effects of combined oral treatments with cyclosporine A and nifedipine or diltiazem References on drug-induced gingival overgrowth in rats. J Periodontol. 1. Kaufman DB, Shapiro R, Lucey MR, et al. Immunosuppression: 2000;71(3):438-443. practice and trends. Am J Transplant. 2004;4(Suppl 9):38- 19. Thomason J, Seymour R, Ellis J, et al. Determinants of gingival 53. overgrowth severity in organ transplant recipients: an exami- 2. Wynn RL, Meiller TF, Crossley, HL. Drug Information Handbook nation of the role of the HLA phenotype. J Clin Periodontol. for Dentistry. 12th edition. Hudson, OH:Lexi-Comp, Inc. 1996;23(7):628-634. 2006:168-169 (azathioprine); 405-411 (cyclosporine); 1075- 20. Cebeci I, Kantarci A, Firatli E, et al. Evaluation of the fre- 1077 (mycophenolate); 1397-1399 (sirolimus); 1437-1444 quency of HLA determinants in patients with gingival over- (tacrolimus). growth induced by cyclosporin A. J Clin Periodontol. 1996; 3. Seymour R, Heasman P. Drugs, Diseases and the Periodontium. 23(8):737-742. Oxford, Oxford University Press. 1992. 21. Brunicardi CF, Andersen DK, Billiar TR, et al. Schwartz’s 4. Calne RY, White DJ, Thiru S, et al. Cyclosporin A in patients re- Principles of Surgery, Eighth Edition. The McGraw-Hill ceiving renal allografts from cadaver donor. Lancet. Companies, Inc; 2005:295-331. 1978;2(8104-8105):1323-1327. 22. Meraw SJ, Sheridan PJ. Medically induced gingival hyperpla- 5. Seymour RA, Heasman PA. Drugs and the periodontium. J sia. Mayo Clin Proc. 1998;73(12):1196-1199. Clin Periodont.1988;15(1):1-16. 6. Lundergan WP. Drug-induced gingival enlargements. Dilantin For additional references to this article, please consult the Grand Rounds in Oral-Systemic Medicine™ hyperplasia and beyond. J Calif Dent Assoc. 1989;17(6):48- digital version of at www.thesystemiclink.com. 52.

44 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO.3

0709gr_44 44 9/14/07 3:58:18 PM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

23. Wysocki GP, Gretzinger HA, Laupacis A, et al. Fibrotic enlarge- 39. Hyckel P, Schleier P, Meerbach A, et al. The therapy of vi- ment of the gingiva: A side effect of cyclosporin. Oral Surg Oral rus-associated epithelial tumors of the face and the lips Med Oral Pathol. 1983;55(3):274-278. in organ transplant recipients. Med Microbiol Immunol. 24. Marshall RI, Bartold PM. A clinical review of drug-induced 2003;192(3):171-176. gingival overgrowth [review]. Aust Dent J. 1999;44(4):219- 40. Cockfield SM. Identifying the patient at risk for post-transplant 232. lymphoproliferative disorder. Transpl Infect Dis. 2001;3(2):70- 25. Hallmon WW, Rossman JA. The role of drugs in the pathogene- 78. sis of gingival overgrowth. A collective review of current con- 41. Qunibi WY, Akhtar M, Ginn E, et al. Kaposi’s sarcoma in cepts [review]. Periodontol 2000. 1999;21:176-196. cyclosporin-induced gingival hyperplasia. Am J Kidney Dis. 26. Khocht A, Schneider LC. Periodontal management of gingival 1988;11(4):349-352. overgrowth in the heart transplant patients: a case report. J 42. Proctor R, Kumar N, Stein A, et al. Oral and dental aspects of Periodontol. 1997;68(11):1140-1146. chronic renal failure. J Dent Res. 2005;84(3):199-208. 27. Thomason J, Kelly P, Seymour R. The distribution of gingival 43. Varga E, Tyldesley WR. Carcinoma arising in cyclosporin- overgrowth in organ transplant patients. J Clin Periodontol. induced gingival hyperplasia. Br Dent J. 1991;171(1):26-27. 1996;23(4):367-371. 44. Korsager B, Spencer ES, Mordhorst CH, et al. Herpesvirus ho- 28. Farge P, Ranchin B, Cochat P. Four year follow-up of oral minis infections in renal transplant recipients. Scand J Infect health surveillance in renal transplant children. Pediatr Dis. 1975;7(1):11-19. Nephrol. 2006;21(6):851-855. 45. Naraqi S, Jackson CG, Jonasson O, et al. Prospective study of 29. James JA, Boomer S, Maxwell AP, et al. Reduction in gingival prevalence, incidence and source of herpesvirus in patients overgrowth associated with conversion from cyclosporin A to with renal allografts. J Infect Dis. 1977;136(4):531-540. tacrolimus [review]. J Clin Periodontol. 2000;27(2):144-148. 46. Armstrong JA, Evans AS, Rao N, et al. Viral infections in renal 30. Asanti-Korang A, Boyle GJ, Webber SA, et al. Experience of transplant recipients. Infect Immun. 1976;14(4):970-975. FK506 immune suppression in pediatric heart transplan- 47. Kletzmayr J, Kreuzwieser E, Watkins-Riedel T, et al. Long-term tation: a study of long-term adverse effects. J Heart Lung oral gancyclovir prophylaxis for prevention of cytomegalovirus Transplant. 1996;15(4):415-422. infection and disease in cytomegalovirus high-risk transplant 31. Thorp M, De Mattos A, Bennett W, et al. The effect of conver- recipients. Transplantation.2000;70(8):1174-1180. sion from cyclosporin to tacrolimus on gingival hyperplasia, 48. Eigner TL, Jastak JT, Bennett WM. Achieving oral health in hirsuitism and cholesterol. Transplantation. 2000;69(6):1218- patients with renal failure and renal transplants. J Am Dent 1220. Assoc. 1986;113(4):612-616. 32. Gagliano N, Moscheni C, Dellavia C, et al. Immunosuppression 49. Slots J. Herpesviral-bacterial synergy in the pathogenesis of hu- and gingival overgrowth: gene and protein expression pro- man periodontitis. Curr Opin Infect Dis. 2007;20(3):278-283. files of collagen turnover in FK506-treated human gingival 50. Peterson DE, Minah GE, Overholser CD et al. Microbiology of fibroblasts. J Clin Periodontol. 2005;32(2):167-173. acute periodontal infections in myelosuppressed cancer pa- 33. Gagliano N, Moscheni C, Torri C, et al. Differential effect tients. J Clin Oncol. 1987;5(9):1461-1486. of cyclosporin A and FK 506 on SPARC mRNA expres- 51. Hassell TM, Roebuck S, Page RC, et al. Quantitative histo- sion by human gingival fibroblasts. Biomed Pharmacother. pathologic assessment of developing phenytoin-induced 2005;59(5):249-252. gingival overgrowth in the cat. J Clin Periodontol. 1982; 34. Margreiter R, Pohanka E, Sparacino V, et al.; the European 9(5):365-372. Switch to Tacrolimus Study Group. Open prospective mul- 52. Fu E, Nieh S, Wikesjo UM. The effect of plaque retention ticenter study of conversion to tacrolimus therapy in renal on cyclosporin-induced gingival overgrowth in rats. J transplant patients experiencing ciclosporin-related side- Periodontol. 1997;68(1):92-98. effects. Transpl Int. 2005;18(7):816-823. 53. Varga E, Lennon MA, Mair LH. Pre-transplant gingival hyper- 35. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ plasia predicts severe cyclosporin-induced gingival over- transplantation [review]. N Engl J Med. 2003;348(17):1681- growth in organ transplant patients. J Clin Periodontol. 1998; 1691. 25:225-230. 36. Spolidorio LC, Spolidorio DMP, Massucato EMS, et al. Oral 54. Thomas DW, Newcombe RG, Osborne GR. Risk factors in the health in renal transplant recipients administered cyclospo- development of cyclosporine-induced gingival overgrowth. rine A or tacrolimus. Oral Dis. 2006;12(3):309-314. Transplantation. 2000;69(4):522-526. 37. Regev E, Zeltser R, Lustmann J. Lip carcinoma in renal allo- 55. Seymour RA, Smith DG. The effect of a plaque control pro- graft recipient with long-term immunosuppressive therapy. gramme on the incidence and severity of cyclosporin-induced Oral Surg Oral Med Oral Pathol. 1992;73(4):412-414. gingival changes. J Clin Periodontol. 1991;18(2):107-110. 38. Thomas DW, Seddon SV, Shepherd JP. Systemic immunosup- 56. Somacarrera ML, Lucas M, Scully C, et al. Effectiveness pression and oral malignancy: a report of a case and review of periodontal treatments on cyclosporine-induced gin- of the literature. Br J Oral Maxillofac Surg. 1993; 31(6):391- gival overgrowth in transplanted patients. Br Dent J. 393. 1997;183(3):89-94.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 44A

0709gr_44 a44 9/14/07 10:57:46 AM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

57. Ellis JS, Seymour RA, Taylor JJ, et al. Prevalence of gingival endocarditis: guidelines from the American Heart Association: overgrowth in transplant patients immunosuppressed with a guideline from the American Heart Association Rheumatic tacrolimus. J Clin Periodontol. 2004;31(2):126-131. Fever, Endocarditis, and Kawasaki Disease Committee, 58. Atilla G, Kutukculer N. Crevicular fluid interleukin-1beta, tu- Council on Cardiovascular Disease in the Young, and the mor necrosis factor-alpha, and interleukin-6 levels in renal Council on Clinical Cardiology, Council on Cardiovascular transplant patients receiving cyclosporine A. J Periodontol. Surgery and Anesthesia, and the Quality of Care and Outcomes 1998;69(7):784-790. Research Interdisciplinary Working Group. J Am Dent Assoc. 59. Williamson MS, Miller EK, Plemons J, et al. Cyclosporin-A 2007;138(6):739-745, 747-760. upregulates interleukin-6 gene expression in human gingiva: 73. Guggenheimer J, Mayher D, Eghtesad B. A survey of dental possible mechanisms for gingival overgrowth. J Periodont. care protocols among U.S. organ transplant centers. Clin 1994;65(10):895-903. Transplant. 2005:19;15-18. 60. Ioannidou E, Kao D, Chang N, et al. Elevated serum inter- 74. Lucas VS, Roberts GJ. Oral-dental health in children with leukin-6 (IL-6) in solid organ transplant recipients is positively chronic renal failure and after transplantation: a clinical associated with tissue destruction and IL-6 gene expression review [review]. Pediatr Nephrol. 2005;20(10):1388-1394. in the periodontium. J Periodontol. 2006;77(11):1871-1878. 75. Garland CG, McGonigal JJ, Frank A, et al. The transdisciplinary 61. Slots, J. Herpesviruses in periodontal diseases [review]. model of service delivery. Lightfoot, VA: Child Development Periodontology 2000. 2005;38:33-62. Resource.1989. 62. Mogensen TH, Paludan SR. Molecular pathways in vi- 76. De Rossi SS, Glick M. Dental considerations for the patient rus-induced cytokine production. Microbiol Mol Biol Rev. with renal disease receiving hemodialysis [review]. J Am 2001:65(1):131-150. Dent Assoc. 1996;127(2):211-219. 63. Mocarski ES. Virus self-improvement through inflammation: 77. Vesterinen M, Ruokonen H, Leivo T, et al. Oral health and no pain, no gain. Proc Natl Acad Sci, USA. 2002;99(6):3362- dental treatment of patients with renal disease. Quint Int. 3364. 2007;38(3):211-221. 64. Clark DA, Emery VC, Griffiths PD. Cytomegalovirus, human 78. Svirsky JA, Nunley J, Dent D, et al. Dental and medical con- herpesvirus-6 and human herpesvirus-7 in hematological siderations of patients with renal disease [review]. J Calif patients [review]. Semin Hematol. 2003;40(2):154-162. Dent Assoc. 1998;26(10):762-770. 65. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complica- 79. Massry SG, Ritz E. The pathogenesis of secondary hyperpara- tions of solid organ and hematopoietic stem cell transplan- thyroidism of renal failure: is there a controversy? Arch Intern tation [review]. Am J Resp Crit Care Med. 2004;170(1):22- Med. 1978;138(Spec No):853-856. 48. 80. Naugle K, Darby ML, Bauman DB, et al. Oral health status of 66. Contreras A, Umeda M, Chen C et al. Relationship between individuals in renal dialysis. Ann Periodontol. 1998;3(1):197- herpesviruses and adult periodontitis and periodontopathic 205. bacteria. J Periodontol. 1999;70(5):478-484. 81. Smith JM, Wong CS, Salamonik EB, et al. Sonic tooth brushing 67. Nowzari H, Jorgensen MG, Aswad S, et al. Human cytomega- reduces gingival overgrowth in renal transplant recipients. lovirus-associated periodontitis in renal transplant patients. Pediatr Nephrol. 2006;21(11):1753-1759. Transplant Proc. 2003;35(8):2949-2952. 82. Lee SC, Fung CP, Lin CC, et al. Porphyromonas gingivalis 68. Mutimer D, Mirza D, Shaw J, et al. Enhanced (cytomegalovi- bacteremia and subhepatic abscess after renal transplanta- rus) viral replication associated with septic bacterial com- tion: a case report. J Microbiol Immunol Infect. 1999;32(3):213- plications in liver transplant recipients. Transplantation. 216. 1997;63(10):1411-1415. 83. Vasanthan A, Dallal N. Periodontal treatment considera- 69. Paya CV, Weisner RH, Hermans PE, et al. Risk factors for cyto- tions for cell transplant and organ transplant patients. megalovirus and severe bacterial infection following liver Periodontology 2000. 2007;44(1):82-102. transplantation: a prospective multivariate time-dependent 84. Somacarrera ML, Hernández, G, Acero J, et al. Factors related analysis. J Hepatol. 1993;18(2):185-195.[Erratum: J Hepatol to the incidence and severity of cyclosporin-induced gingival 1993;19(2):325.] overgrowth in transplant patients. A longitudinal study. J 70. Mackowiak PA, Goggans M, Torres W, et al. Relationship Periodontol. 1994;65(7):671-675. between cytomegalovirus and colonization of the oropharynx 85. Jones CG. Chlorhexidine: is it still the gold standard? by gram-negative bacilli following renal transplantation. Periodontol 2000. 1997;15:55-62. Epidemiol Infect. 1991;107(2):411-420. 86. Pilatti GL, Sampaio JE. The influence of chlorhexidine on 71. Roberts GJ. Dentists are innocent! “Everyday” bacteremia the severity of cyclosporin A-induced gingival overgrowth. J is the real culprit: a review and assessment of the evidence Periodontol. 1997;68(9):900-904. [Erratum in: J Periodontol. that dental surgical procedures are a principal cause of 1998;69(1):102.] bacterial endocarditis in children [review]. Pediatr Cardiol. 87. Kantarci A, Cebeci I, Tuncer O, et al. Clinical effects of perio- 1999;20(5):317-325. dontal therapy on the severity of cyclosporine A-induced gin- 72. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective gival hyperplasia. J Periodont. 1999;70(6):587-593.

44B G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_44 b44 9/14/07 10:24:11 AM Chialastri, Suzuki. Dental implications for the immunocompromised organ transplant patient

88. Aimetti M, Romano F, Debernardi C. Effectiveness of perio- cyclosporine-induced gingival overgrowth with azithromycin- dontal therapy on the severity of cyclosporine A-induced gin- containing toothpaste. Exp Clin Transplant. 2006;4(1):420- gival overgrowth. J Clin Periodontol. 2005;32(8):846-850. 424. 89. Gomez E, Sanchez-Nunez M, Sanchez JE, et al. Treatment of 94. Al Nowaiser A, Lucas VS, Wilson M, et al. Oral health and cyclosporin-induced gingival hyperplasia with azithromycin. caries related microflora in children during the first three Nephrol Dial Transplant. 1997;12(12):2694-2697. months following renal transplantation. Int J Paediatr Dent. 90. Strachan D, Burton I, Pearson GJ. Is oral azithromycin effec- 2004;14(2):108-126. tive for the treatment of cyclosporin-induced gingival hyper- 95. Pilloni A, Camargo PM, Carere M, et al. Surgical treatment plasia in cardiac transplant recipients? J Clin Pharm Ther. of cyclosporin A- and nifedipine-induced gingival enlarge- 2003;28(4):329-338. ment: gingivectomy versus periodontal flap. J Periodontol. 91. Nowicki M, Kohot F, Wiecek A. Partial regression of advanced 1998;69(7):791-797. cyclosporin-induced gingival hyperplasia after treatment with 96. Ilgenli T, Atilla G, Baylas H. Effectiveness of periodontal therapy azithromycin. A case report. Ann Transplant. 1998;3(3):25- in patients with drug-induced gingival overgrowth. Long term 27. results. J Periodontol. 1999;70(9):967-972. 92. Mesa FL, Osuma A, Aneiros J, et al. Antibiotic treatment of 97. Rolland SL, Seymour RA, Wilkins BS, et al. Post-transplant incipient drug-induced gingival overgrowth in adult renal lymphoproliferative disorders presenting as gingival over- transplant patients. J Periodontol Res. 2003;38(2):141-146. growth in patients immunosuppressed with ciclosporin. A 93. Argani H, Pourabbas R, Hassanzadeh D, et al. Treatment of report of two cases. J Clin Periodontol. 2004;31(7):581-585.

44C G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_44 c44 9/14/07 10:26:18 AM Original Article

ORAL HEALTH AND CHRONIC KIDNEY DISEASE: BUILDING A BRIDGE BETWEEN

THE DENTAL AND RENAL Cheryl A. Thomas, RDH† COMMUNITIES Mandy Trolinger, MS, RD‡

Abstract An estimated 20 million Americans are diagnosed with chronic kidney disease (CKD), and another 20 million may be undiagnosed or at risk for kidney disease. Within this population are approximately 450,000 people in whom the disease has progressed to end stage renal disease (ESRD), requiring dialysis or renal transplantation to maintain essential life functions. Many of these patients living on dialysis are medically and dentally indigent. Although several medical care fi nancial assistance programs are available to patients with the role of oral health in systemic disease is often unrecognized or misunderstood. Patients with kidney disease are not only at an increased risk for infection, but also malnutrition, including vitamin and mineral defi ciencies and/or toxicities. The renal diet can be restrictive, which often makes it diffi cult to obtain adequate vitamins and minerals. Performing a physical assessment including an advanced nutrient assessment by evaluating the skin, eyes, nails, and the oral cavity can identify several nutrient defi ciencies. To improve patient outcomes, a collaborative plan between the dental and renal professions must be established to resolve access to care barriers, enhance transdisciplinary communication, implement evidence based practice, and establish favorable nutrition status. The registered dental hygienist and the registered dietitian, with their similar educational backgrounds, are ideal candidates to begin working in unison for the improved health of patients with renal disease.

Citation: Thomas C, Trolinger M. Oral health and chronic kidney disease: building a bridge between the dental and renal communities. Grand Rounds Oral-Sys Med. 2007;3:45-53. (Digital version Grand Rounds Oral-Sys Med. 2007;3:45-53a.) (A complimentary copy of this article may be downloaded at www.thesystemiclink.com.)

Key Words: Chronic kidney disease (CKD), renal disease, nephrology, end stage renal disease (ESRD), prerenal transplantation

Introduction he kidneys control 3 basic life functions: excretion of nitrogenous waste products; regulation of volume, composition, and acid-base balance of plasma; and synthesis of hormones necessary for erythrocyte production, Tbone metabolism, and maintaining blood pressure.1 When the kidneys are functioning correctly, we seldom notice their importance. Even in the early stages of renal disease, there are few noticeable physical symptoms.2 However, if renal function markedly decreases as a result of primary renal disease or as a secondary disease, systemic health suffers.3

The National Kidney Foundation estimates that 1 in 9 Americans (20 million adults) have chronic kidney disease (CKD), and that an additional 20 million Americans are at increased risk.2 Hypertension and non-insulin dependant diabetes mellitus4 (complicated by obesity)5 drive the epidemic of kidney disease (Figure 1). In addition, it is now recognized that mildly increased serum creatinine levels (as measured by standardized laboratory testing) are not a natural part of aging, but rather a red fl ag indicator for reduced renal function.2

Of the 20 million Americans living with kidney disease, approximately 470,000 are living with end stage renal † Consultant, Renal Support Network, Galveston, TX 6 disease (ESRD). Astonishingly, since 1983 this number has ‡ Renal Dietitian, DaVita-Littleton Dialysis, Renal Support almost tripled,6 and by the year 2030, more than 2 million Network, Highlands Ranch, CO

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 45

0709gr_45 45 9/14/07 4:07:18 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

diseases which are responsible for the deaths of millions Figure 1: End stage renal disease (ESRD) prevalence in 2004 of Americans each year.”12 Because the registered dental hygienist and the registered dietitian can identify patients ESRD Prevalence (2004) who are at risk for oral disease and malnutrition, they are 472,099 U.S. residents in an excellent position to refer patients to the appropriate healthcare professional.

Diabetes Several factors contribute to the need for continuing 172,938 education in oral-systemic medicine, including the high number of medically indigent CKD patients; marked Hypertension increases in medically complex ESRD patients; new clinical 114,481 guidelines (such as the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative [KDOQI]13 and Glomerulonephritis Dialysis Outcomes Practice Patterns Study [DOPPS]14); 77,121 and adverse effects of malnutrition. As new guidelines and directives are integrated into medical treatment for Cystic Kidney renal disease, dental providers should review the impact 21,397 that may be directly or indirectly infl uencing dental care (e.g., establishing whether or not antibiotic prophylaxis is All Other indicated for invasive dental treatment, and determining 86,162 whether the type of dialysis access used creates additional risk for infection). A strategic effort is needed to improve Reprinted from the National Kidney and Urologic Diseases Information access to dental care, enhance communication, implement Clearinghouse (NKUDIC), a service of the National Institute of Diabetes evidence-based practice, establish favorable nutrition and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the status, and improve patient outcomes. The registered National Institutes of Health of the U.S. Department of Health and dental hygienist and the registered dietitian, based on Human Services. NIH Publication No. 07–3895, May 2007. similar educational backgrounds, can begin a process of transdisciplinary communication, working collaboratively people are likely to be receiving treatment for kidney toward recognizing and resolving existing voids in patient failure.7 Because the early stages of kidney disease are care.15 typically asymptomatic, many patients (unaware of their risk for kidney disease) wait to seek medical care until Enhancing transdisciplinary communication renal disease has progressed to ESRD.8 Unfortunately, How can both the dental and renal communities ESRD is a bilateral, chronic, and progressive disease communicate effectively and effi ciently to keep up to characterized by irreversible destruction of the renal date on CKD, ESRD, and oral health? A transdisciplinary nephrons.9 Comorbidities are common with ESRD; approach may be the answer. This approach involves systemic complications associated with renal failure an interdisciplinary commitment to patient care, include: cardiovascular (hypertension, congestive heart wherein team members share responsibility for total failure, and pericarditis), gastrointestinal (anorexia, patient care and develop professional relationships that nausea, vomiting, generalized gastroenteritis, peptic ulcer provide specialized learning that should improve patient disease, stomatitis, and candidiasis), neuromuscular, outcomes.15 hematologic, and dermatologic systems.10 As a result, clinical management of ESRD patients often extends into Dental hygienists and registered dietitians — shared multiple disciplines of medicine. educational background. The registered dental hygienist and the registered dietitian have a similar educational Financial constraints and challenges within the renal background of basic science courses including general population are commonplace; however, fi nancial assistance chemistry, anatomy, physiology, biochemistry, micro- for medical (but not dental) care is available.11 According biology, pathology, nutrition, and pharmacology that will to the American Dental Hygienists Association (ADHA), enhance transdisciplinary communication.16 In addition, barriers to oral health care are a critical issue in the preventive care is a major focus of oral and nutritional United States due to disparities in the healthcare delivery care.16 Although the minimal educational requirements system.12 In the ADHA 2001 Access to Care position paper to become a registered dental hygienist vary from state (part of the Surgeon General’s 2000 report, Oral Health to state, the minimal educational requirement to become in America), untreated poor oral health is described as, a registered dietitian is a bachelor’s degree, dietetic “a silent epidemic promoting the onset of life-threatening internship, and completion of a registration examination.17

46 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_46 46 9/14/07 4:07:45 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

However, the complexity of care for patients with ESRD the NKF has released guidelines13, with topics including reinforces the need for a higher level of education for the vascular access for dialysis treatments, diabetes, dental hygienist; such requirements would be met through hemodialysis and peritoneal dialysis adequacy, anemia, the ADHA proposed Advanced Dental Hygiene Practitioner nutrition, dyslipidemia, bone metabolism, hypertension, designation, whereby competency is established with cardiovascular disease (CVD), and CKD itself. At present, a Master’s Degree.12 These higher minimal educational the K/DOQI guidelines do not specifi cally address oral requirements would enhance communication between health or the complications associated with it; however, the registered dental hygienist and registered dietitian. they do address several aspects of care that indirectly affect oral health. In accordance with new scientifi c practice Role of patient participation in transdisciplinary care. It is evidence through the Dialysis Outcomes Practice Patterns the opinion of both authors that motivating patients with Study21, the medical and dental clinical recommendations CKD to increase their own involvement in the healthcare for patients living with ESRD are sure to be altered and process can result in decreased infections, decreased interdisciplinary communication will become even more hospitalizations, and improved outcomes. For example, imperative. A comprehensive list of K/DOQI topics can be dental providers can facilitate patient involvement by found at the National Kidney Foundation K/DOQI website involving other care team members in development and at http://www.kidney.org/professionals/kdoqi/guidelines.cfm. delivery of pre- and postoperative clinical instructions. This can ameliorate patient frustration due to common Dialysis Outcomes and Practice Patterns Study (DOPPS). neurological side effects such as confusion, paranoia, DOPPS is an ongoing global research program and apathy, and thus engage patients in the oral hygiene studying clinical practice trends and patient outcomes necessary to improve outcomes.18 These authors strongly from international hemodialysis studies.21 Countries believe — based on our personal experience with ESRD and participating in DOPPS research include Australia, our credentials as allied healthcare providers — that dental Belgium, Canada, France, Germany, Italy, Japan, New and medical providers must also assess patient quality of Zealand, Spain, Sweden, the United Kingdom, and the life issues. Such issues include overall happiness, sense of United States.22 well-being, ability to continue working or exercising, and the current knowledge, skills, or motivation to prevent DOPPS research is unique in its longitudinal approach, comorbidities such as diabetes, hypertension, etc. This with a focus on the full range of unit practice patterns assessment, which could be done by the patient’s dialysis which may relate to clinically important patient outcomes, social worker or during the patient’s dental assessment and with comorbidity factors adjusted to a greater extent interview, can offer providers valuable insights toward than previously possible.21 Furthermore, international improving patient care. Furthermore, when the patient participation provides an unprecedented comparison of is invited into the decision-making process, adherence variability in practice patterns and outcomes.21 This will to healthcare recommendations, and therefore patient enhance an understanding of the relationships between outcomes, are improved. For these reasons, we believe various treatment effects and patient outcomes.21 that patient participation is an essential factor in the success of transdisciplinary care. The DOPPS hypothesis is that differences in practice patterns correlate with outcome differences, and patient Evidence-based dental management of patients living outcomes will improve through better understanding of the with CKD/ESRD associated factors.21 Based on this hypothesis, there will be Kidney Disease Outcome Quality Initiative (K/DOQI a large infl ux of new information regarding patient care guidelines). Between 1989 and 1999, the incidence and over the next several years. Like the K/DOQI Guidelines, prevalence of ESRD doubled.19 As a result, in 1999, the DOPPS research does not include oral healthcare National Kidney Foundation’s K/DOQI guidelines became recommendations for patients living on dialysis. However, an integral part of nephrology practice throughout the it does contain a plethora of clinical research that has U.S.19 Since its inception, the objective of K/DOQI guidelines an indirect association with oral health, i.e., vascular has been to improve quality of care and patient outcomes access, CVD, and secondary hyperparathyroidism.14 Both of all patients living with kidney disease by developing nephrology and dental professionals will greatly benefi t clinical practice guidelines for the management of patients from this emerging evidence-based research. More in various stages of kidney disease.19 information about DOPPS is available at http://www. dopps.org/data_request.aspx. The K/DOQI guidelines represent the fi rst comprehensive effort to provide evidence-based guidance for development Treatment modalities for patients with CKD and ESRD. of strategies that would have a measurable impact on Treatment modalities for patients with CKD and ESRD quality of life in patients receiving dialysis.20 Since 1997, vary.19 For patients living with CKD, results can be very

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 47

0709gr_47 47 9/14/07 4:08:12 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

favorable if the disease is detected early.19 With early metabolism in patients with diabetes undoubtedly play a detection and implementation of angiotensin-converting major role in susceptibility to infection and periodontal enzyme inhibitors (ACE inhibitors) or angiotensin disease.30 Uncontrolled or poorly controlled diabetes has receptor blockers (ARBs), loss of renal function can often been associated with increased susceptibility and could be prevented or delayed.23 However, the early stages of alter oral fl ora for years prior to dialysis therapy.30 Because renal disease are typically asymptomatic, and treatment is patients living with diabetes represent one of the largest frequently delayed until ESRD.2 Treatment modalities for sectors of the dialysis population, and often present with ESRD include solid organ transplantation, hemodialysis, complex medical histories, clinical management requires and peritoneal dialysis.24 The United Network for Organ skillful communication and understanding of these Sharing reports that over 96,000 people are currently multifaceted medical issues. solid organ waiting list candidates.25 Of the candidates listed, an overwhelming number (over 70,000) are patients Cardiovascular disease is the major cause of morbidity and awaiting renal transplantation.25 Although current mortality in patients with CKD (including renal transplant treatment modalities for ESRD are not a “cure” for ESRD, recipients).31 Researchers recently confi rmed that there is the miracle of organ transplantation offers those living a direct relationship between high serum phosphorus levels with ESRD a less inhibited lifestyle than would be feasible and CVD.32 Cardiovascular complications of CKD include: with hemodialysis or periotoneal dialysis. However, renal left ventricular hypertrophy (secondary to anemia and/or transplantation does come with signifi cant risks for hypertension), cardiac failure, hypertension, pericarditis, cardiovascular disease and infection.4 progressive arteriosclerosis, cardiac arrhythmias (due to hyperkalemia), and calcinosis.33 Infective endocarditis Though the renal transplant community is growing rapidly, occurs in 2-9% of patients receiving hemodialysis (a rate it is even more remarkable that over 70% of the estimated which is reported signifi cantly higher than in persons 470,000 patients with ESRD are receiving dialysis with rheumatic heart disease).28 With the recent update treatment.26 Although many patients may favor organ in antibiotic premedication guidelines for dentistry,34 transplantation as a treatment modality, contraindications medical and dental providers will need to carefully include various types of neoplastic disease, HIV infection, consider infection risk in patients on dialysis. Indeed, with AIDS, morbid obesity, smoking, some infectious processes, ongoing global research (DOPPS) and the high incidence active systemic disease, and irreversible vital organ of comorbidities in the dialysis population, more research failure.24 Furthermore, some patients may be fearful or is warranted in this area. uninterested in organ transplant therapy. Although dialysis is a lifesaving procedure, current treatment modalities Dental management of the patient with CKD/ESRD. As replace only 15% of renal function.27 Unfortunately, DOPPS research progresses, dental providers will need to this long-term accumulation of toxic waste and edema stay current with new ESRD treatment strategies. As oral- routinely leave the patient susceptible to other systemic systemic health research progresses, nephrologists will complications.28 similarly need to stay current with emerging information that affects patients with ESRD. With advancing medical expertise in the fi eld of nephrology, the life expectancy of ESRD patients will continue to The specifi c oral complications which are commonly increase, and the rising population of ESRD patients observed with ESRD patients include: pallor of the oral will require dental care.27 The dental and nephrology mucosa secondary to anemia, diminished salivary fl ow healthcare providers will need to communicate and resulting in chronic dry mouth and parotid infections collaborate in providing quality care to this expanding due to severe fl uid restrictions, patients frequently immuno“complex” population. complain of a metallic-like taste, and the saliva often has an ammonia- type odor due to uremia.10 Also noted are CKD risk factors: diabetes, CVD. Patients with diabetes, stomatitis, and radiographic evidence of loss of lamina hypertension, and a family history of renal disease are dura, demineralized bone, and localized radiolucent jaw at highest risk for CKD.2 (African Americans, Hispanics, lesions.10 Pacifi c Islanders, Native Americans, and seniors are also at high risk.)2 Among all new cases of ESRD in 2004, 70% had Anemia. Oral complications of the dialysis patient include diabetes, 80% had hypertension29 and, more than 35% of pallor of the oral mucosa due to impaired secretion of all new patients starting dialysis are living with diabetes.27 the hormone erythropoietin, resulting in anemia.28 Regardless of the dialysis treatment modality, patients Hematological complications found in the patients with living with diabetes generally show evidence of wasting ESRD are anemia (due to low erythropoietin), platelet and malnutrition.30 The collective effects of altered cellular dysfunction, and impaired cell-mediated immunity.35 response, impaired tissue integrity, and altered collagen Dental patients who have CKD or who are receiving

48 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_48 48 9/14/07 4:08:38 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

Figure 2: Mature/pronounced elbow primary Figure 3: AV graft, which can resemble an AV ﬁ stula AV ﬁ stula

responsible for monitoring mineral balance, while calcitriol regulates intestinal calcium absorption. PTH also controls the renal excretion of phosphorus, increases serum calcium by releasing calcium from bone and increasing calcium reabsorption by the kidney. Calcitriol synthesis is also increased by PTH.

Both radiography and laboratory testing of intact PTH hormone are very important in the investigation and diagnosis of secondary hyperparathyroidism.37 Although Brown tumors (osteoclastomas, i.e., dialysis treatments may have new, recurrent, or radiolucent cysts associated with renal osteodystrophy) undiagnosed anemia; therefore, the registered dental had been more commonly associated with primary hygienist should alert the renal healthcare team if signs hyperparathyroidism, they are increasingly being of anemia are present during a dental visit. seen with renal osteodystrophy in patients with ESRD, and may be evident on panoramic and periapical Uremic stomatitis and xerostomia. Stomatitis and radiographs.37 Extraosseous calcifi cations are more xerostomia are prevalent in patients on dialysis. common in secondary hyperparathyroidism than Stomatitis is characterized by burning red mucosa, and primary hyperparathyroidism, and can manifest as can interfere with vital nutritional intake (e.g., calcium, tumoral calcifi cation associated with bone erosions, phosphorus) in patients on dialysis.30 Xerostomia is chondrocalcinosis, vascular calcifi cation, calcifi ed common due to strict fl uid restrictions and adverse side pulmonary nodules, cerebral subcortical calcifi cation, effects of medications.28 Other conditions may coexist or calcifi cation within the eyes, layering of soft-tissue contribute to stomatitis and xerostomia.28 Diagnosis and calcifi cation, cardiac calcifi cations, renal calcifi cation, treatment of oral complications are critical; if untreated, and hepatic calcifi cation.37 Because secondary these conditions undoubtedly impair the ability for most hyperparathyroidism is radiographically evident patients to obtain adequate nutrition. (radiolucent Brown tumors, radio opaque carotid calcifi cations, and radio opaque calcifi cations found in Bone and mineral metabolism. Mitch and Klahr36 describe soft tissues), dental professionals can help screen patients the following metabolic process. As kidney function with ESRD for subtle and extreme manifestations of declines, calcitriol production and phosphorus excretion secondary hyperparathyroidism, through routine dental decrease, which results in phosphorus retention and intraoral and extraoral radiographs. contributes to the development of hyperparathyroidism. Parathyroid hormone (PTH) and 1,25-dihydroxycholecal- Vascular access in patients receiving dialysis: ciferol (calcitriol), the active form of vitamin D, regulate impact on dental care calcium and maintain phosphorus levels. PTH is mostly Patients receiving dialysis treatments (for photographs

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 49

0709gr_49 49 9/14/07 4:09:06 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

of a dialyzer and hemodialysis Table 1 delivery system, see the Clinical Oral symptoms of common vitamin and mineral deﬁ ciencies in patients Decision-Making Tools section at on dialysis www.thesystemiclink.com) have different access options for the site Vitamin Function Oral Symptoms of Defi ciency at which blood will be removed and returned during dialysis, B Vitamins Part of metabolic pathways Cheilosis of the lips, angular including:38 involved in energy production, cheilitis (can also result from • Arteriovenous (AV) fi stula nucleic (DNA and RNA) synthesis, poorly fi tting dentures), (Figure 2) — a surgical procedure some neural processes46 fi liform atrophy, bald tongue47 that connects an artery and vein •Thiamin (B1): Apthous ulcers together through anastomosis, on the tongue47 which matures and/or develops •Ribofl avin (B2): Magenta providing a permanent dialysis colored tongue47 access site. •Niacin (B3): Scarlet glossitis, • AV graft (Figure 3) — a synthetic fi liform papillae progressing tube implanted under the skin in to complete atrophy47 the arm; this is an artifi cial vein •Pyridoxine (B6): Filiform used for the dialysis access. papillary hypertrophy, • Central venous catheter glossodynia47 — a plastic catheter with 2 •Cobalamin (B12): Filiform lumens is inserted into a vein papillary atrophy, glossitis, in either the neck, chest, or leg glossodynia, pale or scarlet near the groin; used as a temporary tongue, aphthous ulcers47 access when other access sites fail, •Folic acid: Pale lips, pale or advanced planning for dialysis tongue, aphthous ulcers47 is not possible. Vitamin C Antioxidant, aids in iron Bleeding gums, tooth loss, Infection of the dialysis access absorption, participates in gingivitis47 area (regardless of type of access) collagen synthesis, neurotransmitter is an ongoing concern, and can synthesis, reduces infl ammation result in septicemia, septic emboli, due to its role in prostaglandin infective endarteritis, and infective synthesis48 endocarditis.28 It is critical that dental providers understand the Iron Energy production, part of Pale lips/tongue, fi liform rate of infection for each type of hemoglobin that helps carry oxygen atrophy, bald tongue, scarlet access when deciding if antibiotic throughout the body46 tongue, atrophied tongue47 premedication is appropriate. Furthermore, blood pressure Zinc Assists in immune function, Extraoral dermatitis, should not be taken in the arm growth and development, infl uences lichenifi cation around the used for dialysis access, and the behavior and learning performance, mouth, peeling of lips, angular patient should not be positioned wound healing, taste perception46 cheilitis,47 poor taste acuity43 in a way that increases pressure on the arm with the dialysis access. However, dental providers are generally unable to people living with ESRD.28 Therefore, the current oral visually differentiate between the different types of access health focus should now shift to oral biofi lms and its (Figures 2 and 3). Therefore, it is important for dental systemic ramifi cations. ESRD patients are at high risk providers to have a comprehensive understanding of the for pneumonia;40 therefore, education should be focused various areas for vascular access in their patients who toward its prevention. Other respiratory complications are undergoing dialysis treatments, to facilitate optimal of the ESRD patient include: infection, hyperventilation patient outcomes. (Kusmaul’s respiration — secondary to acidosis), and pulmonary edema (secondary to left-sided cardiac Impact of oral biofi lms and pneumonia in patients with failure).41 ESRD Due to uremia, there is a low incidence of decay in A strong relationship has been established between

50 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_50 50 9/14/07 4:09:43 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

morbidity and mortality.36,43 As Table 2 mentioned earlier calcium and Food sources high in vitamins B and C, and trace minerals iron and zinc phosphorus balance is important. Vitamin Food Sources Calcium imbalances can lead to neural and/or muscular problems,44 and in combination with Thiamin (B1) Ham, legumes, liver, nuts, pork, whole-grain or enriched breads phosphorus imbalances, can result and cereals46 in secondary hyperparathyroidism and calcium deposits in the blood Ribofl avin (B2) Cottage cheese, leafy green vegetables, meat, milk, yogurt, vessels.43 Potassium imbalances whole-grain or enriched bread and cereals46 can lead to cardiac arrhythmia and muscle weakness, which can Niacin (B3) Beef, brewer’s yeast, Cornish game hen, highly fortifi ed result in cardiac arrest.43 Many breakfast cereal, poultry, swordfi sh, trout, tuna, veal47 vitamin and mineral imbalances can occur in patients on dialysis. Pyridoxine (B6) Beef, fortifi ed oatmeal, highly fortifi ed ready-to-eat cereals, These imbalances can result pasta, rice, soy-based meat substitutes47 from poor appetite, depression, gastrointestinal symptoms, diffi culty Cobalamin (B12) Beef, clams, crab, herring, highly fortifi ed ready-to-eat cereals, chewing and/or swallowing, milk, organ meats, oysters, salmon, shellfi sh, trout, tuna47 and diffi culty with grocery shopping and cooking;45 or, due Folic Acid Leafy green vegetables, legumes, liver, seeds46 to the dialysis process, dietary restrictions, excretion alterations Vitamin C Citrus fruits, potatoes, tomatoes, tomato juice47 to maintain homeostasis, dialysate contamination.36 If patients on Iron Beef, iron fortifi ed breads or cereals, lamb, veal47 dialysis are nutrient defi cient, the defi ciency tends to be in water Zinc Beef, bran cereal, bread, eggs, liver, milk, pork, wheat germ47 soluble vitamins (B and C) more than the fat soluble vitamins, usually periodontal disease and bacterial pneumonia.42 The due to the dialysis process;43 and, in the trace minerals iron personal experience of the author (Thomas) is that few and zinc.36,46 Certain vitamin and mineral imbalances can adjunct nephrology providers are aware of current oral/ be identifi ed within the oral cavity of the patient on dialysis systemic research. In addition, education about medical (Table 1).47 complexities in the ESRD population is underemphasized in the oral health profession. Therefore, in the authors’ Water-soluble vitamins are absorbed directly into the blood opinion, a synergistic effort between the registered dental and easily travel throughout the body. Healthy kidneys hygienist and the registered dietitian could result in a manage these vitamins and excrete them as needed. These reduced incidence of bacterial pneumonia in the ESRD vitamins are usually found in the liquid compartments of population and improved patient outcomes. food. On the other hand, fat-soluble vitamins are found in fats and oils of food. Fat-soluble vitamins must enter the Impact of nutritional defi ciencies on oral-systemic lymph before entering the blood and they require protein health in patients with CKD/ESRD carriers in order to move throughout the body. Since these Nutrition is a vital part of care for patients with CKD or vitamins tend to become trapped in fat-associated cells, ESRD. Diet modifi cations for these patients can include, and the kidneys are not aware of the fat-soluble vitamins, but are not limited to, adjustments in protein, potassium, the excess is not excreted. Overall, fat-soluble vitamins phosphorus, calcium, vitamins, and mineral intake.43 can be ingested occasionally to maintain adequate levels, Recommendations generally include increasing high value however most water-soluble vitamins do not remain in the protein (animal sources) intake, lowering phosphorus body, so they must be consumed more often.46 intake, restricting potassium (depending on dialysis modality and residual renal function), and restricting Defi ciency in fat-soluble vitamins (D, E, A, and K) is not as fl uids to maintain fl uid status.43 common as water soluble vitamin defi ciency in patients with renal disease; however, toxicities can occur.43 Vitamin Maintaining adequate protein stores improves the healing A or E supplementation is not recommended.43 The dialysis process, maintains oncotic pressure, and decreases process does not remove vitamin A and renal excretion

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 51

0709gr_51 51 9/14/07 4:10:10 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

is diminished to almost none.43 High levels of vitamin Although organ transplantation is often the favored A may be related to anemia, atherosclerosis, problems treatment modality for ESRD, an overwhelming number of the retina, hypercalcemia,43 and dark margination of patients are currently awaiting organ donation for of alveolar ridge.47 Vitamin E supplementation is not renal transplantation, and many patients do not qualify. recommended, as more research is needed in this area.43 Some patients refuse renal transplantation. As evidence- However, vitamin E defi ciency can cause aphthous ulcers based practice evolves in nephrology and dentistry, a of the tongue.47 Supplementation of vitamin K is not structured means of communication and education must recommended due to its involvement in clot formation or be established between these two disciplines. Without patients on anticoagulant therapy.43 Lastly, active vitamin such collaboration, dental treatment could result in injury D analogues are used as a treatment for suppressing the or infection to the dialysis access (or sepsis), and medical parathyroid gland,43 and inactive vitamin D supplements care may be complicated by systemic conditions resulting are being used more in the kidney setting; however, more from dental infection and oral biofi lms (e.g., diabetes and research is needed in this area.49,50 pneumonia). Successful long-term outcomes, for patients on dialysis or awaiting renal transplant, will depend Managing nutritional defi ciencies in patients with CKD/ on this collaboration. The transdisciplinary care team ESRD. In order to correct some of the nutrient defi ciencies, would benefi t from contributions by the registered dental most patients on dialysis take a renal vitamin consisting hygienist and registered dietitian, who share a similar primarily of a B-vitamin complex with some vitamin C. It educational background, and offer professional expertise is important that patients refrain from taking the vitamin that can minimize access to care barriers, enhance before treatment, since most of the vitamin will be lost due transdisciplinary communication, implement evidence- to the dialysis process.43 A patient can also focus on foods based practice, establish favorable nutritional status, and (within the patient’s renal diet) high in certain vitamins ultimately, improve patient outcomes. and minerals (Table 2). Through improved screening, education, and consultation/referral, registered dental References hygienists and registered dietitians can work together to 1. Bricker SL, Langlais RP, Miller CS. Oral Diagnosis, Oral improve the oral-systemic health of patients with CKD/ Medicine, and Treatment Planning. Philadelphia, PA: Lea & ESRD (Table 3). Fibiger; 1994. 2. National Kidney Foundation. The facts about chronic kidney Conclusion disease (CKD). 2007. Available at: http://www.kidney.org/ The patient receiving hemodialysis treatment for kidneydisease/ckd/index.cfm. Accessed July 24, 2007. ESRD often presents with comorbidities and a complex 3. Langman CB. The epidemic of chronic kidney disease. medical history. As the prevalence of ESRD continues Medscape General Medicine. 2006;8(3):55. Available at: http:// to escalate in the U.S., dental professionals will see an www.medscape.com/viewarticle/543683. Accessed May 20, unprecedented number of patients with CKD and ESRD. 2007.

Table 3 Strategies to achieve effective integration of oral health and nutrition services for patients with CKD/ESRD

Strategies for the... Level of Care Registered Dental Hygienist (RDH) Registered Dietitian (RD)

Screening Include diet screening, education, and referral for Include oral health screening in nutrition oral infectious disease prevention/control, optimal assessment protocols masticatory function and management of other oral diseases as a component of comprehensive dental care

Education Provide diet and nutrition education consistent Recognize oral manifestations of systemic with the Dietary Guidelines for Americans diseases and provide patients with dietary (http://www.health.gov/dietaryguidelines) guidance to maximize oral intake

Consultation/ Consult with and refer patients to registered dietitians Confer with and refer patients to dental Referral for management of nutrition risk due to compromised professionals for management of oral oral health (e.g., ESRD, xerostomia, diabetes) diseases and/or risk factors for oral diseases

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 52

0709gr_52 52 9/14/07 4:10:43 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

4. National Kidney and Urologic Diseases Information 20. National Kidney Foundation. K/DOQI Guidelines 2000: Clearinghouse. Kidney and urologic diseases statistics for History of DOQI. 2001. Available at: http://www.kidney.org/ the United States. Available at: http://kidney.niddk.nih.gov/ professionals/kdoqi/guidelines_updates/doqi_up_foreword. kudiseases/pubs/kustats/index.htm. Accessed May 30, 2007. html. Accessed May 28, 2007. 5. Cignarelli M, Lamacchia O. Obesity and kidney disease. Nutr 21. Arbor Research Collaborative for Health. The Dialysis Metab Cardiovasc Dis. 2007 Jun 30; [Epub ahead of print] Outcomes and Practice Patterns Study (DOPPS) research 6. United States Renal Data System. 2006 ADR/Reference Tables approach. 2007. Available at: http://www.dopps.org/Approach. – Prevalence, Table B1. Available at: http://www.usrds.org/ aspx. Accessed May 27, 2007. reference.htm. Accessed July 24, 2007. 22. Arbor Research Collaborative for Health. People working on the 7. Szczech L, Lazar I. Projecting the United States ESRD population: Dialysis Outcomes and Practice Patterns Study (DOPPS). 2007. issues regarding treatment of patients with ESRD. Kidney Int Available at: http://www.dopps.org/People.aspx. Accessed May Suppl. 2004;(90):S3-7. 12, 2007. 8. National Kidney Foundation. National Kidney Foundation’s 23. Giatras I, Lau J, Levey AS. Angiotensin-converting-enzyme new KEEP Report shows risk factors for chronic kidney inhibition and progressive renal disease study group. Effect of disease still going unaddressed. November 14, 2005. Available angiotensin-converting enzyme inhibitors on the progression of at: http://www.kidney.org/news/newsroom/newsitem. nondiabetic renal disease: a meta-analysis of randomized trials. cfm?id=306. Accessed Aug 1, 2007. Angiotensin-Converting-Enzyme Inhibition and Progressive 9. De Rossi SS, Glick M. Dental considerations for the patient Renal Disease Study Group. Ann Intern Med. 1997;127(5):337- with renal disease receiving hemodialysis. J Am Dent Assoc. 345. [EDITOR NOTE for online edition: Full text article available 1996;127(2):211-9. [EDITOR’S NOTE for online edition: full at: http://www.annals.org/cgi/content/full/127/5/337] text article link is http://jada.ada.org/cgi/reprint/127/2/211] 24. Winsett RP, Martin J, Reed L, et al. Kidney transplantation. 10. University of Louisville School of Dentistry. Chronic renal In: Organ Transplantation: Concepts, Issues, Practice, and failure, dialysis, and dental management, P&G Dental Outcomes. Medscape; 2002. Available at: http://www.medscape. ResourceNet. Available at: http://www.dentalcare.com/soap/ com/viewarticle/443490_5. Accessed May 20, 2007. intermed/dialysis.htm. Accessed July 24, 2007. 25. United Network for Organ Sharing. 2007. Available at: http:// 11. Witten B. Financial Assistance is Available. Kidney Beginnings: unos.org/. Accessed June 9, 2007. The Magazine. June/July 2007. Available at: http://www.aakp. 26. United States Renal Data System. 2006 ADR/Reference Tables org/newsletters/KB-The-Magazine/Feature-Story/Financial- – Treatment Modalities, Tables D11, D14. Available at http:// Assistance/index.cfm. Accessed June 24, 2007. www.usrds.org/reference.htm. Accessed July 24, 2007. 12. American Dental Hygienists Association. ADHA access to care 27. Daugirdas JT, Blake PG, Ing TS. Handbook of Dialysis, Fourth facts & stats. 2007. Available at: http://www.adha.org/media/ Edition. Philadelphia, PA: Lippincott, Williams and Wilkins; facts/access.htm. Accessed May 31, 2007. 2006. 13. National Kidney Foundation. K/DOQI guidelines. 2007. Available 28. Little JW, Falace D, Miller C, et al. Dental Management of the at: http://www.kidney.org/professionals/kdoqi/guidelines.cfm. Medically Compromised Patient. 6th Edition. St. Louis, MO: Accessed May 12, 2007. Mosby; 2002. 14. Arbor Research Collaborative for Health. Dialysis Outcomes 29. United States Renal Data System. 2006 ADR/Reference Tables and Practice Patterns Study (DOPPS) — Publications. 2007. — Patient Characteristics, Table C17. Available at http://www. Available at: http://www.dopps.org/dopps_Pubs.aspx. Accessed usrds.org/reference.htm. Accessed July 24, 2007. May 12, 2007. 30. Newman MG, Takei H, Klokkevold PR, et al. Carranza’s Clinical 15. Garland CG, McGonigel JJ, Frank A, et al. The transdisciplinary Periodontology, 10th Edition. Philadelphia, PA: W.B. Saunders; model of service delivery. Lightfoot VA: Child Development 2006. Resources; 1989. 31. National Kidney Foundation. K/DOQI clinical practice guidelines 16. American Dental Hygienists Association. Earning a dental for cardiovascular disease in dialysis patients: Overview of hygiene education. 2006. Available at: http://www.adha.org/ epidemiology of cardiovascular disease. 2005. Available at: careerinfo/rdhedu.htm. Accessed May 21, 2007. http://www.kidney.org/professionals/KDOQI/guidelines_cvd/ 17. Commission on Dietetic Registration. 2007. Available at: http:// overview.htm. Accessed May 28, 2007. www.cdrnet.org/. Accessed June 11, 2007. 32. Foley RN. Phosphorus comes of age as a cardiovascular risk 18. Guidelines for the psychological management of chronic factor. Arch Intern Med. 2007;167(9):873-874. kidney disease patients (for the Psychologist). Indian J Nephrol. 33. Block G, Port FK. Calcium phosphate metabolism and 2005;15(Suppl 1):S103-S106. Available at: http://medind.nic. cardiovascular disease in patients with chronic kidney disease. in/iav/t05/s1/iavt05s1p103.pdf. Accessed July 31, 2007. Semin Dial. 2003;16(2):140-147. 19. National Kidney Foundation. K/DOQI CKD Guidelines: Evaluation, Classification, and Stratification. 2002. Available For additional references to this article, please consult the Grand Rounds in Oral-Systemic Medicine™ at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/ digital version of at www.thesystemiclink.com. p2_background.htm. Accessed April 7, 2007.

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 53

0709gr_53 53 9/14/07 4:11:11 PM Thomas, Trolinger. Oral health and chronic kidney disease ...

34. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective 2 diabetes: Systemic manifestations and exercise implications. endocarditis: guidelines from the American Heart Association: Phys Ther. 2004;84(5):454-463. a guideline from the American Heart Association Rheumatic 42. Suzuki N, Yoshida A, Nakano Y. Quantitative analysis of multi- Fever, Endocarditis, and Kawasaki Disease Committee, species oral biofilms by TaqMan Real-Time PCR. 2005. Clin Med Council on Cardiovascular Disease in the Young, and the Res. 2005;3(3):176-185. [EDITOR’S NOTE for online edition: Council on Clinical Cardiology, Council on Cardiovascular full text article available at: http://www.pubmedcentral.nih. Surgery and Anesthesia, and the Quality of Care and Outcomes gov/articlerender.fcgi?artid=1237159] Research Interdisciplinary Working Group. J Am Dent Assoc. 43. Byham-Gray L, Wiesen K. A Clinical Guide to Nutrition Care 2007;138(6):739-745, 747-760. in Kidney Disease. Chicago, IL: American Dietetic Association; 35. Zachée P, Vermylen J, Boogaerts MA. Hematologic aspects of 2004. end-stage renal failure [review]. Ann Hematol. 1994;69(1):33- 44. National Institutes of Health Office of Dietary Supplements. 40. Dietary supplement fact sheet: Calcium. Available at: http://ods. 36. Mitch WE, Klahr S (eds). Handbook of Nutrition and the Kidney, od.nih.gov/factsheets/calcium.asp#h8. Accessed July 24, 2007. 3rd edition. Philadelphia, PA: Lippincott-Raven Publishers; 45. Leon JB, Albert JM, Gilchrist G, et al. Improving albumin levels 1998:87-89. among hemodialysis patients: a community-based randomized 37. Khan AN, Jabeen F, Macdonald S. Hyperparathyroidism, controlled trial. Am J Kidney Dis. 2006;48(1):28-36. secondary. WebMD eMedicine, September 8, 2005. Available 46. Whitney E, Rolfes S. Understanding Nutrition, Seventh Edition. at: http://www.emedicine.com/radio/topic356.htm. Accessed St. Paul, MN: West Publishing Company; 1996. May 20, 2007. 47. McCann L, Kelly MP. Integrating physical findings into 38. National Kidney Foundation. K/DOQI guidelines 2000: advanced practice nutrient assessment. Unpublished. Guidelines for vascular access. 2001. Available at: http://www. Presented at the National Kidney Foundation 2007 Spring kidney.org/professionals/kdoqi/guidelines_updates/doqiupva_ Clinical Meeting, April 13, 2007; Orlando, Florida. i.html#doqiupva1. Accessed May 28, 2007. 48. Famiglietti MB. National Support Pocket Reference, Second 39. United States Department of Health and Human Services Edition. Tulsa, OK: Specialty Cards; 2000. Centers for Medicare and Medicaid Services. Fistula first 49. Saab G, Young DO, Gincherman Y, et al. Prevalence of vitamin breakthrough. Available at: http://www.cms.hhs.gov/ESRDQua D deficiency and the safety and effectiveness of monthly lityImproveInit/04_FistulaFirstBreakthrough.asp#TopOfPage. ergocalciferol in hemodialysis patients. Nephron Clin Pract. Accessed June 10, 2007. 2007:105(3):c132-8. 40. Kumar S. Inflammation and infection: implications for chronic 50. Taskapan H, Wei M, Oreopoulos DG. 25(OH) vitamin D3 in and end-stage kidney disease. 2003. Available at: http://www. patients with chronic kidney disease and those on dialysis: medscape.com/viewprogram/2832_pnt. Accessed July 24, 2007. rediscovering its importance. Int Urol Nephrol. 2006;38(2):323- 41. Evans N, Forsyth E. End-stage renal disease in people with type 329.

53A G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_53 a53 9/14/07 10:15:54 AM As a courtesy to the professions, Grand Rounds in Oral- Systemic MedicineTM has provided patient education materials and templates of letters to assist dentists in developing collaborative relationships with the medical TOOLS FOR community. Readers are invited to reproduce these copyrighted materials by accessing and downloading (for free) this information from www.thesystemiclink.com.

To download a fi le of this patient education information, go to: www.thesystemiclink.com Valuable Opportunity for Student Participation ...

Editor’s Note: Our best and brightest dental and dental hygiene students have an opportunity to actively participate in the design and development of important patient education materials. This not only enhances students’ educational experiences but it also provides them with useful publication skills so that they can become the next generation of journal contributors and effective advocates for the clinically applied mission of Grand Rounds. The honor of being selected as the student author of patient education materials is offered to students at all dental and dental hygiene schools. We encourage faculties who work with promising students to submit their names for consideration for this honorary invitation to contribute to the editorial mission of Grand Rounds.

In this issue of Grand Rounds, we are happy to recognize Kristin Haun, senior dental hygiene student at the University of Colorado (with oversight from faculty mentor Dr. Terri Tilliss), for her excellent work in preparing the patient education tool for implementation entitled “The Compromised Immune Dr. Terri Tilliss (left) with senior dental System and Your Mouth”. Thank you, Kristin. — CH hygiene student Kristin Haun.

54 G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3

0709gr_54 54 9/14/07 3:58:47 PM IMPLEMENTATION

To assist dentists in developing collaborative relationships with the medical community, Grand Rounds in Oral-Systemic Medicine™ has provided templates for dentists working in collaboration with physicians of at-risk patients.

This letter may be customized for individual patients by editing the fi elds (which appear in red typeface) as they relate to the unique risk profi le and periodontal treatment plan of a specifi c patient.

A Microsoft Word document of this template may be downloaded at: www.thesystemiclink.com

G RAND ROUNDS IN ORAL-SYSTEMIC MEDICINE • SEPTEMBER 2007 • VOL. 2, NO. 3 55

0709gr_55 55 9/14/07 3:59:19 PM Ad Sales Need CE? East: “Easy as 1, 2, 3” Chris Page 1. Log on to www.ineedce.com (518) 373-0622 2. Select and review course

3. Enter answers & payment information Graded Instantly! Key Accounts: Print off veriﬁ cation Craig Dickson form immediately! (630) 690-2472 More Courses Added Every Month!

Southeast: Courses: David Hurlbrink Cosmetic and restorative Oral-body connection Endodontics Orthodontics (717) 244-3148 Ergonomics Pathology Hygiene Periodontology Implants/surgery Pharmacology Infection control Prevention Midwest/West: Lasers Prosthodontics Latex allergy Radiology Amy Frazin, RDH Legal Tooth whitening Medical (773) 745-0202

Midwest/South: (216) 398-7822 The Academy of Dental Therapeutics and Stomatology is an ADA CERP Recognized Provider. Marvin R. Ashworth (918) 832-9266 Advertisers Index Advertiser Page

Colgate-Palmolive Company ...... C2 DENTSPLY Pharmaceutical ...... 7-8 DENTSPLY Pharmaceutical ...... 23 Diamond Age Systems ...... 5 Florida Probe Corporation ...... 3 OMNI Preventive Care, A 3M ESPE Company ...... C3, C4 P&G Professional Oral Health...... 11

0709gr_56 56 9/14/07 4:22:51 PM INDICATION: Peridex Oral Rinse is indicated for use between Additional time may be required to complete the reevaluated and given a thorough prophylaxis at intervals no dental visits as part of a professional program for the treatment prophylaxis. Discretion should be used when prescribing longer than six months. of gingivitis as characterized by redness and swelling of the to patients with anterior facial restorations with rough gingivae, including gingival bleeding upon probing. Peridex surfaces or margins. If natural stain cannot be removed Recommended use is twice daily rinsing for 30 seconds, Oral Rinse has not been tested among patients with acute from these surfaces by a dental prophylaxis, patients should morning and evening after tooth brushing. Usual dosage is 15ml necrotizing ulcerative gingivitis (ANUG). For patients having be excluded from Peridex Oral Rinse treatment if permanent of undiluted Peridex Oral Rinse. Patients should be instructed coexisting gingivitis and periodontitis, see PRECAUTIONS. discoloration is unacceptable. Stain in these areas may be to not rinse with water, or other mouthwashes, brush teeth, or difficult to remove by dental prophylaxis and on rare eat immediately after using Peridex Oral Rinse. Peridex Oral DESCRIPTION: Peridex is an oral rinse containing 0.12% occasions may necessitate replacement of these Rinse is not intended for ingestion and should be expectorated chlorhexidine gluconate (1,1’-hexamethylene bis[5-(p- restorations. after rinsing. chlorophenyl) biguanide] di-D-gluconate) in a base containing 3. Some patients may experience an alteration in taste water, 11.6% alcohol, glycerin, PEG-40 sorbitan diisostearate, perception while undergoing treatment with Peridex Oral HOW SUPPLIED: flavor, sodium saccharin, and FD&C Blue No.1. Peridex Rinse. Rare instances of permanent taste alteration following Peridex Oral Rinse is supplied as a blue liquid in: is a near-neutral solution (pH range 5-7). Peridex is a salt of Peridex Oral Rinse use have been reported via post- • 16 fl. oz. (473ml) (NDC 51284-620-22) chlorhexidine and gluconic acid. Its chemical structure is: marketing product surveillance. amber plastic bottles with child resistant dispensing closures • 4 fl. oz. (118ml) (NDC 51284-620-12) PREGNANCY: TERATOGENIC EFFECTS: Pregnancy amber plastic bottles with child resistant dispensing closures Category B. Reproduction studies have been performed • 64 oz. (NDC 51284-620-32) in rats and rabbits at chlorhexidine gluconate doses up to white plastic bottle with pump dispensing closure 300mg/kg/day and 40mg/kg/day respectively, and have not revealed evidence of harm to fetus. However, adequate and DIRECTIONS FOR USE: Swish 15ml (one tablespoon) well-controlled studies in pregnant women have not been done. undiluted for 30 seconds, then spit out. Use after breakfast and Because animal reproduction studies are not always predictive before bedtime. Or, use as prescribed. NOTE: To minimize CLINICAL PHARMACOLOGY: Peridex Oral Rinse of human response, this drug should be used during pregnancy medicinal taste, do not rinse with water immediately after use. provides antimicrobial activity during oral rinsing. The clinical only if clearly needed. significance of Peridex Oral Rinse’s antimicrobial activities is not WHAT TO EXPECT WHEN USING PERIDEX ORAL RINSE: clear. Microbiological sampling of plaque has shown a general NURSING MOTHERS: It is not known whether this drug is Peridex Oral Rinse is prescribed to treat gingivitis, to help reduce reduction of counts of certain assayed bacteria, both aerobic and excreted in human milk. Because many drugs are excreted in the redness and swelling of the gums, and also to help control anaerobic, ranging from 54-97% through six months use. Use of human milk, caution should be exercised when Peridex Oral any gum bleeding. Peridex Oral Rinse should be used regularly Peridex Oral Rinse in a six month clinical study did not result Rinse is administered to nursing women. In parturition and as directed by a dentist, in addition to daily brushing. Peridex in any significant changes in bacterial resistance, overgrowth of lactation studies with rats, no evidence of impaired parturition should be spit out after use. It should not be swallowed. potentially opportunistic organisms or other adverse changes in or of toxic effects to suckling pups was observed when the oral microbial ecosystem. Three months after Peridex Oral chlorhexidine gluconate was administered to dams at doses that Peridex Oral Rinse may cause some tooth discoloration, or Rinse use was discontinued, the number of bacteria in plaque were over 100 times greater than that which would result from a increase in tartar (calculus) formation, particularly in areas had returned to baseline levels and resistance of plaque bacteria person’s ingesting 30ml of Peridex Oral Rinse per day. where stain and tartar usually form. It is important to see to chlorhexidine gluconate was equal to that at baseline. a dentist for removal of any stain or tartar at least every six PEDIATRIC USE: months or more frequently if a dentist advises. PHARMACOKINETICS: Pharmacokinetic studies with Clinical effectiveness and safety of Peridex Oral Rinse have not • Both stain and tartar can be removed by your dentist Peridex Oral Rinse indicate approximately 30% of the active been established in children under the age of 18. or hygienist. Peridex Oral Rinse may cause permanent ingredient, chlorhexidine gluconate, is retained in the oral cavity discoloration of some front-tooth fillings. following rinsing. This retained drug is slowly released in the CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT • To minimize discoloration, you should brush and floss daily, oral fluids. Studies conducted on human subjects and animals OF FERTILITY: In a drinking water study in rats, carcinogenic emphasizing areas which begin to discolor. demonstrate chlorhexidine gluconate is poorly absorbed from effects were not observed at doses up to 38mg/kg/day. • Local hypersensitivity and sometimes generalized allergic the gastrointestinal tract. The mean plasma level of chlorhexidine Mutagenic effects were not observed in two mammalian in reactions have also been reported. Peridex Oral Rinse should not gluconate reached a peak of 0.206 µg/g in humans 30 minutes vivo mutagenesis studies with chlorhexidine gluconate. The be used by persons who have a sensitivity to it or its components. after they ingested a 300mg dose of the drug. Detectable levels highest doses of chlorhexidine used in a mouse dominant-lethal • Peridex Oral Rinse may taste bitter to some patients and can of chlorhexidine gluconate were not present in the plasma of assay and a hamster cytogenetics test were 1000mg/kg/day and affect how foods and beverages taste. This will become less these subjects 12 hours after the compound was administered. 250mg/kg/day, respectively. No evidence of impaired fertility noticeable in most cases with continued use of Peridex Oral Excretion of chlorhexidine gluconate occurred primarily was observed in rats at doses up to 100mg/kg/day. Rinse. through the feces (~90%). Less than 1% of the chlorhexidine • To avoid taste interference, rinse with Peridex Oral Rinse gluconate ingested by these subjects was excreted in the urine. ADVERSE REACTIONS: The most common side effects after meals. Do not rinse with water or other mouthwashes associated with chlorhexidine gluconate oral rinses are: 1) an immediately after rinsing with Peridex Oral Rinse. CONTRAINDICATIONS: Peridex Oral Rinse should not increase in staining of teeth and other oral surfaces; 2) an increase be used by persons who are known to be hypersensitive to in calculus formation; and 3) an alteration in taste perception; If you have any questions or comments about Peridex Oral chlorhexidine gluconate or other formula ingredients. see WARNINGS and PRECAUTIONS. Oral irritation and local Rinse, contact your dentist or pharmacist. allergy-type symptoms have been spontaneously reported as WARNINGS: The effect of Peridex Oral Rinse on periodontitis side effects associated with use of chlorhexidine gluconate rinse. STORE ABOVE FREEZING (32°F or 0°C) has not been determined. An increase in supragingival The following oral mucosal side effects were reported during Caution: Federal law prohibits dispensing without prescription. calculus was noted in clinical testing in Peridex Oral Rinse placebo-controlled adult clinical trials: aphthous ulcer, grossly users compared with control users. It is not known if Peridex obvious gingivitis, trauma, ulceration, erythema, desquamation, REFERENCES: 1. Data on file. OMNII Oral Pharmaceuticals. Oral Rinse use results in an increase in subgingival calculus. coated tongue, keratinization, geographic tongue, mucocele, 2. Briner WW, Kayrouz GA, Chanak MX. Comparative Calculus deposits should be removed by a dental prophylaxis and short frenum. Each occurred at a frequency of less than antimicrobial effectiveness of a substantive (0.12% at intervals not greater than six months. Hypersensitivity 1.0%. chlorhexidine) and a nonsubstantive (phenolic) mouthrinse and generalized allergic reactions have occurred. SEE in vivo and in vitro. Compendium. 1994 Sep;15(9):1158, CONTRAINDICATIONS. Among post marketing reports, the most frequently reported 1160, 1162 passim; quiz 1170. 3. Balbuena L. Stambaugh oral mucosal symptoms associated with Peridex Oral Rinse are KI, Ramirez SG, Yeager C. Effects of topical oral antiseptic PRECAUTIONS: stomatitis, gingivitis, glossitis, ulcer, dry mouth, hypesthesia, rinses on bacterial counts of saliva in healthy human subjects. GENERAL: glossal edema, and paresthesia. Otolaryngol Head Neck Surg. 1998 May; 118(5):625-9. 4. Gultz 1. For patients having coexisting gingivitis and periodontitis, J, Kaim JM, DeLeo J 4th, Scherer W. An in vivo comparison the presence or absence of gingival inflammation following Minor irritation and superficial desquamation of the oral mucosa of the antimicrobial activities of three mouthrinses. J Clin treatment with Peridex Oral Rinse should not be used as a have been noted in patients using Peridex Oral Rinse. Dent. 1998;9(2):43-5. 5. Logothetis DD, Martinez-Welles JM. major indicator of underlying periodontitis. Reducing bacterial aerosol contamination with a chlorhexidine 2. Peridex Oral Rinse can cause staining of oral surfaces, such There have been cases of parotid gland swelling and gluconate pre-rinse. J Am Dent Assoc. 1995 Dec;126(12):1634-9. as tooth surfaces, restorations, and the dorsum of the tongue. inflammation of the salivary glands (sialadenitis) reported in patients using Peridex Oral Rinse. Not all patients will experience a visually significant increase Manufactured for: in toothstaining. In clinical testing, 56% of Peridex Oral Zila Pharmaceuticals, Inc. OVERDOSAGE: Ingestion of 1 or 2 ounces of Peridex Oral Rinse users exhibited a measurable increase in facial anterior 5227 N. 7th Street Rinse by a small child (~10kg body weight) might result stain, compared to 35% of control users after six months; Phoenix, AZ 85014-2800 in gastric distress, including nausea, or signs of alcohol 15% of Peridex Oral Rinse users developed what was judged www.zila.com to be heavy stain, compared to 1% of control users after six intoxication. Medical attention should be sought if more than 4 months. Stain will be more pronounced in patients who have ounces of Peridex Oral Rinse is ingested by a small child or if Available from: heavier accumulations of unremoved plaque. Stain resulting signs of alcohol intoxication develop. OMNI Preventive Care, A 3M ESPE Company from use of Peridex Oral Rinse does not adversely affect 1500 N. Florida Mango Road, Suite 1 health of the gingivae or other oral tissues. Stain can be DOSAGE AND ADMINISTRATION: Peridex Oral Rinse West Palm Beach, FL 33409 removed from most tooth surfaces by conventional therapy should be initiated directly following a dental 1.800.445.3386 professional prophylactic techniques. prophylaxis. Patients using Peridex Oral Rinse should be www.omnipreventivecare.com Revision: December 2006

PERIDEX is a registered trademark of Zila Pharmaceuticals, Inc. © ZILA Pharmaceuticals, Inc. 2006 ZILA-22-2006 December 2006 Printed in USA.

0709gr_c3 c3 9/14/07 3:36:18 PM Fear Of Flossing?

Gingival bleeding? Make sure patients know it’s not the floss.

If patients are afraid to floss because their gums bleed, first let them know that it’s not the floss that is causing the problem and that daily flossing actually helps improve gum health. Then start the patient on PERIDEX® chlorhexidine gluconate 0.12% therapy, the oral rinse indicated for the treatment of gingivitis as characterized by redness and swelling of the gingivae, including gingival bleeding on probing. That’s a claim you will not hear from the makers of OTC mouthwashes. For more information, call 800-445-3386 or visit www.omnipreventivecare.com.

PERIDEX is indicated for use between dental visits as part of a professional program for the treatment of gingivitis. Patients with a known sensitivity to Chlorhexidine Gluconate should not use PERIDEX. The effect of PERIDEX on periodontitis has not been determined. Common side effects associated with the use of PERIDEX include an increase in the staining of oral surfaces, an increase in calculus formation, and an alteration in taste perception. Please see adjacent page for full prescribing information.

©3M 2007. 3M, ESPE and OMNI are trademarks of 3M or 3M ESPE AG. PERIDEX is a registered trademark of Zila Pharmaceuticals, Inc.

0709gr_c4 c4 9/14/07 3:36:35 PM REPORT OF THE INDEPENDENT PANEL OF EXPERTS OF THE SCOTTSDALE PROJECT

AUTHORS

Casey Hein, BSDH, MBA; Charles Cobb, DDS, PhD; Anthony Iacopino, DMD, PhD

INDEPENDENT PANEL OF EXPERTS

Charles Cobb, DDS, PhD; D. Walter Cohen, DDS; Möise Desvarieux, MD, PhD; Sheila Garris, MD, FACP; Casey Hein, BSDH, MBA; Anthony Iacopino, DMD, PhD; Evanthia Lalla, DDS, MS; Brian Mealey, DDS, MS; Lynnae Millar, MD; Steven Offenbacher, DDS, PhD, MMSc; Robert Ostfeld, MD, MS; David Paquette, DDS, MPH, DMSc; Shailesh Patel, BM, ChB, DPhil, FRCP; Louis Rose, DDS, MD; Maria Ryan, DDS, PhD; Sen Souvik, MD, MS, FAHA; Maurizio Trevisan, MD, MS; Karen Williams, RDH, PhD

The Scottsdale Project and the Report of the Independent Panel of Experts of The Scottsdale Project were funded by an unrestricted educational grant awarded to PennWell® Corporation by Colgate-Palmolive

0709GRsupp_rev_1 1 9/24/07 10:23:42 AM GUEST EDITORIAL

Periodontal Disease and Endocrinology/Diabetology

by Shailesh B. Patel, BM, ChB, DPhil, FRCP Shailesh B. Patel, BM, ChB, DPhil, FRCP, Professor and Chief, he art and science of medicine has a long and rich history. A new concept highlighted and Division of Endocrinology, championed can alter the practice of medicine. For over 1,000 years, such ideas have fre- Metabolism, and Clinical quently led to practice changes. What is new and modern is the rigor with which we view these Nutrition, Medical College T of Wisconsin, Milwaukee, innovative concepts. Evidence-based medicine is now the standard. However, rounds or teaching ses- Wisconsin sions are too often stifled by cries of “There are no clinical trials”, or “Where is the evidence”? In the absence of clinical data, these excuses should not temper “judgment-based practice”. “Judgment-based practice” relies on established basic and clinical scientifi c principles, on experience (personal and collective), and on using procedures or therapies that have been shown to be effective, pose no untoward risk (do no harm), and may prove benefi cial (a positive risk-benefi t ratio). The Scottsdale Project brought together a group of professionals from all branches of healthcare to highlight an important and neglected area: the constellation of periodontitis, diabetes, and adverse outcomes. The link between dental health, oral fl ora, and systemic illness is well known, e.g., in subacute bacterial endocarditis. Enlightened cardiothoracic surgeons now ask their patients before undergoing elective cardiac surgery to receive clearance from their dentists (as this improves patient morbidity and mortality), above and beyond valvular procedures. Purulence anywhere in the body needs to be treated and the mouth is no different. Judgment-based practice would dictate that treating purulence in the mouths of diabetic patients is something good. Periodontitis can be readily screened, treated and controlled, but we are not doing it. Good management of any patient with a chronic disease demands a holistic approach; treating not just the organ, but the body, the mind and even the soul. There are many reasons why we as clinicians fail to be holistic. Finding the time to take a good clinical history, perform a thorough physical exam, adequately answer our patients’ questions and then meet extensive practice guidelines is challenging. For diabetic patients, annual eye, foot, lipid, and urine protein exams are documented routinely. How- ever, we do not examine the diabetic patient’s mouth systematically or document if they have had their annual dental exam. This highlights the difference between evidence-based medicine and judgment-based practice. In the systematic review of the literature considered for The Scottsdale Project, a wealth of evidence shows that periodontitis is a signifi cant comorbidity in patients with diabetes. Yes, we still need more studies for evidence-based medicine. However, the lack of these trials should not derail judgment-based practice. I would urge the American Diabetes Association and the American College of Clinical Endocrinologists to consider, at a minimum, a “judgment-based” statement that an annual dental exam for gum and periodontal health in all diabetic patients is required. However, another aspect of this problem may be more diffi cult to solve. In clinical medicine, whether a patient has insurance or not, chronic illnesses can usually be managed, as there are both state and federal resources to help provide care, despite struggles. Unfortunately, there are few resources for dental coverage in the state and federal systems (even the Vet- erans Administration does not provide for dental coverage). With already burdensome medical costs, to pay out-of-pocket to receive a dental exam is unaffordable for those that are at the greatest risk. Despite sound judgment, the oral-systemic connection between health and disease remains lost to our healthcare insurers and our politicians. Periodontitis, the infl ammation of the gums, is part of medicine and as such should be part of medical healthcare.

2 Grand Rounds Supplement | September 2007

0709GRsupp_rev_2 2 9/24/07 10:24:14 AM GUEST EDITORIAL

Periodontal Disease and Cardiology

by Robert J. Ostfeld, MD, MSc Robert J. Ostfeld, MD, MSc, Assistant Professor hen I learned about the opportunity to become involved in The Scottsdale Project, a cross- of Medicine, Albert Ein- stein College of Medicine disciplinary conference examining the potential connection between periodontal disease Attending Cardiologist, and systemic health, I was very intrigued. Often, as medical professionals, we are accused W Montefi ore Medical Cen- of being myopic, focusing on our own particular area of expertise to the exclusion of others. Clearly, ter, New York, New York diseases impact all aspects of a person. Hence, the theme of uniting specialists across disciplines was exciting, as we all share the same goals of preventing and treating disease. And it made intuitive sense that teamwork would lead to better science and better outcomes for our patients. From the beginning it was clear that everyone shared that excitement; however, we found that we did not necessarily share the same language. Phrases such as “ROMI”, rule out myocardial infarction, or “DOE”, dyspnea on exertion, are common knowledge to physicians (or at least cardiologists), but not with dentists. The same holds true for terms specifi c to dentistry. We found that we needed to bridge this semantic di- vide. With the vernacular hurdles behind us, we set out to rigorously examine the data. There were many fantastic perspectives. There was an endocrinologist, numerous epidemiologists, periodontists, dentists, primary care providers, a cardiologist and an obstetrician. With each person sharing their expertise and analysis of the literature, it was evident that the end product would be very well thought out and guided by data, not preconception. As a myopic cardiologist, one particular area I found myself drawn to was the potential link between periodontal disease and atherosclerosis. The fi rst question that came to mind was about causality. Does periodontal disease cause atherosclerosis? The answer is that we do not know. We do know, however, that many studies demonstrate that periodontal disease is associated with an increased risk of atherosclerosis. But there is the chicken and egg question. Which one came fi rst? Perhaps persons with atherosclerosis simply care for their teeth less and have more periodontal disease. Or perhaps periodontal disease promotes atherosclerosis. We cannot be sure at this time, but the picture does become somewhat clearer. We know that periodontal disease is associated with elevated markers of systemic infl ammation, a known promoter of atherosclerosis. Furthermore, data suggests that treating periodontal disease may reduce markers of systemic infl ammation and improve vascular function. So intriguing hints are there. Although there is no conclusive evidence that periodontal disease is directly implicated in atherosclerosis, no one is suggesting that this lack of evidence should preempt prevention and progressive intervention of periodontal disease. Wouldn’t it be both fascinating and motivating to know that in addition to keeping your gums healthy, your smile attractive and perhaps even diabetes at bay, treating periodontal disease may actually be healthy for your heart as well? Time and further research will tell. Based on the data to date I believe this is something very important to explore. Equally important is the theme of coming together. Given the large burden of atherosclerosis, diabetes and periodontal disease, increasing awareness across disciplines may help to facilitate both research and patient care. Clearly no one expects the cardiologist to know the nuances of periodontal disease or the dentist to be up to date on the latest study about atherosclerosis. But if the cardiologist and/or dentist can help to identify diseases that previously were considered out of their spheres of reference and can enable patients to obtain appropriate care, then something great will have evolved from this body of science, regardless of whether evidence supports a causal relationship.

Grand Rounds Supplement | September 2007 3

0709GRsupp_rev_3 3 9/24/07 10:24:33 AM Report of the Independent Panel of Experts of The Scottsdale Project

Foreword

Beyond Research: Building a Solid Foundation for Implementation of Period0ntal-Systemic Science

disconnect between scientifi c knowledge and primary healthcare practice is not a new phenomenon; it has been well described for many chronic diseases throughout the history of medicine. It was 264 years after the discovery that citrus fruits A prevent scurvy that Britain fi nally adopted universal preventive policy to help scorbutic sailors.* Fast forward to today and consider the length of time it took for the National Cholesterol Education Program to promote understanding of the dangers of high blood cholesterol as a major cause of coronary heart disease and the relatively long adoption curve associated with the acceptance of cholesterol-lowering drugs we know today as “statins”.† The fi rst adult treatment panel report, the Report on the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, was published in 1988.‡ In the clinical advisory statement§ published in 2002, members of the writing committee concluded, “Statin therapy holds great promise for reducing the incidence of major coronary events, coronary procedures, and stroke in high-risk patients. At present this potential has not been fully realized...” Unfortunately, the application of emerging research related to periodontal-systemic links appears to follow this slow pace of knowledge diffusion and like the delayed acceptance of statin drugs, the potential for intervention of periodontal disease to decrease the risk for systemic injury has not been fully recognized. The Report of the Independent Panel of Experts of The Scottsdale Project addresses this disconnect. In this landmark report, the signifi cance of oral health in promoting whole body health and the importance of medical-dental collaboration in ensuring this outcome is redefi ned. As a result, The Scottsdale Project has special signifi cance for medical and dental communities in that it represents an initial attempt to begin diffusing this information into both medical and dental practice by proposing development of a transdisciplinary model of care with the hope of improving health outcomes. Simultaneously, it is important to recognize areas of uncertainty where other research is needed. In many respects The Scottsdale Project was unprecedented. This was the fi rst time a panel composed of medical and dental experts from research, academia, and clinical practice examined the scientifi c evidence to determine whether it was strong enough to support the development of guidelines for the clinical practice of dentistry and medicine to assist practitioners in identifying, cross-referring, and coordinating care of patients who are either undiagnosed or at risk for periodontal disease, diabetes, and cardiovascular disease (CVD). To ensure that The Scottsdale Project would yield meaningful outcomes and forward thinking opinions on the state of this research, health professionals with expertise in periodontology, endocrinology/diabetology, cardiology, cerebrovascular medicine, and epidemiology were represented. This 18-member panel was charged with weighing the evidence to determine whether it was appropriate to develop guidelines. Experts were selected based on expertise in areas of relevant research, clinical capability, willing- ness to consider the data objectively, and in an unbiased and balanced manner. The outcome of the proceedings was made infi nitely more valuable by the collective strength of the combined intellectual capital and unique perspectives of the individuals involved in this initiative. The Scottsdale Project was an in- * Lind J. A Treatise of the Scurvy. Edinburgh: dependent initiative, and as such, the individual participants were not fi nancially compen- Printed by Sands, Murray and Cochran sated nor did they represent any professional organizations. Rather, the opinions derived for A. Kincaid and A. Donaldson. 1753. from the conference represent a collaborative effort to offer direction to better serve the † University of Texas Southwestern Medical health needs of the U.S. population. Center. National Cholesterol Education Program. Available at: http://www.utsou- The opinions derived by the expert panel were the product of careful deliberation over thwestern.edu/utsw/cda/dept27717/fi- 3 days of proceedings that included expert testimony, intense discussion of the evidence les/97623.html. Accessed July 30, 2007. gathered from a systematic review of over 118 articles, and debate over the strength of the ‡ Report on the Expert Panel on Detection, evidence to support the experts’ answers to 8 focused questions. These fi ndings, subsequent Evaluation, and Treatment of High Blood Arch Intern Med. recommendations, and discussion of their scientifi c rationale are detailed in the following Cholesterol in Adults. 1988;148:36-69. report. This methodology was adopted to enable the panel of experts to address the broader The Scottsdale Project § Pasternak RC, Smith SC Jr., Bairey-Merz goal of , which was to determine whether there was suffi cient evidence CN, et al. ACC/AHA/NHLBI Advisory on to support the development of guidelines. Accordingly, the independent panel of experts of the use and safety of statins. J Am Coll The Scottsdale Project sought to resolve 2 key issues, addressed in the following questions: Cardiol. 2002;40:567-572.

4 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_4 4 9/24/07 10:24:50 AM Report of the Independent Panel of Experts of The Scottsdale Project

Key Issue I – Is it appropriate to develop guidelines that assist dental providers in identifying patients who have or who are at risk for diabetes and/or CVD, or screening patients for undiagnosed diabetes and/or CVD who need to be referred to physicians? Key Issue II – Is it appropriate to develop guidelines that assist medical providers in identifying patients who have or who are at risk for periodontal disease, or screening patients who may have undiagnosed periodontal disease who need to be referred to dentists? The panel of experts was concordant in their recommendation that indeed it is appropriate to develop guidelines to assist dental and medical providers in identifying patients at risk for periodontal disease, diabetes, and CVD. Furthermore, members of the expert panel felt that it is an obligation of the professions to be as thorough as possible in searching for information that may lead to a diagnosis of periodontal disease, diabetes, and CVD. The following report provides greater detail of the recommendations offered by the expert panel in addition to scientifi cally supported rationale to support those recommendations. Ultimately, broad change in clinical practice will depend on reform in healthcare policy and professional education, both of which are infl uenced by the various organizations that represent physicians, dentists, nurses, dental hygienists, diabetes educators, physician assistants, dieticians, and other allied healthcare disciplines, in addition to the insurance industry. As such, the recommendations derived from The Scottsdale Project should be viewed as a foundation for building a broader consensus by concerned organizations. It must be recognized that there are medical and dental providers who not only provide state-of-the-art care to their patients, but also communicate to their peers the importance of doing the same. Accordingly, the purpose of this report is to disseminate what a group of highly respected researchers, academicians, and practitioners believe is an initial appropriate course of action regarding development of clinical practice guidelines that may assist both medical and dental practitioners in identifying and managing patients at risk for serious disease states with oral-systemic implications. I want to thank the many scientists, clinicians, and advocates from professional groups who gave generously of their time and expertise without expectation of remuneration. Without their support, commitment to serve, and dedication to seeking unbiased opinion, The Scottsdale Project would not have been possible, and the important recommendations derived from the conference would have been forfeited. In addition, I appreciate the representatives and their respective organizations for participating and observing during the opening day of the proceedings. Most importantly, I want to acknowledge Colgate’s commitment to oral-systemic science, and thank the company for its timely and generous educational grant in funding the 18 months of planning, scientifi c review, and conference proceedings necessary to bring about the level of credible and unbiased expert opinions provided in the Report of the Independent Panel of Experts of The Scottsdale Project. In fact, this report may have already had far reaching implications for the healthcare community at large. The report was prereleased to several organizations and at the time the report went to press, these organizations were considering the fi ndings of the report as the basis for developing guidelines, or revising existing guidelines, to promote medical-dental collaboration in diabetes, CVD, and periodontal disease intervention. Accordingly, I believe this report has fulfi lled one of its predefi ned purposes, i.e., to provide a framework for change and to challenge professional organizations within medicine and dentistry to engage in meaningful dialogue relative to implementation of this body of science, which up until this time had eluded discussions on healthcare reform. Other organizations have awaited the outcome of The Scottsdale Project to carry forward the messages and promote recommendations detailed by the panel of experts in the report. Clearly there is a need for shared responsibility in medicine and dentistry in the comanagement of chronic disease states associated with the oral-systemic link. To that end, it is my hope, along with the others who served on The Scottsdale Project, that discussions stimulated by this report will lead to the creation of innovative models for medical-dental collaboration that may be embraced by healthcare providers, educational institutions, government agencies, and public-private partnerships. “Health care is among the best endowed of all industries in the richness of its science base...yet, an enormous amount of that scientifi c knowledge remains unused.”** So true, yet this results in a delay of evidence-based practice. Consequently, the public we are privileged to serve fails to reap the benefi t of the research that they have funded through tax supported grants for scientifi c investigation. In seeking to reverse this trend, The Scottsdale Project may provide an historical marker that pinpointed the time when real change in prevention and treatment of chronic diseases associated with oral diseases began to take shape. Time will tell.

To universal health,

Casey Hein, BSDH, MBA Chief Editor of Grand Rounds in Oral-Systemic Medicine™ [email protected]

** Berwick DM. Disseminating innovations in health care. JAMA. 2003;289(15):1969-1975.

Grand Rounds Supplement | September 2007 5

0709GRsupp_rev_5 5 9/24/07 10:25:05 AM Report of the Independent Panel of Experts of The Scottsdale Project

INTRODUCTION he impetus for The Scottsdale Project was the need to increase recognition among various health professionals of the expanding base of evidence supporting interrelationships between infl ammatory periodontal disease, diabetes, coronary heart disease, T and ischemic stroke. The purpose of The Scottsdale Project was to bring together a wide range of medical and dental experts to dialogue about the meaningfulness and usefulness of this current body of knowledge as it relates to the need for and appropriateness of guidelines for clinical decisions and patient management. The conference, which was convened on April 11-13 in Scottsdale, Arizona, was the culmination of over 14 months of extensive planning, communication with various professional stakeholder groups, and an in-depth review and summary of relevant scientifi c literature.

As defi ned in its preamble, The Scottsdale Project was led during the planning phase by a group of individuals representing academic, research, and clinical medicine and dentistry. Their common bond was recognition of the potential threat that periodontal disease may pose to systemic health, specifi cally related to the increased risk for complications of diabetes, and the development of atherosclerotic induced diseases, i.e., coronary heart disease and ischemic stroke. Accordingly, as a primary effort, it was suggested that a conference be convened to determine whether current evidence is strong enough to support the adoption of periodontal disease as a modifi able risk factor in decreasing the risk for diabetic complications and the development of heart disease and stroke.

Secondly, this group of individuals perceived a need among clinicians for basic guidelines for the medical-dental comanagement of patients who have increased risk for diabetes, or who have already been diagnosed with diabetes, who may also have periodontal disease. In this regard, those who were involved in the planning phase of The Scottsdale Project acknowledged that there are a number of studies that demonstrate that periodontal therapy has the potential to positively impact glycemic control; however, these individuals also succinctly noted that the evidence to support this is inconclusive at this time.

Thirdly, those involved in the planning phase of The Scottsdale Project acknowledged that medical-dental collaboration in bilateral screening may promote early identifi cation of patients either at risk for, or who have undiagnosed periodontal disease, diabetes or cardiovascular disease (CVD). Subsequently, it was proposed that guidelines for bilateral point-of-care screening for certain diseases (i.e., medical providers screening for periodontal disease and dental providers screening for diabetes and CVD) be developed. Given that diabetes is now considered a risk equivalent for myocardial infarctions, it was also recognized that any gains in early identifi cation of patients at risk for diabetes or undiagnosed diabetes has the potential to impact the epidemic nature of CVD.

If there is suffi cient evidence to support the proposals as set forth in the preamble of The Scottsdale Project (as stated above), this has far reaching implications for the healthcare community at large. In seeking these answers, the expert panel of The Scottsdale Project responded to 8 focused questions which provided the framework for resolution of the following 2 key issues related to guideline development:

Key Issue II – Is it appropriate to develop guidelines that assist medical providers in identifying patients who have or who are at risk for periodontal disease, or screening patients who may have undiagnosed periodontal disease who need to be referred to dentists?

OVERVIEW OF PERIODONTAL-SYSTEMIC MEDICINE

Broadly classifi ed, periodontal diseases include gingival diseases (both plaque-induced and non-plaque induced), chronic periodontitis, aggressive periodontitis, periodontitis as a manifestation of systemic diseases, necrotizing periodontal diseases, in addition to several other classifi cations that are less prevalent.1 This classifi cation system is based on the concept of bacterial- host interaction, which maintains that plaque-induced periodontal diseases are infections and that the host response is largely determined by risk factors such as smoking, diabetes, and genetic predisposition.2 The most common periodontal diseases are plaque-induced gingivitis and chronic periodontitis; both are infections that require a dental management process parallel to that of infections that require medical management. Much of the destruction observed in these infections occurs as a result of host infl ammatory and immunologic responses to predominately gram-negative anaerobic bacteria within the subgingival biofi lm.

6 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_6 6 9/24/07 10:25:23 AM Report of the Independent Panel of Experts of The Scottsdale Project

A healthy periodontium is clinically characterized by fi rm radiographs and tooth mobility may be present. An advanced gingival tissue with a coral pink color (variations in melanin case of chronic periodontitis is characterized by a loss of greater pigmentation among different racial groups),2 a scalloped shape than 1/3 of the supporting periodontal tissues and PD greater coming to a triangular point between teeth,3 and a shallow (2- than 6 mm with clinical features similar to slight to moderate 3 mm) gingival sulcus (Figure 1A).3 Plaque-induced gingivitis stage of periodontitis (Figure 1D).6 Attachment and bone loss is a reversible condition that is diagnosed by the presence of seen in chronic periodontitis are associated with an increase in infl ammation of the gingival tissue. The infl ammation is limited gram-negative organisms (known to be especially pathogenic to the gingival tissue and does not extend into surrounding and virulent)3 in the subgingival plaque biofi lm. Most forms of attachment or bone (Figure 1B).4 Gingivitis may be characterized periodontitis represent chronic infl ammatory lesions that may by the presence of any of the following clinical signs: redness and exhibit slow continuous progression or relatively short bursts of edema of the gingival tissue, bleeding upon provocation, changes disease activity.7,8 in contour and consistency, presence of calculus and/or plaque, and no radiographic evidence of crestal bone loss. Chronic Periodontitis usually has a coexisting gingivitis associated periodontitis is defi ned as infl ammation of the gingiva extending with it though many of the studies reported in The Scottsdale into the adjacent attachment apparatus.5 This disease process is Report are mainly dealing with patients with periodontitis characterized by loss of clinical attachment due to the destruction rather than gingivitis alone. Much of the destruction observed of the periodontal ligament and loss of adjacent supporting in these infections occurs as a result of host infl ammatory and bone. In cases of slight to moderate chronic periodontitis immunologic responses to the bacteria within dental plaque.2 (Figure 1C), up to 1/3 of the supporting periodontal tissues The infection begins when gram-negative anaerobic bacteria* have been lost, with pocket depths (PD) up to 6 mm.5 Clinical form colonies that grow and embed themselves (along with presentation includes edema, erythema, gingival bleeding upon probing, and/or suppuration. Bone loss may be evident in * Porphyromonas gingivalis, Tannerella forsythensis, and Treponema denticola

Figure 1. Anatomical depiction and clinical presentation of the progression from a healthy periodontium to advanced chronic periodontitis.

A. B. C. D. Healthy Periodontium Gingivitis Slight to Moderate Advanced Chronic Periodontitis Chronic Periodontitis

Photographs courtesy of Charles Cobb, DDS, PhD

Grand Rounds Supplement | September 2007 7

0709GRsupp_rev_7 7 9/24/07 10:25:41 AM Report of the Independent Panel of Experts of The Scottsdale Project

other species) in biofi lms. These biofi lms extend apically along destruction.10 During the late 1970s and early 1980s, researchers the surface of tooth roots to incite formation of the periodontal isolated specifi c gram-negative microorganisms thought to be pockets and destruction of the alveolar bone and the collagenous particularly virulent periodontal pathogens and adopted the attachment fi bers of the periodontal ligament.9 specifi c plaque hypothesis. A few years later, researchers began to realize that periodontitis in patients could vary greatly despite Over the last 50 years the etiological theory of periodontal the quantity or qualitative levels of bacteria and that the existence disease has evolved from rather simplistic hypotheses to a closer of bacterial plaque alone was insuffi cient to explain the sequelae understanding of the complexities of host-bacterial interaction of periodontal disease, namely the loss of connective tissue and and the realization that periodontitis has a systemic effect. In alveolar bone. When it was discovered that all individuals are not the 1960s researchers thought periodontal disease was simply equally susceptible to periodontal diseases, scientists during the caused by the mechanical irritation of calculus deposits located mid-1980s theorized that the degradation of the periodontium either near gingival tissues and/or attached to root surfaces was mediated by host-bacterial interaction, and that it is the host’s subgingivally. During the decade of 1965-1975, the nonspecifi c response to the presence of bacteria that determines this tissue plaque hypothesis dominated research. This postulated that it destruction. The host-bacterial interaction theory recognizes that was the quantity of nonspecifi ed bacteria, and not the virulence although bacteria is necessary to initiate the cascade of events of individual species that was responsible for periodontal that occur in periodontal diseases, bacteria alone is insuffi cient

Figure 2. Illustration of theorized mechanism linking periodontal disease to atherosclerosis-induced diseases such as coronary heart disease and ischemic stroke.

1. Oral fl ora forms subgingival biofi lm and initiates periodontal disease with resultant bone loss and periodontal pocketing 2. Endotoxins, enzymes, and metabolic by-products produced by gram-negative microfl ora cause ulceration and necrosis of pocket epithelial lining 3. Epithelial breach leads to invasion of underlying connective tissue and blood vessels by bacteria and endotoxins (bacteremia/endotoxemia) 4. Host immune response leads to accumulation of infl ammatory cells (neutrophils, monocytes) and production of pro-infl ammatory cytokines (IL-1, TNF-α)

8 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_8 8 9/24/07 10:25:58 AM Report of the Independent Panel of Experts of The Scottsdale Project

in inducing periodontal disease or its progression. Subsequently, ling rationale for prevention and early intervention. Accumulat- there has been much investigation of risk factors that infl uence ing evidence suggests that periodontal infection may increase the the host response, such as smoking, diabetes, and genetic risk risk for atherosclerosis induced conditions such as coronary heart factors.11 These risk factors have become generally accepted as disease and stroke (Figure 2), adverse pregnancy outcomes, com- having a negative infl uence on the host response; the role of plications of diabetes, respiratory diseases, neurodegenerative other risk indicators such as stress, obesity, hormonal infl uences, diseases, among other oral-systemic relationships currently un- immunocompromised states, and osteoporosis (among others) der investigation. Three etiological mechanisms are implicated in are also under investigation. the infl ammatory pathway linking periodontal disease to systemic damage: 1) metastatic spread of gram negative bacteria that gain Little did we know that Hippocrates’ claim that “infectious access to the vasculature as a result of breach of the compromised diseases can cause infl ammatory changes at distant body sites” epithelial lining of periodontal pockets; 2) metastatic injury from and the Focal Infection Theory of the 1920s would become the the effects of the circulating toxins of periodontal pathogens; and prevailing hypothesis in periodontology. As evidence of peri- 3) metastatic infl ammation caused by the immunologic response odontal infection’s infl uence on chronic infl ammatory disease to the pathogens and their toxins.12,13 states continues to mount, the current etiological theory of periodontal disease extends beyond its local affect, making a compel- Throughout Oral Health in America,14 then Surgeon General

5. Cytokines are transported to liver and stimulate production of acute phase proteins (C-reactive protein, ﬁ brinogen) 6. Combined effect of bacteremia/endotoxemia, circulating cytokines, and acute phase proteins damages endothelial lining of coronary arteries leading to atheroma formation

Grand Rounds Supplement | September 2007 9

0709GRsupp_rev_9 9 9/24/07 10:26:19 AM Report of the Independent Panel of Experts of The Scottsdale Project

Satcher reinforced the message that “oral health and general dentistry is faced with the conundrum of ‘what is’ versus ‘what health are inseparable”, and that “oral health is integral to should be’.” general health”. Another common thread running through the report was that the mouth “is a portal of entry for infections that If the medical profession begins to identify patients who have can affect local tissues and may spread to other parts of the body” periodontal disease or who may be at risk for periodontal disease, with references to the associations between periodontal disease and the dental profession screens patients for undiagnosed CVD and diabetes, heart disease and stroke and adverse pregnancy and/or diabetes, the impact on the prevalence of these life- outcomes. The report went on to say that improvements in threatening chronic conditions may offer unprecedented gains in oral health depend on multidisciplinary and interdisciplinary longevity. Over 70 million Americans have CVD.19 This translates approaches to research and on the ability of practitioners to into 1 in 4 people with some form of CVD. Statistics related to apply that research effectively. The need to change nondental the failure to assess risk and diagnose CVD are haunting. For healthcare providers’ perception of the importance of oral example, research indicates that for 50% of men and 64% of health was also discussed. Satcher challenged medical and dental women who died suddenly of coronary heart disease, there was no healthcare providers that they “should be ready, willing, and previous recognition of the disease.20 Furthermore, a signifi cant able to work in collaboration to provide optimal healthcare for proportion of the population with identifi ed risk factors for CVD their patients”. As a prerequisite for interdisciplinary services, are not diagnosed with CVD, and are therefore not being treated the report highlighted the need for curriculum changes and adequately for CVD.20 multidisciplinary training. The report also called for the development of risk assessment tools and diagnostic markers Current predictions suggest that by 2030 there will be 23 to allow clinicians to determine which individuals are more million individuals with diagnosed diabetes, 7 million with susceptible to a given disease, thereby providing a basis for more undiagnosed diabetes, with another estimated 70 million with targeted intervention strategies for those at high risk. Given impaired fasting or postprandial glucose.21 Direct costs of the estimates of periodontal disease prevalence and speculation diabetes could be close to $175 billion/year; indirect costs could that it is dramatically underdiagnosed, early identifi cation be an additional $75 billion/year. Even now the economic and and appropriate treatment of periodontal disease is critical in personal burden of diabetes outpaces our current healthcare achieving these intervention strategies. delivery system.

The lack of a standard defi nition of periodontal disease and How might medical-dental collaboration impact these disease issues related to access to dental care for a substantial percentage trajectories? This was the focus of The Scottsdale Project. of the U.S. population confounds the attempts of epidemiologists to pinpoint the prevalence of periodontal diseases. However, ORDER OF PROCEEDINGS AND DESCRIPTION recent investigation into the validity of self-reported periodontal OF OPINION BUILDING PROCESS disease and its use in attaining more accurate measurements of periodontal disease prevalence is promising.15 It has recently The Scottsdale Project was a 3-day conference. The conference been estimated that at least 50% of adults in the U.S. have some was organized to provide an opportunity for professional level of gingival infl ammation, or gingivitis.16 Periodontal disease organizations and other relevant stakeholder groups to observe is highly prevalent, affecting about 34% of the U.S. population the proceedings on the opening day. Several key organizations* older than 30 years, with severe periodontal disease estimated were invited to send a representative to deliver a short presentation in 13% of the population.17 Given the prevalence of periodontal during the morning of the fi rst day that specifi cally addressed disease and statistics generated from consumer surveys and several important questions: practice management statistics, it appears that periodontal 1. Does your organization recognize the evolving body of evidence disease may be signifi cantly underdiagnosed in the United that supports a relationship between oral and systemic health/ States. In a 2005 paper entitled “Diagnosis and Treatment of disease? Periodontal Disease: A Crisis of Direction”, Cobb18 wrote: “In 2. If so, what has your organization done to create awareness spite of our current understanding of the etiology and clinical among its constituency or develop clinical protocols that characteristics of chronic periodontitis, there is still a confl ict address the oral-systemic relationship? between what many private practitioners consider to be chronic 3. If not, what have been the hurdles to acceptance of the evidence periodontitis requiring treatment versus the recent description of oral-systemic links? and reclassifi cation of periodontitis by the 1999 International 4. What future direction would your organization propose in Workshop for a Classifi cation of Periodontal Disease and order to advance oral-systemic medicine and collaboration Conditions. In other words, when clinically defi ning (i.e., among healthcare providers? diagnosing) chronic periodontitis for the purpose of treatment,

* American Academy of Periodontology, American Diabetes Association, National Dental Association, American Dental Hygienists’ Association, America’s Health Insurance Plans

10 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_10 10 9/24/07 10:26:38 AM Report of the Independent Panel of Experts of The Scottsdale Project

A number of other key organizations† sent representatives to voice recorded and transcribed to ensure accuracy of fi ndings. observe the fi rst day of the proceedings. On the fi rst morning, Dr. Maria Ryan presented an overview of relevant research. The METHODOLOGY afternoon session began with Dr. Charles Cobb’s presentation on the etiology of periodontal disease, which provided important The development of The Scottsdale Project was directed by a background information to medical experts serving on the conference planning committee, which consisted of 8 individuals panel. Dr. Karen Williams acted as the moderator of the opinion from the expert panel. The planning meeting was held 4 months building process. A series of focused questions were individually before the consensus conference; language specifi c to the discussed. Prerecorded video testimony of Dr. Brian Mealey preamble was discussed, issues related to scientifi c methodology was played to provide the expert panel with a starting point for were addressed, and the committee identifi ed a small group of their discussions. Small working groups comprised of experts professional organizations that would be invited to observe and/or with heterogeneous backgrounds were assigned responsibility present during the opening day of the proceedings in Scottsdale. for drafting recommendations. Answers to the focused questions, recommendations, and fi nal conclusions related to Following this planning meeting, the planning committee the appropriateness of guidelines for clinical decision making developed 5 questions designed to determine whether there was and comanagement of patients who are at risk for or already suffi cient evidence to support collaboration between medical diagnosed with periodontal disease and CVD were derived by the and dental providers in the intervention of periodontal disease, expert panel during open forum, and facilitated highly interactive diabetes, and CVD. In addition, the committee developed a system discussions. Proceedings throughout the 3 day conference were for grading the evidence. During the conference proceedings, the expert panel revised and expanded the 5 original focused questions † Academy of General Dentistry, American Association of Diabetes Educators, American to 8 focused questions listed in the sections below (“Grading the Association of Dental Assistants, The Forsythe Institute Evidence” and “Weighing the Evidence”).

Table 1. Oxford Grades for Level of Evidence As part of the planning process, a search of the literature and review (Used for grading of evidence to support answers to focused questions of the evidence was conducted derived from experts’ opinion from The Scottsdale Project) by independent research analysts Evidence Description with expertise in medical/dental literature. The search was limited to Level 1a SR (with homogeneity*) of RCTs studies in humans including (only) Level 1b Individual RCT (with narrow confi dence interval) randomized controlled clinical trials, + Level 1c All or none meta-analyses, literature reviews, Level 2a SR (with homogeneity*) of cohort studies epidemiologic studies specifi c to Level 2b Individual cohort study (including low quality RCT; e.g., <80% follow-up) relevant topics, and consensus papers Level 2c “Outcomes” research; ecological studies published from 2000 to March 2007. Level 3a SR (with homogeneity*) of case-control studies The search was conducted through Level 3b Individual case-control study PubMed utilizing MeSH key words ‡ Level 4 Case series (and poor quality cohort and case control studies ) specifi cally related to associations Level 5 Expert opinion without explicit critical appraisal, or based on physiology, bench between the following relevant links: research or “fi rst principles” • periodontal disease and infl am- SR: Systematic Review; RCTs: Randomized Clinical Trials mation * The term homogeneity refers to a systematic review that is free of worrisome variations (heterogene- • diabetes and periodontal disease ity) in the directions and degrees of results between individual studies. Not all systematic reviews with • infl ammation and diabetes statistically signifi cant heterogeneity need be worrisome, and not all worrisome heterogeneity need be • periodontal disease and CVD statistically signifi cant. + Met when all patients died before the Rx became available, but some now survive on it; or when some • infl ammation and CVD patients died before the Rx became available, but none now die on it. • diabetes and CVD ‡ A poor quality cohort study is one that failed to clearly defi ne comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and nonexposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a In addition, all of the participating suffi ciently long and complete follow-up of patients. A poor quality case control study is one that failed to experts were asked to submit articles clearly defi ne comparison groups and/or failed to measure exposures and outcomes in the same (prefer- that met the inclusion criteria but ably blinded), objective way in both cases and controls and/or failed to identify or appropriately control that may not have been identifi ed known confounders. during the literature search. Several Source: Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Available at: http://www.mcw.edu/display/ displayFile.asp?docid=5540&fi lename=/User/fvastalo/Oxford_Levels.pdf. Accessed April 27, 2007. experts identifi ed and recommended additional articles with earlier

Grand Rounds Supplement | September 2007 11

0709GRsupp_rev_11 11 9/24/07 10:26:53 AM Report of the Independent Panel of Experts of The Scottsdale Project

publication dates for the purpose of supporting additional planning committee had proposed for grading the level of discussions during the proceedings of The Scottsdale Project. A total of evidence. After careful consideration during early discussions 118 articles met the initial inclusion criteria and were incorporated in Scottsdale, the expert panel recommended that this grading into the review. Methodology and data were extrapolated from system be replaced by the more rigorous criteria contained in the full text versions of these articles and reviewed by independent Oxford Grades for Level of Evidence (Table 1). Two members research analysts, who graded the evidence according to criteria, of the expert panel (physician and dentist, both PhD trained) originally defi ned by the conference planning committee, and performed a calibrated review of previously graded evidence organized relevant information into evidence summaries. Panel summaries of all articles to ensure that the level of evidence was experts were provided online access to evidence summaries and graded according to the Oxford Grades for Level of Evidence primary source documents via a portal specially designed for The criteria, making revisions to evidence grades as necessary. Scottsdale Project, as well as hard copies of summaries. Members of the expert panel were asked to review the evidence summaries prior Eight Focused Questions: The expert panel was tasked with to the conference so that discussions at the conference would be considering the quality of evidence during ensuing discussion of based on existing literature. Where literature was not available, the 8 focused questions. panel of experts offered concordant expert opinions in addressing 1. Is there evidence that periodontal diseases result in an increase focused questions and recommendations. in local and systemic infl ammatory response? 2. Does the evidence support the concept that periodontal GRADING OF EVIDENCE TO SUPPORT ANSWERS TO FOCUSED disease is a complication of diabetes? QUESTIONS 3. Is there evidence that in people with diabetes, periodontal During the initial proceedings, the panel of experts evaluated disease is associated with poor glycemic control and/or other the adequacy and appropriateness of the system the conference complications of diabetes?

Table 2. Oxford Criteria for Grading Recommendations

(Used to grade the experts’ recommendations derived from answers to focused questions speciﬁ c to The Scottsdale Project)

Evidence Description

Level A Recommendation supported by consistent level 1 studies Level B Recommendation supported by consistent level 2 or 3 studies or extrapolations* from level 1 studies Level C Recommendation supported by level 4 studies or extrapolations* from level 2 or 3 studies Level D Recommendation supported by level 5 evidence or troubling, inconsistent or inconclusive studies of any level

*“Extrapolations” are where data is used in a situation that has potentially clinically important differences than the original study situation. Source: Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Available at: http://www.mcw.edu/display/displayFile.asp?docid=5540&ﬁ lename=/User/fvastalo/Oxford_Levels.pdf. Accessed April 27, 2007.

Table 3. United States Preventive Services Task Force (USPSTF) System for Grading Recommendations

Evidence Description

Level A There is good evidence that the service improves important health outcomes and concludes that benefi ts substantially outweigh harms. Therefore, it is recommended that clinicians routinely provide the service to eligible patients. Level B There is at least fair evidence that the service improves important health outcomes and concludes that benefi ts outweigh harms. Therefore, it is recommended that clinicians routinely provide the service to eligible patients. Level C There is at least fair evidence that the service can improve health outcomes but concludes that the balance of benefi ts and harms is too close to justify a general recommendation. Therefore, there is no recommendation for or against routine provision of the service.

Level D There is at least fair evidence that the service is ineffective or that harms outweigh benefi ts. Therefore, routinely providing this service to asymptomatic patients is not recommended. Level I The evidence is insuffi cient to recommend for or against routinely providing the service; evidence that the service is effective is lacking, of poor quality, or confl icting and the balance of benefi ts and harms cannot be determined.

Source: United States Preventive Services Task Force (USPSTF). Screening for obesity in adults: recommendations and rationale. Ann Intern Med. 2003;139(11):930-932.

12 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_12 12 9/24/07 10:27:11 AM Report of the Independent Panel of Experts of The Scottsdale Project

4. Is there evidence that treating periodontal disease results in and USPSTF criteria explained in Tables 2 and 3; the graded a decrease in the local and systemic infl ammatory response? recommendations for the 8 focused questions are described in 5. Is there evidence that periodontal disease interventions may Table 5. The scientifi c rationale and additional studies supporting improve outcomes in diabetes (glycemic control, development/ these recommendations, as derived from the experts’ discussions, progression of complications of diabetes)? are described below. 6. Is it appropriate to develop guidelines for the medical-dental comanagement of those at risk for diabetes or those previously DISCUSSION OF SCIENTIFIC RATIONALE diagnosed with diabetes who may also have periodontal disease in an attempt to positively impact glycemic control FOR RECOMMENDATIONS DERIVED FROM and reduce the risk of diabetic complications? EXPERTS’ DISCUSSION DURING 7. Is periodontal disease associated with atherosclerosis-induced THE SCOTTSDALE PROJECT diseases such as coronary heart disease or ischemic stroke? 8. Is there evidence that intervention of periodontal disease Focus #1 – Periodontal Disease and Increased Infl ammatory decreases the risk for CVD or reduces the incidence of Response coronary heart disease or ischemic stroke? Eight of the reviewed articles (5 [level 5]23-27 and 3 [level 2b]91-93) have addressed the bacterial/host response relationship in the In answering these questions, statements were carefully drafted pathogenesis of infl ammatory periodontal disease, the potential by the panel of experts during the proceedings and explicitly for bacteremia, and the role of locally produced proinfl ammatory written to refl ect solidarity of opinion using the best available mediators. evidence. The major fi ndings and conclusions reached by the expert panel regarding these focused questions provided the basis Three studies (1 [level 2c]94 and 2 [level 5]95,96) speculate that for recommendations for guideline development, as embodied in the infl amed and ulcerated subgingival pocket epithelium presents Key Issues I and II as stated earlier. a portal of entry for pathogenic periodontal bacteria, many being gram-negative anaerobes. The presence of periodontal bacteria in GRADING OF RECOMMENDATIONS atheromatous plaques — supported by evidence from 5 studies (4 The expert panel provided individual recommendations and [level 3b]97-100 and 1 [level 4]101 — offers indirect support for the supporting rationales for the answers for each of the focused role of bacteremia in periodontal disease. questions. One of the diffi culties in assigning a grade to the recommendations was that the Oxford Criteria for Grading Geerts and colleagues102 (level 2c) found that endotoxin and Recommendations alone (Table 2) were not suffi cient for grading other outer membrane antigens derived from gram-negative recommendations related to direct patient care or formulation anaerobic microbes may gain access to the circulatory system of clinical guidelines. Consequently, recommendations of the and exert systemic or distant effects. Likewise, 3 studies (1 [level expert panel have been graded according to 2 sets of criteria; 2a],103 1 [level 2b],22 and 1 [level 5]24) demonstrated that locally the Oxford Criteria for Grading Recommendations (not to be produced proinfl ammatory mediators (such as IL-1, TNF-α,

confused with Oxford Grades for Level of Evidence designed IL-6, and PGE2), after gaining entry into the circulatory system, to weigh evidence to support answers to focused questions) and exert a systemic effect. the grading criteria utilized by United States Preventive Services Task Force (USPSTF) (Table 3). The combined use of these sets Eight studies (5 [level 2b]22,30,33,104,105 and 3 [level 3b]35,36,106) of criteria allowed for grading both the strength of evidence to reported higher plasma C-reactive protein (CRP) levels in patients support recommendations that do not directly deal with patient with periodontitis versus nondiseased controls. In addition, 2 care (Oxford), and grading the magnitude of the net benefi t studies36,107 (level 3b) reported an association of poor oral health (benefi ts minus harms) of recommendations that deal with patient with increased fi brinogen levels. Lastly, 5 studies (3 [level 1b],28,32,45 care and/or formulation of clinical guidelines (USPSTF). 1 [level 2b],46 and 1 [level 4]47) demonstrated a decrease in plasma levels of IL-1β, IL-6, and CRP following nonsurgical treatment WEIGHING THE EVIDENCE of periodontitis, offering indirect support for the concept that localized periodontal infl ammation is associated with a systemic First, evidence relevant to the expert panel’s discussions during infl ammatory response. The Scottsdale Project was graded on a scale of 1a-5 according to criteria of the Oxford Grades for Level of Evidence, as defi ned Focus #2 – Periodontal Disease as a Complication of Diabetes in Table 1. Then, answers were developed in response to each The concept that periodontal disease is an important of the 8 focused questions; the levels of evidence assigned to complication of diabetes is supported by evidence from 7 studies individual references supporting those answers are listed in Table (6 [level 2b],37-39,108-110 and 1 [level 3b]40). It is generally accepted 4. Finally, recommendations derived from experts’ discussions that people with diabetes have decreased immune responses during The Scottsdale Project were graded according to the Oxford and are therefore more susceptible to infections. People with

Grand Rounds Supplement | September 2007 13

0709GRsupp_rev_13 13 9/24/07 10:27:27 AM Report of the Independent Panel of Experts of The Scottsdale Project

Figure 3. The potential for a bidirectional relationship between diabetes and periodontal disease.

Evidence suggests that people with diabetes are signiﬁ cantly more susceptible to periodontal disease, that periodontal infection complicates glycemic control and enhances insulin resistance and hyperglycemia, and that poor glycemic control causes increased susceptibility to re-infection and increases the severity of periodontal disease.

diabetes are also known to have atherosclerotic changes in reported improvements in periodontal health following therapy,

their blood vessels that make them prone to a decreased but no signifi cant reductions in HbA1c values. Aldridge and vascular supply to the periodontium. Because of this, people colleagues115 (level 2b) interpreted the lack of improvement

with diabetes are more susceptible to any infection including in HbA1c values as an indication that metabolic control may be infections of the periodontium. Furthermore, the fi nding that dominant in the relationship between diabetes and periodontal untreated moderate to severe periodontitis appears to adversely health. The study by Christgau and colleagues116 (level 2b) impact glycemic control (Figure 3) is supported by 6 studies (1 essentially demonstrated that patients with well controlled [level 2a],58 2 [level 2b],43,111 1 [level 3b],44 and 2 [level 5]24,112). diabetes and patients without diabetes have similar responses Acute bacterial and viral infections are known to increase to periodontal treatment, e.g., decreased probing depth, clinical insulin resistance in people with diabetes and may, in fact, result attachment levels, bleeding on probing, oxidative burst response of in prolonged problems with glycemic control, as reported by polymorphonuclear leukocytes (PMN) to TNF-α and f-Met-Leu- Mealey and Oates58 (level 2a). Phe (fMLP), and decreases in periodontal pathogenic microbes.

Additionally, Engebretson and colleagues113 (level 4) suggest Focus #3 – Association of Periodontal Disease with Glycemic that periodontitis-associated circulating TNF-α may contribute Control to insulin resistance. Indirect evidence may be gleaned from 4 The presence of untreated moderate to severe periodontitis studies (3 [level 2b]49,51,114 and 1 [level 3b]53) involving people appears to adversely impact glycemic control, as shown in 5 studies with type 1 and type 2 diabetes with severe periodontitis with (1 [level 2a],58 1 [level 2b],111 1 [level 3b],44 and 2 [level 5]25,112). improvements in glycemic control following nonsurgical Indirect evidence from 5 small clinical trials (3 [level 2b],49,51,114 53 117 periodontal therapy, i.e., reductions in hemoglobin A1c (HbA1c) 1 [level 3b], and 1 [level 4] ), all involving patients with type 1 and levels. type 2 diabetes with severe periodontitis, indicate improvements in glycemic control following nonsurgical periodontal therapy, 55 56,115,116 In contrast, 4 studies (1 [level 1a] and 3 [level 2b] ) i.e., reductions in HbA1c levels.

14 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_14 14 9/24/07 10:27:45 AM Report of the Independent Panel of Experts of The Scottsdale Project

Further, 3 studies (1 [level 3b],44 1 [level 2a],42 and 1 [level greater respectively), compared to patients with no disease or mild 1b]41) offer evidence supporting the concept that patients with periodontitis. Likewise, the incidence of end stage renal disease in diabetes and chronic periodontitis have a higher incidence of individuals with moderate or severe periodontitis or in those who nephropathy. Saremi and colleagues42 (level 2a) reported that were edentulous was 2.3, 3.5, and 4.9 times greater, respectively, periodontal disease is a strong predictor of mortality from diabetic compared with those with no disease or mild periodontitis. Lastly, nephropathy and ischemic heart disease in Pima Indians with Thorstensson and colleagues44 (level 3b) reported that in 39 case- type 2 diabetes. Shultis and colleagues41 (level 1b) investigated control pairs, renal disease (proteinuria) was associated with the effect of periodontitis on development of overt nephropathy, severe periodontitis. defi ned as macroalbuminuria, and end stage renal disease in patients with type 2 diabetes. The incidence of macroalbuminuria Evidence from 5 studies (1 [level 1b],118 2 [level 2a],119,120 and was signifi cantly elevated in subjects with moderate or severe 2 [level 5]121,122) has well established that diabetes is a major risk periodontitis or who were edentulous (2.0, 2.1, and 2.6 times factor for coronary vascular disease (CVD). As such, diabetes may

Table 4. Focused Questions, Answers, and Level of Evidence Assigned to Supporting References, Derived from Experts’ Discussions during The Scottsdale Project Evidence

Focused Questions and Answers Level Supporting References (Oxford) Question #1 – Is there evidence that periodontal diseases result in an increase in local and systemic infl ammatory response? There is evidence that periodontal diseases result in an increase in local and systemic 2b Loos22 infl ammatory response. Both gingivitis and periodontitis elicit a local gingival increase 23 24 25 in infl ammatory biomarkers, including interleukin-1 beta (IL - 1β), tumor necrosis factor DeNardin, Gemmell, Loos, 5 26,27 alpha (TNF - α), interleukin-6 (IL - 6), and prostaglandin E (PGE ). Offenbacher 2 2 Periodontitis is also associated with elevated serum markers of systemic infl ammation, 1b D’Aiuto28 including high sensitivity C-reactive protein (hsCRP), soluable Intercellular Adhesion 2b Ide,29 Noack,30 Schaumberg31 Molecules (sICAM), and IL - 6. 1b D’Aiuto32 Both the local and systemic response are positively associated with increasing severity 2b Ide,29 Craig,33 D’Aiuto34 of periodontitis. 3b Buhlin,35 Wu36 Question #2 – Does the evidence support the concept that periodontal disease is a complication of diabetes? There is evidence that diabetes can affect the periodontium and that periodontitis is an important, although often unrecognized, complication of diabetes. (Note: A large body 2b Lalla,37 Campus,38 Jones39 of non-human mechanistic studies, not reviewed for this project, also support that the pathogenesis of periodontitis is similar to that of other diabetic complications and 40 justify viewing it as such.) 3b Lim Question #3 – Is there evidence that in people with diabetes, periodontal disease is associated with poor glycemic control and/or other complications of diabetes? 1b Shultis41 The current available evidence indicates that in people with diabetes, periodontal 2a Saremi42 disease at baseline is associated with poor glycemic control, nephropathy, and CVD. 2b Taylor43 3b Thorstensson44 Question #4 – Is there evidence that treating periodontal disease results in a decrease in the local and systemic infl ammatory response? Several studies support the concept that periodontal treatment can reduce local oral 1b D’Aiuto,28,32 Tonetti45 levels of infl ammatory mediators and systemic markers of infl ammation. Although such studies suggest that periodontal therapy may reduce serum IL - 6 and CRP, and 2b D’Aiuto34,46 arrest progression of periodontal disease, larger randomized controlled clinical trials are needed to investigate whether treatment of periodontal disease decreases local and 4 Yamazaki47 systemic infl ammatory responses. Question #5 – Is there evidence that periodontal disease interventions may improve outcomes in diabetes? There are mixed fi ndings regarding whether periodontal disease interventions may im- Almas,48 Grossi,49 Rodrigues,50 2b prove outcomes in diabetes (glycemic control, development/progression of complications Stewart51 of diabetes). Some studies show that periodontal treatment improves glycemic control in 3b Iwamoto,52 Kiran,53 Schara54 patients with diabetes. Other studies do not show a relationship between periodontal treatment and improved 1a Janket55 glycemic control. Adequate, well-designed multicenter randomized controlled trials have not been performed. To date, no data are available regarding the potential impact of peri- 2b Jones,39 Promsudthi56 odontal therapy on nephropathy or CVD in patients with diabetes.

Grand Rounds Supplement | September 2007 15

0709GRsupp_rev_15 15 9/24/07 10:28:04 AM Report of the Independent Panel of Experts of The Scottsdale Project

be considered a risk equivalent for CVD.123 As noted in Focus #2 with diabetes, further elevating the risk for development of above, the presence of untreated moderate to severe periodontitis atherosclerosis and/or CVD in people with diabetes. Only 2 has a detrimental effect on glycemic control. Further, there is studies (1 [level 2b]109 and 1 [level 3b]44) offer direct evidence considerable data from 9 studies (2 [level 1b],28,32 5 [level 2b],29- supporting an association of periodontal disease in patients with 31,33,34 and 2 [level 3b]35,36) indicating that untreated moderate to diabetes or CVD. Thus, there is an obvious need for future studies severe periodontitis is associated with a systemic infl ammatory that focus on patients with diabetes and a concomitant diagnosis response. Similarly, there is a signifi cant amount of data from 17 of moderate to severe periodontitis to determine association with studies (1 [level 2a],85 3 [level 2b],64,67,124 12 [level 3b],70,72-74,76,80- cardiovascular status. 84,125,126 and 1 [level 4]101) indicating that untreated moderate to severe periodontitis is associated with atherosclerosis and/or The fact that evidence supports an adverse effect of diabetes on CVD. Thus, it would appear that a diagnosis of moderate to the periodontium does not necessarily mean that the practicing severe periodontitis would be considered a comorbid condition health-care community is aware of that evidence. Currently there

Table 4. Focused Questions, Answers, and Level of Evidence Assigned to Supporting References, Derived from Experts’ Discussions during The Scottsdale Project (cont’d.) Evidence Focused Questions and Answers Level Supporting References (Oxford) Question #6 – Is it appropriate to develop guidelines for the medical-dental comanagement of those at risk for diabetes or those previously diagnosed with diabetes who may also have periodontal disease in an attempt to positively impact glycemic control and reduce the risk of diabetic complications? Yes, it appropriate to develop guidelines for the medical-dental comanagement of those 2a Khader,57 Mealey58 at risk for diabetes or those previously diagnosed with diabetes who may also have 2b Lalla37 periodontal disease in an attempt to positively impact glycemic control and reduce the 4 Bakhsandeh59 risk of diabetic complications. Periodontal disease is a chronic disease that jeopardizes 5 Nassar,60 Nishimura,61 Southerland62 the periodontium, causing local and systemic infl ammation. Periodontal disease is also epidemiologically associated with impaired glycemic control, 2a Saremi42 nephropathy, and CVD. 5 Nishimura,61 Southerland62 Though studies looking at the effect of treatment of periodontal disease on glycemic 1a Janket55 control, nephropathy, and CVD are limited, an improvement in glycemic control has 48 49 50 2b Almas, Grossi, Rodrigues, been demonstrated (Question #5 above), and a decrease in CVD and nephropathy are Stewart51 also possible secondary effects of treatment. 3b Iwamoto,52 Kiran,53 Schara54 5 Southerland62 Question #7 – Is periodontal disease associated with atherosclerosis-induced diseases such as coronary heart disease or ischemic stroke? 28 A broad range of observational studies demonstrate a consistent moderate association 1b D’Aiuto 63 between different measures of periodontal disease, coronary heart disease, ischemic 2a Janket Beck,64 Hung,65 Joshipura,66 stroke, and measures of atherosclerosis. 2b Montebugnoli,67 Wu68 3a Meurman69 Briggs,70 Czerniuk,71 Deliagyris,72 Desvarieux,73,74 Dorfer,75 3b Engebretson,76 Grau,77 Holmlund,78 Lee,79 Lopez,80 Persson,81 Slade,82 Spahr,83 Tabrizi84 There are also some observational studies and meta-analyses that demonstrate no 2a Khader85 associations or very weak associations between periodontal disease, coronary heart 2b Howell86 disease, ischemic stroke, and measures of atherosclerosis. 3b Nakib87 Question #8 – Is there evidence that periodontal disease intervention decreases the risk for CVD or reduces the incidence of coronary heart disease or ischemic stroke? Whether intervention for periodontal diseases improves CVD or reduces the incidence Tonetti45 of coronary heart disease or ischemic stroke has not been fully answered. Early studies 1b demonstrate that periodontal treatment improves endothelial function. However, to date, intervention trials looking at the effect of periodontal treatment on coronary heart 2b Mercanoglu88 disease and ischemic stroke have not been performed. Randomized controlled trials with subclinical and clinical outcomes are needed to fully answer this question. Deter- mination of optimal treatment schemes and identifi cation of patient groups most likely 4 Elter,89 Seinost90 to benefi t from intervention are needed.

16 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_16 16 9/24/07 10:28:22 AM Table 5. Focused Question Topics – Graded Recommendations Derived from Experts’ Discussions during The Scottsdale Project

Grade Recommendations

Focused Question Topic #1 – Periodontal disease and increased inﬂ ammatory response

■ If a patient’s systemic inﬂ ammatory markers are measured and found to be elevated, the oral cavity should be considered as a potential contributor. ■ There must be greater recognition of the link between oral and systemic health. This should prompt changes in undergraduate ‡ B and graduate education and Continuing Medical Education as well as Continuing Dental Education. ■ In addition, there is a need to shift away from the conventional silo thinking, which has historically divided medicine and dentistry, to the creation of a forum to stimulate and sustain ongoing dialogue on the relevance of shared responsibility for overall health outcomes.

Focused Question Topic #2 – Periodontal disease as a complication of diabetes

■ Novel public relations campaigns and educational programming should be created and implemented to increase awareness among current practitioners in both dentistry and medicine that diabetes can affect the periodontium and that periodontitis is an important, although often unrecognized complication of diabetes. ■ Novel campaigns should be created and implemented, with a focus on educational reform to ensure that dental and medical providers are aware that periodontitis is an important, though often unrecognized complication of diabetes and as such, understand the implications of this for the health of patients. Such campaigns might include the dissemination of packets or B‡ “tool kits” offered by professional groups such as the American Diabetes Association, American Heart Association, American Dental Association, and the American Academy of Periodontology. The information in the packet/kit would be speciﬁ cally designed to help the professional constituency educate their patients. ■ A health promotion or direct-to-the-patient campaign should be created and implemented, with a focus on educating the public. In addition, a self-assessment tool that allows the public to assess individual risk for periodontal disease and educates the public on the association between periodontal disease and diabetes should be developed and posted on the Web portals of professional organizations throughout the healthcare industry.

Focused Question Topic #3 – Association of periodontal disease with glycemic control

■ There must be increased awareness that treatment and preventive interventions for periodontal disease have the potential to favorably affect the systemic infl ammatory response. ■ Patients with diabetes should be informed of the current data regarding the effects of periodontitis on glycemic control and ‡ risk for nephropathy and CVD. B ■ Due to a potential association between the infl ammation generated by periodontal diseases and systemic infl ammation and the associated sequelae, it is recommended that general guidelines be developed addressing the management of the infl ammatory burden imposed by periodontal diseases. Said guidelines should be proposed, validated, reviewed, and appropriately updated on an ongoing basis, by an independent commission comprised of both medical and dental professionals.

Focused Question Topic #4 – Periodontal disease treatment and decreased inﬂ ammatory response § ■ Larger randomized controlled clinical trials are needed to investigate whether treatment of periodontal disease decreases local I and systemic inﬂ ammatory responses before further recommendations can be made.

Focused Question Topic #5 – Periodontal disease interventions and diabetes outcomes

■ Additional studies are required to determine whether intervention of periodontal disease improves other health outcomes; however, there is no harm in advocating intervention of periodontal disease. Because ﬁ ndings are mixed, the panel cannot make speciﬁ c recommendations. ‡ B ■ However, given the collective and diverse experience of the members of the expert panel, the recommendation is for close, enhanced communication between medical and dental practitioners in the comanagement of treatment and response outcomes in diabetes. This is crucial for optimal case management. Feedback from physicians is critical to determining the modality of oral intervention. Feedback from dentists is critical to maximize medical intervention (e.g., glycemic control).

‡ Based on (a) current available peer reviewed literature that demonstrates consistent level 2 or 3 data and some level 1 data (Oxford); and (b) consideration of the magnitude of the net benefi t (USPSTF). § Currently available data in peer reviewed literature are inconsistent and therefore no fi rm conclusion can be reached. Therefore, no specifi c practice interventions were recommended. The group emphasized the need for large, randomized, controlled clinical trials and recommended that these be done before further recommendations can be made. ** Based on (a) current available peer reviewed literature that demonstrates some level 2 or level 3 data as well as expert opinion in the fi eld (Oxford); and (b) consideration of the potential benefi ts of transdisciplinary practice models (USPSTF). ‡‡ Based on the current available peer reviewed literature that demonstrates consistent level 2 or 3 data and some level 1 data (Oxford). This type of evidence does not lend itself to USPSTF grading criteria. §§ Based on (a) current available peer reviewed literature that demonstrates consistent level 2 data and some level 1 data (Oxford); (b) consideration of the potential benefi t (USPSTF); and (c) taking into account the lack of randomized controlled trials.

Grand Rounds Supplement | September 2007 17

0709GRsupp_rev_17 17 9/24/07 10:28:39 AM Table 5. Focused Question Topics – Graded Recommendations Derived from Experts’ Discussions during The Scottsdale Project (cont’d.)

Grade Recommendations

Focused Question Topic #6 – Potential guideline development for patients at risk for diabetes and periodontal disease ■ It is strongly recommended that medical and dental teams collaborate in patient identifi cation (screening), referral and management of periodontal disease in the patient with diabetes. ■ Dental management of those at risk for diabetes or those previously diagnosed with diabetes who may also have periodontal disease should consist of the following (during the initial visit and updated as needed at follow-up visits): 1. Determine the date of the patient’s last medical evaluation and obtain an adequate medical history and list of current medications; there should be an emphasis on determining the level of glycemic control or average blood sugars 2. Establish communication with the treating physician to confi rm the information reported by the patient a. Inform physician of dental diagnosis b. Establish level of glycemic control and cardiovascular status (specifi cally, past and current HbA values) through com- 1c munication with patient’s physician 3. Develop an integrated treatment plan a. Treat acute infection b. Promote a healthy lifestyle (advise about ABCs: HbA , Blood pressure, and Cholesterol) 1c c. Encourage tobacco use cessation d. Educate about oral-systemic links in people with diabetes e. Modify treatment plan based on patient profi le • Nonsurgical vs. surgical therapy • Antibiotics (systemic vs. local) • Host modulatory therapy B** • More frequent dental visits (follow-up) 4. Consider other oral manifestations of diabetes a. Caries − appropriate restorative and preventive care b. Dry mouth − saliva substitutes, adequate hydration c. Candidiasis − antifungals if necessary d. Comorbidities/associated medications (e.g., calcium channel blockers) 5. Special considerations a. Prevent and manage hypoglycemic events • Use a glucometer to monitor the potential for hypoglycemic episodes • When possible, avoid treating patients during peak activity periods with insulin or oral hypoglycemic medications • Know how to manage a hypoglycemic event b. Discuss with the patient’s physician the potential impact of long and/or complicated dental procedures, or consultation with the physician should be done as deemed appropriate ■ Medical management of those at risk for diabetes or those previously diagnosed with diabetes who may also have periodontal disease should consist of the following (during the initial visit and updated as needed at follow-up visits): 1. Screening for signs and symptoms associated with periodontal disease 2. Referral to the dentist when periodontal disease is suspected 3. Recommendations for biannual dental examinations and treatment as necessary 4. Recommendations for strict compliance to patient self care/oral hygiene 5. Provide dental provider with routine reports of patients’ HbA lab values and any other reports that may indicate increased 1c risk for complications of diabetes

Focused Question Topic #7 – Periodontal diseases and atherosclerosis-induced diseases

■ Medical and dental communities should begin to recognize periodontal disease as a potential source of systemic inﬂ amma- B‡‡ tion subsequently placing exposed individuals at greater risk for the development and progression of atherosclerosis-induced diseases, such as coronary heart disease and ischemic stroke. However, a strict evidence-based decision making process indicates that treatment of periodontal disease should be recommended on the basis of its beneﬁ ts in oral health.

Focused Question Topic #8 – Potential of periodontal disease interventions to decrease risk for CVD

■ Periodontal disease should be treated for its oral benefi ts, regardless of the evidence for or against the benefi t in coronary heart disease and stroke. It is a chronic infection that can result in tooth loss and systemic infl ammation. Since treatment of C§§ periodontal disease has been shown to improve endothelial function, it may have the potential to reduce the incidence of coronary heart disease and stroke; however, this needs to be confi rmed by randomized controlled intervention trials. Until that time, it is recommended to aggressively treat periodontal disease in patients with high risk for, or a previous history of, CVD and cerebrovascular disease.

are no guidelines for management of the infl ammatory burden of Focus #4 – Periodontal Disease Treatment and Decreased periodontal disease, other than to diagnose and treat according Infl ammatory Response to traditional standards. There are no “best treatment” guidelines Eight studies (3 [level 1b],28,32,45 2 [level 2b],34,46 2 [level 3b],52,127 for the control of local infl ammation that consider the systemic and 1 [level 4]47) support the concept that nonsurgical periodontal response to such treatment. therapy can reduce local oral levels of infl ammatory mediators

18 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_18 18 9/24/07 10:29:00 AM Report of the Independent Panel of Experts of The Scottsdale Project

and systemic markers of infl ammation. However, 3 studies29,128,129 study is noteworthy because it also demonstrated signifi cant (level 2b) report that, in fact, periodontal therapy induces an reductions in serum lipid levels (low density lipoprotein increase in plasma levels. However, the latter studies report only cholesterol and triglycerides) after periodontal treatment, short-term results (3 months), and at least 1 study45 (level 1b) linking periodontal health to improvements in other risk has noted a transient increase in serum markers followed by a factors for atherosclerosis. progressive decrease, achieving signifi cant low levels at 6 months • Rodrigues and colleagues50 (level 2b) represents a prospective post-therapy. clinical study of a small group of people with type 2 diabetes and moderate periodontal disease. The results demonstrated The inconsistent results reported by these relatively few that one-stage nonsurgical periodontal therapy improved clinical trials indicate the need for further investigations using periodontal health, as evidenced by clinical indices (PD, larger subject populations, longer posttreatment intervals for loss of attachment, gingival bleeding) and glycemic control

data collection, and well defi ned endpoints for measurement and (signifi cant reductions in HbA1c levels). analysis. • Schara and colleagues54 (level 3b) represents a small clinical pilot trial of people with type 1 diabetes where full mouth Focus #5 – Periodontal Disease Interventions and Diabetes disinfection was used to decrease oral microbial burden. Outcomes The results demonstrated that full mouth disinfection, even Despite the studies that demonstrate improvements in in the absence of mechanical removal of the plaque biofi lm, glycemic control after periodontal therapy, inconsistencies and improved periodontal health as evidenced by clinical indices weak study designs remain a barrier to defi nitive conclusions. (PD, loss of attachment, gingival bleeding) and glycemic

This is illustrated best by the meta-analysis performed by Janket control (signifi cant reductions in HbA1c levels). This result and colleagues55 (level 1a), which demonstrated that there was has important implications for settings and patients where

no statistically signifi cant reduction in HbA1c after periodontal traditional nonsurgical therapy is not possible. 51 therapy. However, the absolute reductions in HbA1c (0.4% without • Stewart and colleagues (level 2b) represents a prospective antibiotics and 0.7% with antibiotics) might be considered clinical study of a small group of type 2 diabetes and moderate clinically signifi cant to many physicians and dentists. periodontal disease who received periodontal treatment over an 18-month period. Consistent with other studies, the results The following 6 prospective cohort, case-control, and clinical demonstrated that nonsurgical periodontal therapy improved trials were prominent in discussions and decision-making: periodontal health (PD, loss of attachment, gingival bleeding) 49 • Grossi and colleagues (level 2b) represents a prospective, and glycemic control (signifi cant reductions in HbA1c levels). randomized, blinded, placebo controlled trial. The experimental groups were small, detracting from the ultimate strength of Several studies have failed to demonstrate signifi cant changes

the study. However, the results demonstrated that treatment of in fasting blood glucose or HbA1c levels after periodontal periodontal disease using adjunctive antimicrobials in patients therapy. Jones and colleagues39 (level 2b) reported on a single- with type 2 diabetes improved glycemic control as evidenced blind randomized clinical trial of 4-month duration. Results

by signifi cant reductions in HbA1c levels. Improved glycemic demonstrated no change in HbA1c levels after periodontal control corresponded to improved periodontal health as treatment. The moderate sample size was larger than all measured by clinical indices (PD, loss of attachment, gingival previous studies. The question will be whether these fi ndings bleeding). can be generalized, as the study was conducted in a Veteran’s • Iwamoto and colleagues52 (level 3b) represents a single cohort Administration setting using a predominantly white older male study with a small number of subjects that did not use an population. Promsudthi and colleagues56 (level 2b) conducted untreated control group due to ethical concerns. Thus, the a 3-month prospective clinical study of a very small group study is not considered to be particularly strong. The results of subjects with type 2 diabetes. Results demonstrated that demonstrated that antimicrobial periodontal therapy was although periodontal health improved, no signifi cant change in

effective in improving metabolic control in patients with fasting blood glucose or HbA1c levels occurred after periodontal type 2 diabetes through signifi cant reductions in circulating treatment. α TNF- , fasting insulin levels, and HbA1c levels, linking insulin resistance to the relationship of periodontal disease and type 2 Focus #6 – Potential Guideline Development for Patients at diabetes. Risk for Diabetes and Periodontal Disease • Kiran and colleagues53 (level 3b) represents a prospective Despite some inconsistencies and the fact that some clinical study of a small group of patients with type 2 diabetes areas have not been adequately addressed (e.g., the effect of and moderate periodontal disease. These results demonstrated treatment of periodontal disease on nephropathy and CVD), 7 that nonsurgical periodontal therapy improved periodontal studies provide level 2b-3b evidence for recommendations that health (PD, loss of attachment, gingival bleeding) and glycemic specifi cally address glycemic control (Table 4, Focus Question 48-54 42,57,58 37 control measured by signifi cant reductions in HbA1c levels. The #5). Eight other studies (3 [level 2a], 1 [level 2b], 1

Grand Rounds Supplement | September 2007 19

0709GRsupp_rev_19 19 9/24/07 10:29:18 AM Report of the Independent Panel of Experts of The Scottsdale Project

[level 4],59 and 3 [level 5]60-62) support transdisciplinary practice in controlling diabetes-associated complications including recommendations, demonstrating the relationship between periodontitis. diabetes and its complications, periodontal disease, and systemic • Southerland and colleagues62 (level 5) demonstrated the infl ammation. The members of the expert panel were unanimous bidirectional relationship between diabetes and periodontal in proposing that there are other benefi ts of systemic disease disease, whereby diabetes represents a systemic disease outcomes resulting from improved oral health, and that these predisposing to oral infection, and once that oral infection potential benefi ts justify improved communication between is established, periodontitis serves as a metabolic stressor healthcare providers. that accelerates systemic disease progression. It appears that the incidence of CVD is increased in patients with diabetes, The following 4 studies and investigations were prominent in in part because diabetes and periodontal infections are both discussions and decision-making: associated with a systemic infl ammatory response leading to • Bakhsandeh and colleagues59 (level 4) represents a cross- more extensive atherosclerosis that develops at an earlier age sectional study demonstrating that patients with diabetes in diabetic patients. This study also provided suggestions for have poor periodontal status and little knowledge concerning improving oral health outcomes and reducing complications proper oral hygiene/oral health. of diabetes in this patient population. • Khader and colleagues57 (level 2a) confi rms this study, and represents a recent large meta-analysis of the Medline database Saremi and colleagues42 (level 2a) represents a moderate from 1970-2003 that included 21 observational studies. size prospective longitudinal study in Pima Indians. Results • Lalla and colleagues37 (level 2b) represents a small prospective demonstrated that periodontal disease is a strong predictor of clinical study of subjects with type 1 and type 2 diabetes, mortality from diabetic complications (ischemic heart disease and demonstrating that periodontal therapy signifi cantly reduces nephropathy) in patients with type 2 diabetes. immune cell production of TNF-α and circulating levels of CRP. This result provides evidence for reduction of systemic Focus #7 – Periodontal Diseases and Atherosclerosis-Induced infl ammatory markers associated with atherosclerosis-related Diseases complications in diabetes. Evidence from 5 studies (2 [level 1b],28,32 1 [level 2b],30 and • Mealey and Oates58 (level 2a) conducted a meta-analysis from a 2 [level 5]25,130) supports a systemic effect of periodontitis (and broad PubMed search of studies in the last 20 years, including possibly gingivitis) associated bacteremias/endotoxemias and data from over 3,500 adults with diabetes. The analysis entry of infl ammatory mediators into the circulatory system. relied on original data from small studies of diverse patient There is strong evidence from 2 studies (1 [level 1b]131 and 1 populations and/or studies that variably defi ne parameters of [level 2b]132) that infl ammation plays a dominant role in the diabetes/glycemic control. This study demonstrated consistent pathogenesis of atherosclerosis and that atherosclerosis is a fi ndings that diabetes increases the risk for periodontal disease major component of cardiovascular and cerebrovascular diseases. and increases the extent/severity of periodontal disease. Larsen and colleagues133 (level 1b) recently indicated that control Additionally, the analysis revealed evidence that periodontal of infl ammation improves glycemic control in diabetes; Bogaty disease initiates or exacerbates insulin resistance through and colleagues134 (level 1b) suggested that anti-infl ammatory elevations in serum levels of TNF-α. therapies may be effective in reducing cardiovascular risk.

Three recent comprehensive reviews emphasize the connection Several types of observational studies were prominent in between periodontal disease, diabetes, systemic infl ammation, discussions and decision-making: and the potential for improved oral health to reduce diabetic • The fi rst type consisted of 6 retrospective, cross-sectional, or complications: case comparison designs (3 [level 2b]64-66 and 3 [level 3b]72,78,79). • Nishimura and colleagues61 (level 5) demonstrated that exag- Beck and colleagues64 (level 2b) demonstrated that both gerated host immune responses are the fundamental mecha- moderate and severe periodontal disease were signifi cantly nisms by which patients at risk for diabetes, those already di- associated with carotid intima-media wall thickness (a measure agnosed with diabetes, and obese patients are prone to severe of preclinical atherosclerosis) suggesting that periodontal periodontitis; and, that periodontal infection and infl amma- disease plays a role in atheroma formation. Deliagyris and tion further exacerbates host immune responses accelerating colleagues72 (level 3b) demonstrated that periodontal therapy development of complications such as nephropathy and mac- produces signifi cant reductions in circulating infl ammatory rovascular disorders. biomarkers (IL-6 and CRP) and that the association between • Nassar and colleagues60 (level 5) demonstrated that adjunctive CRP and periodontal disease in patients with acute myocardial anti-infl ammatory therapies are highly effective for treatment infarction is independent of other risk factors. Hung and of periodontal disease in patients with diabetes. This is colleagues65 (level 2b) demonstrated that there is an inverse signifi cant because it confi rms that therapies targeting the relationship between the number of remaining teeth and specifi c infl ammatory mechanisms in diabetes may have value CVD while Lee demonstrated this inverse association for

20 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_20 20 9/24/07 10:29:36 AM Report of the Independent Panel of Experts of The Scottsdale Project

ischemic stroke. This supports that tooth loss is an important conducted a systematic review of published retrospective/ indicator of past history of periodontal disease and systemic prospective studies and meta-analyses, confi rming that the infl ammation. preponderance of studies report signifi cant associations • The second study type consisted of 7 randomized, prospective between periodontal and coronary heart disease as well as case-control designed (level 3b) studies.70,75,77,80,81,83,84 Dorfer stroke. and colleagues75 (level 3b) conducted a large case-control study linking periodontal disease to cerebral ischemia. It was actually Three studies (1 [level 2b],86 1 [level 3b] observational study,87 the largest study of its kind and shows the strongest association and 1 [level 2a] meta-analysis85) failed to demonstrate signifi cant between these two entities. The study controlled for many associations (i.e., there were no associations or only very weak confounding factors and used meticulous determination of associations) between periodontal disease and coronary heart dental status. Spahr and colleagues83 (level 3b) conducted a disease, or between periodontal disease and cerebrovascular moderate size case-control study linking periodontal disease disease. Howell and colleagues86 (level 2b) conducted a to coronary heart disease, and demonstrated a dose-response prospective cohort study where periodontal disease was self- relationship between oral microbial burden and heart disease reported, potentially leading to misclassifi cation and biasing the severity. It was a well controlled study of consecutive patients study to the null. Nakib and colleagues87 (level 3b) conducted with clinically confi rmed coronary heart disease. Tabrizi and a prospective cohort study that found no association between colleagues84 (level 3b) conducted a small twin study of 10 periodontal disease and coronary artery calcifi cation. The study monozygotic pairs (1 twin with coronary heart disease and 1 was small and underpowered. Khader and colleagues85 (level twin without coronary heart disease), confi rming that poor 2a) conducted a meta-analysis of observational studies (only 8 periodontal status was comparable in both twins. studies for periodontal disease and coronary heart disease, only • The third study type consisted of 8 prospective cohort designs 6 studies for periodontal disease and cerebrovascular disease). (2 [level 2b]67,68 and 6 [level 3b]71,73,74,76,82,87). Desvarieux and No signifi cant associations were demonstrated; study selection colleagues73 (level 3b) conducted a moderate sized study that complicated the analysis due to wide variability in study demonstrated a signifi cant association between tooth loss designs. and carotid artery plaques; in another moderate sized study, Desvarieux and colleagues74 (level 3b) demonstrated a signifi cant There are potential benefi ts of periodontal disease treatment association between oral microbial burden and carotid artery as a method for reducing systemic infl ammation and subsequently intima-media wall thickness. Slade and colleagues82 (level improving glycemic control in diabetes or reducing cardiovascular 3b) conducted a large study demonstrating a signifi cant risk. Larsen and colleagues133 (level 1b) represents a small association between periodontal disease and CRP levels. Wu multicenter randomized, double-blind, parallel group, controlled and colleagues68 (level 2b) conducted a large National Health trial. This study demonstrated that blockade of IL-1 improves

and Nutrition Estimate Studies (NHANES) cohort study that glycemia (as evidenced by signifi cant reductions in HbA1c demonstrated a signifi cant association between periodontal levels), and signifi cantly reduces circulating markers of systemic disease and ischemic stroke. This was a particularly strong infl ammation. Bogaty and colleagues134 (level 1b) represents a study because it focused on PD measurements (not on tooth small randomized, double-blind, parallel group, placebo controlled loss) in a national representative sample of the U.S. population trial. This study demonstrated that COX-2 inhibition signifi cantly (NHANES data). In addition, it provides some specifi city to the reduces circulating markers of systemic infl ammation associated observed association between PD and stroke because it shows with cardiovascular risk. However, it is important to consider that the link between PD and ischemic stroke but not between PD recent studies involving COX-2 inhibitors have been linked to and nonischemic stroke (exactly what one would expect from increased risk of myocardial infarction. the hypothesized mechanisms). • The fourth study type consisted of a prospective, randomized, Focus #8 – Potential of Periodontal Disease Interventions to controlled parallel arm intervention trial (level 1b);135 and the Decrease Risk for CVD fi fth study type consisted of 2 (level 2a) meta-analyses63,85 and 1 In addition to evidence that periodontitis results in systemic (level 3a) systematic review.69 D’Aiuto and colleagues135 (level infl ammation,25,28,30,32,130 as discussed in Focus #7 above, there is 1b) conducted a small study demonstrating that periodontal strong evidence in 2 studies (1 [level 1b]131 and 1 [level 2b]132) therapy signifi cantly decreased circulating infl ammatory that infl ammation plays a dominant role in the pathogenesis of biomarkers (IL-6 and CRP). Janket and colleagues63 (level 2a) atherosclerosis, and that atherosclerosis is a major component of conducted a large meta-analysis that confi rmed a signifi cant cardiovascular and cerebrovascular diseases. association between periodontal disease and coronary heart disease as well as stroke. This study also demonstrated that the Four recent studies (1 [level 1b],45 1 [level 2b],88 and 2 [level risk is higher for persons less than 65 years of age emphasizing 4]89,90) provide evidence for improved endothelial function after the importance of prevention and early intervention for periodontal treatment: periodontal disease. Meurman and colleagues69 (level 3a) • The study by Mercanoglu and colleagues88 (level 2b) was a

Grand Rounds Supplement | September 2007 21

0709GRsupp_rev_21 21 9/24/07 10:29:54 AM Report of the Independent Panel of Experts of The Scottsdale Project

small prospective controlled trial of cohorts with chronic undiagnosed diabetes and/or CVD who need to be referred to periodontitis and without any atherosclerotic vascular disease. physicians? Brachial artery responses to reactive hyperemia (endothelium- dependent dilatation, EDD) and sublingual nitroglycerin (en- Consensus Statement: Yes, it is appropriate to develop guidelines dothelium-independent dilatation, EID) were measured using to assist dental providers in identifying patients who are at risk high-resolution vascular ultrasound before and after initial for diabetes and/or CVD. A thorough search for patient-provided periodontal therapy. At baseline, EDD and EID were signifi - information that may lead to a diagnosis to improve oral and cantly impaired in patients with chronic periodontitis. After systemic health should be conducted by dental providers. nonsurgical periodontal therapy, EDD and EID improved signifi cantly. Recommendation (USPSTF Level A): The American Diabetes • The study by Tonetti and colleagues45 (level 1b) was a moderate Association has established criteria for screening for diabetes.136 sized prospective trial of patients with moderate periodontal With the epidemic increase of diabetes in the past 10 years, the disease assessing endothelial function by measurement of dentist and dental hygienist have a greater responsibility than the diameter of the brachial artery (fl ow-mediated dilatation, ever before in carefully screening patients. The expert panel of [FMD]) before and after treatment. FMD was greater within The Scottsdale Project recommends increasing awareness of the 60 days after treatment and the degree of improvement was diabetic profi le and these screening criteria within the dentist and associated with improvement in clinical measures of periodontal dental hygienist communities. disease. • The study by Elter and colleagues89 (level 4) represented a The risk of having undiagnosed diabetes with newly diagnosed small prospective trial of healthy adults with moderate to severe periodontal disease is unknown; however, periodontal disease is periodontitis who underwent complete mouth disinfection and associated with diabetes. Indeed a very fi rst attempt to explore the were evaluated to determine if periodontal therapy would result contribution of periodontal fi ndings in assessing the probability in improved endothelial function using EDD and EID of the for unrecognized diabetes in the dental offi ce was reported by brachial artery. Periodontal treatment resulted in signifi cant Borrell and colleagues.137 The study suggested that the dental offi ce improvements in periodontal pocketing and EDD. could provide an important opportunity to identify individuals • The study by Seinost and colleagues90 (level 4) was a small unaware of their diabetic status, and is the fi rst step of the effort prospective controlled trial assessing the effects of treatment for to develop a tool to assist dentists in such an endeavor. Although severe periodontitis on FMD of the brachial artery. The groups there was a spread of opinion among the panel’s experts regarding were matched for age, sex, and cardiovascular risk factors. how screening protocols should be incorporated into dental care FMD was signifi cantly lower in patients with periodontitis settings, the expert panel was concordant in recommending the than in control subjects and periodontal treatment resulted in a following: signifi cant improvement in FMD. 1. Patients at risk for diabetes (information obtained from thorough family and personal medical history), regardless of Taken together, these initial studies indicate that treatment oral presentation, should be referred by dentists to laboratories of periodontitis reverses endothelial dysfunction. Randomized to have their fasting blood glucose levels checked and/or controlled trials are needed to determine if this is the case. Whether referred to the physician for further diagnostic evaluation. improved endothelial function will translate into a benefi cial 2. Patients with severe periodontitis (severe for age, failure effect on atherogenesis and cardiovascular/cerebrovascular events to respond to treatment, abscesses) or fungal infection should needs further investigation. be considered for referral to the physician for screening for diabetes. CONCLUSIONS OF THE INDEPENDENT PANEL 3. If laboratory testing for diabetes is performed in a dental care setting, it should be done in accordance with American OF EXPERTS REGARDING APPROPRIATENESS Diabetes Association screening guidelines (fasting blood OF GUIDELINE DEVELOPMENT glucose) with appropriate follow up of laboratory data and communication with the physician. The answers to the focused questions and their companion 4. For the patient who has been diagnosed with diabetes and/ recommendations provide the rationale for solidarity of expert or CVD, dentists should work collaboratively with physicians opinion regarding whether suffi cient evidence currently exists to to achieve the best possible patient care outcomes. A set of support the development of guidelines. guidelines should be developed to defi ne what is important for bidirectional interprofessional communication. KEY ISSUE I 5. Patients at risk for CVD should be referred to the physician. Question: Is it appropriate to develop guidelines that assist There was a lack of consensus regarding the optimal screen- dental providers in identifying patients who have or who are ing method for coronary heart disease or stroke (e.g., risk as- at risk for diabetes and/or CVD, or screening patients for sessment tools developed by the American Heart Association,

22 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_22 22 9/24/07 10:30:18 AM Report of the Independent Panel of Experts of The Scottsdale Project

Framingham Risk Assessment). However, the expert panel referred to the dental provider. recommended referral to a physician for additional assessment of CVD risk for those dental patients who have not Recommendation (USPSTF Level A): The American Academy of had a medical evaluation within 2 years, and 2 or more of Periodontology has developed guidelines4-6 for the diagnosis and the following: older than 50 years of age, at risk for diabetes assessment of patients with periodontal disease. The guidelines mellitus, hypertension, dyslipidemia with a family history of include periodontal probing and intraoral radiographic diagnosis, coronary heart disease or stroke, tobacco use, and/or a his- which are not feasible in most medical settings. Nevertheless, tory consistent with CVD. physicians can screen for signs and symptoms associated with 6. Patients already diagnosed with diabetes who do not have a periodontal disease based on patient history, symptoms, and treating physician are at high risk for cardiovascular events and a visual assessment of the patient’s teeth and gums. Signs of should be seen by a physician. periodontal disease include: • red, sore, swollen, receding, or bleeding gums KEY ISSUE II • loose or sensitive teeth, separation of teeth Question: Is it appropriate to develop guidelines that assist • presence or history of oral abscesses medical providers in identifying patients who are at risk for • halitosis periodontal disease, or screening patients who may have • missing teeth undiagnosed periodontal disease who need to be referred to • accumulation of food debris or plaque around teeth dentists? Accordingly, the expert panel of The Scottsdale Project Consensus Statement: Yes, it is appropriate to develop guidelines recommended that medical providers screen and refer all patients to assist medical providers in identifying patients who are at suspected as having periodontal disease as outlined in Figure risk for periodontal disease, or screening patients who may 4, as well as the following management plan for patients with have undiagnosed periodontal disease who need to be referred diabetes. to dentists. Medical providers’ recognition of the signs and 1. Patients with diabetes should be medically managed as symptoms associated with periodontal disease may identify recommended by the American Diabetes Association. patients who are either at risk or are undiagnosed who should be 2. Patients with diabetes should have a dental exam at a minimum of twice a year, or more frequently if advised by the dental provider, and receive appropriate dental/periodontal care. Figure 4. Expert panel recommendations for physicians to 3. There should be close communication between the primary screen and refer patients with signs of periodontal disease. care physician and the dentist. 4. Medical providers should advise the patient with periodontal disease that it is a chronic infection of the gums and an The physician should ask the patient: Have you seen a dental provider in the last year? important complication of diabetes. 5. Medical providers should also advise patients that periodontal disease has been associated with signifi cant health problems, including worse metabolic control and other complications of NO YES diabetes, coronary artery disease, and stroke. 6. Medical providers should advise the patient that periodontal disease can be treated by the dentist and dental hygienist. Refer to a dental The physician should then 7. If the patient has not seen a dentist within the last year or if provider ask the patient (and/or there are signs of periodontal disease, the patient should be perform an oral exam): advised to make an appointment to see the dental provider Do you have any of the right away. following? The currently available evidence was assessed in the formulation Bleeding gums of these recommendations; the expert panel’s recommendations Unsteady teeth for clinical guidelines should not be interpreted to mean that the Gum recession scientifi c evidence is fully adequate.

SPECIAL NOTE Refer to a dentist as appropriate At the time the Report of the Independent Panel of Experts of The Scottsdale Project went to press, the American Diabetes Association suggested that the report be referred to its professional practice

Grand Rounds Supplement | September 2007 23

0709GRsupp_rev_23 23 9/24/07 10:30:40 AM Report of the Independent Panel of Experts of The Scottsdale Project

committee (guideline committee) to summarize the report’s 16. Albandar JM, Kingman A. Gingival recession, gingival bleeding, recommendations and reference the report in the 2008 Standards and dental calculus in adults 30 years of age and older in the United J Periodontol of Medical Care in Diabetes. States, 1988-1994. . 1999;70(1):30-43. 17. Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults age 30 years of age and older in the U.S. J Periodontol. DISCLOSURE 1999;70(1):13-29. [Erratum in: J Periodontol 1999;70(3):351.] Casey Hein received an honorarium for oversight of The 18. Cobb CM. Diagnosis and treatment of periodontal disease: a crisis of Triage Scottsdale Project and authorship of the Report of the Independent direction. . 2005;1:15-20. Panel of Experts of The Scottsdale Project. 19. American Heart Association. Heart Disease and Stroke Statistics — 2005 Update. Dallas, TX: American Heart Association; 2004. Available at: http://www.americanheart.org/presenter.jhtml?identifi er=1928. Accessed December 6, 2005. 20. Glick M, Greenberg BL. The potential role of dentists in identifying patients’ risk of experiencing coronary heart disease events. J Am REFERENCES Dent Assoc. 2005; 136(11):1541-1546. 1. Armitage GC. Development of a classifi cation system for periodontal 21. Bloomgarden ZT. Developments in diabetes and insulin resistance diseases and conditions [review]. Ann Periodontol. 1999;4:1-6. [review]. Diabetes Care. 2006;29(1):161-167. 2. Rose LF, Cohen DW, Genco RJ, et al. Periodontics: Medicine, Surgery, 22. Loos BG, Craandijk J, Hoek FJ, et al. Elevation of systemic markers and Implants. 2nd ed. St. Louis, MO: Elsevier Mosby; 2004. related to cardiovascular diseases in the peripheral blood of 3. Newman MG, Takei HH, Carranza FA. Clinical Periodontology; 9th periodontitis patients. J Periodontol. 2000;71(10):1528-1534. edition. Philadelphia, PA: W.B. Saunders Co; 2002. 23. De Nardin E. The role of infl ammatory and immunological mediators 4. American Academy of Periodontology. Parameter on plaque-induced in periodontitis and cardiovascular disease [review]. Ann Periodontol. gingivitis. J Periodontol. 2000;71(5 Suppl):851-852. 2001;6(1):30-40. 5. American Academy of Periodontology. Parameter on chronic 24. Gemmell E, Marshall RI, Seymour GJ. Cytokines and prostaglandins periodontitis with slight to moderate loss of periodontal support. in immune homeostasis and tissue destruction in periodontal disease J Periodontol. 2000;71(5 Suppl):853-855. [review]. Periodontol 2000. 1997;14:112-143. 6. American Academy of Periodontology. Parameter on chronic 25. Loos BG. Systemic markers of infl ammation in periodontitis [review]. periodontitis with advanced loss of periodontal support. J Periodontol. J Periodontol. 2005;76(11 Suppl.):2106-2115. 2000;71(5 Suppl):856-858. 26. Offenbacher S. Periodontal diseases: pathogenesis [review]. Ann 7. Löe H, Anerud A, Boysen H, et al. Natural history of periodontal Periodontol. 1996;1(1):821-878. disease in man. Rapid, moderate and no loss of attachment in 27. Offenbacher S, Elter JR, Lin D, et al. Evidence for periodontitis as a Sri Lankan laborers 14 to 16 years of age. J Clin Periodontol. tertiary vascular infection. J Int Acad Periodontol. 2005;7(2):39-48. 1986;13(5):431-445. 28. D’Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic 8. Jeffcoat MK, Reddy MS. Progression of probing attachment loss in infl ammation: control of the local infection is associated with a reduction adult periodontitis. J Periodontol. 1991;62:185-189. in serum infl ammatory markers. J Dent Res. 2004;83(2):156-160. 9. Page RC, Offenbacher S, Schroeder HE, et al. Advances in the 29. Ide M, Jagdev D, Coward PY, et al. The short-term effects of pathogenesis of periodontitis: Summary of developments, clinical treatment of chronic periodontitis on circulating levels of endotoxin, implications and future directions. Periodontol 2000. 1997;14:216-248. C-reactive protein, tumor necrosis factor-alpha, and interleukin-6. 10. Page RC, Kornman KS, Tonetti MS. The host response to the J Periodontol. 2004;75(3):420-428. microbial challenge in periodontitis: Assembling the players. 30. Noack B, Genco RJ, Trevisan M, et al. Periodontal infections Periodontol 2000. 1997;14:33-53. contribute to elevated systemic C-reactive protein level. J Periodontol. 11. Salvi GE, Lawrence HP, Offenbacher S, et al. Infl uence of risk factors 2001;72(9):1221-1227. on the pathogenesis of periodontitis: An introduction. Periodontol 31. Schaumberg DA, Glynn RJ, Jenkins AJ, et al. Effect of intensive 2000. 1997; 14:9-11. glycemic control on levels of markers of infl ammation in type 1 12. Li X, Kolltveit KM, Tronstad L, et al. Systemic diseases caused by diabetes mellitus in the diabetes control and complications trial. oral infection. Clin Microbiol Rev. 2000;13(4):547-558. Circulation. 2005;111(19):2446-2453. 13. Iacopino AM. Periodontitis and diabetes interrelationships: role of 32. D’Aiuto F, Nibali L, Parkar M, et al. Short-term effects of intensive infl ammation. Ann Periodontol. 2001;6(1):125-137. periodontal therapy on serum infl ammatory markers and cholesterol. J Dent Res. 2005;84(3):269-273. 14. U.S. Department of Health and Human Services. Oral Health in America: A Report of the Surgeon General. Rockville, MD: U.S. 33. Craig RG, Yip JK, So MK, et al. Relationship of destructive Department of Health and Human Services, National Institute of periodontal disease to the acute-phase response. J Periodontol. Dental and Cranial Research, National Institutes of Health; 2000. 2003;74(7):1007-1016. 15. Eke PI, Genco RJ. CDC Periodontal Disease Surveillance 34. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease and C-reactive Project: background, objectives, and progress report. J Periodontol. protein-associated cardiovascular risk. J Periodont Res. 2004;39(4):236- 2007;78:1366-1371. 241.

24 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_24 24 9/24/07 10:31:00 AM Report of the Independent Panel of Experts of The Scottsdale Project

35. Buhlin K, Gustafsson A, Pockley AG, et al. Risk factors for 54. Schara R, Medvescek M, Skaleric U. Periodontal disease and diabetes cardiovascular disease in patients with periodontitis. Eur Heart J. metabolic control: a full-mouth disinfection approach. J Int Acad 2003;24(23):2099-2107. Periodontol. 2006;8(2):61-66. 36. Wu T, Trevisan M, Genco RJ, et al. Examination of the relation 55. Janket SJ, Wightman A, Baird AE, et al. Does periodontal treatment between periodontal health status and cardiovascular risk factors: improve glycemic control in diabetic patients? A meta-analysis of serum total and high density lipoprotein cholesterol, C-reactive intervention studies. J Dent Res. 2005;84(12):1154-1159. protein, and plasma fi brinogen. Am J Epidemiol. 2000;151(3):273- 56. Promsudthi A, Pimapansri S, Deerochanawong C, et al. The effect of 282. periodontal therapy on uncontrolled type 2 diabetes mellitus in older 37. Lalla E, Cheng B, Lal S, et al. Diabetes mellitus promotes periodontal subjects. Oral Dis. 2005;11(5):293-298. destruction in children. J Clin Periodontol. 2007;34(4):294-298. 57. Khader YS, Dauod AS, El-Qaderi SS, et al. Periodontal status of 38. Campus G, Salem A, Uzzau S, et al. Diabetes and periodontal disease: diabetics compared with nondiabetics: a meta-analysis. J Diabetes a case-control study. J Periodontol. 2005;76(3):418-425. Complications. 2006;20(1):59-68. 39. Jones JA, Miller DR, Wehler CJ, et al. Does periodontal care improve 58. Mealey BL, Oates TW. American Academy of Periodontology. glycemic control? The Department of Veterans Affairs Dental Diabetes mellitus and periodontal diseases [review]. J Periodontol. Diabetes Study. J Clin Periodontol. 2007;34(1):46-52. 2006;77(8):1289-1303. 40. Lim LP, Tay FB, Sum CF, et al. Relationship between markers of 59. Bakhshandeh S, Murtomaa H, Mofi d R, et al. Periodontal treatment metabolic control and infl ammation on severity of periodontal disease in needs of diabetic adults. J Clin Periodontol. 2007;34(1):53-57. patients with diabetes mellitus. J Clin Periodontol. 2007;34(2):118-123. 60. Nassar H, Kantarci A, van Dyke TE. Diabetic periodontitis: a 41. Shultis WA, Weil EJ, Looker HC, et al. Effect of periodontitis on model for activated innate immunity and impaired resolution of overt nephropathy and end-stage renal disease in type 2 diabetes. infl ammation [review]. Periodontol 2000. 2007;43:233-244. Diabetes Care. 2007;30(2):306-311. 61. Nishimura F, Iwamoto Y, Soga Y. The periodontal host response with 42. Saremi A, Nelson RG, Tulloch-Reid M, et al. Periodontal disease and diabetes [review]. Periodontol 2000. 2007;43:245-253. mortality in type 2 diabetes. Diabetes Care. 2005;28(1):27-32. 62. Southerland JH, Taylor GW, Offenbacher S. Diabetes and periodontal 43. Taylor GW, Burt BA, Becker MP, et al. Non-insulin dependent infection: making the connection. Clinical Diabetes. 2005;23:171- diabetes mellitus and alveolar bone loss progression over 2 years. 178. J Periodontol. 1998;69(1):76-83. 63. Janket SJ, Baird AE, Chuang SK, et al. Meta-analysis of periodontal 44. Thorstensson H, Kuylenstierna J, Hugoson A. Medical status and disease and risk of coronary heart disease and stroke. Oral Surg Oral complications in relation to periodontal disease experience in insulin- Med Oral Pathol Oral Radiol Endod. 2003;95(5):559-569. dependent diabetics. J Clin Periodontol. 1996;23(3 Pt 1):194-202. 64. Beck JD, Elter JR, Heiss G, et al. Relationship of periodontal disease 45. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of periodontitis to carotid artery intima-media wall thickness: the atherosclerosis and endothelial function. N Eng J Med. 2007;356(9):911-920. risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol. 2001;21(11):1816-1822. 46. D’Aiuto F, Parkar M, Tonetti MS. Acute effects of periodontal therapy on bio-markers of vascular health. J Clin Periodontol. 2007;34(2):124- 65. Hung HC, Joshipura KJ, Colditz G, et al. The association between 129. tooth loss and coronary heart disease in men and women. J Public Health Dent. 2004;64(4):209-215. 47. Yamazaki K, Honda T, Oda T, et al. Effect of periodontal treatment on the C-reactive protein and proinfl ammatory cytokine levels in 66. Joshipura KJ, Hung HC, Rimm EB, et al. Periodontal disease, tooth Japanese periodontitis patients. J Periodontal Res. 2005;40:53-58. loss, and incidence of ischemic stroke. Stroke. 2003;34(1):47-52. 48. Almas K, Al-Lazzam S, Al-Quadairi A. The effect of oral hygiene 67. Montebugnoli L, Servidio D, Miaton RA, et al. Periodontal health instructions on diabetic type 2 male patients with periodontal improves systemic infl ammatory and hemostatic status in subjects diseases. J Contemp Dent Pract. 2003;4(3):24-35. with coronary heart disease. J Clin Periodontol. 2005;32(2):188-192. 49. Grossi SG, Skrepcinski FB, DeCaro T, et al. Treatment of periodontal 68. Wu T, Trevisan M, Genco RJ, et al. Periodontal disease and risk disease in diabetics reduces glycated hemoglobin. J Periodontol. of cerebrovascular disease: the fi rst national health and nutrition 1997;68(8):713-719. examination survey and its follow-up study. Arch Int Med. 2000;160(18):2749-2755. 50. Rodrigues DC, Taba MJ, Novaes AB, et al. Effect of non-surgical periodontal therapy on glycemic control in patients with type 2 69. Meurman JH, Sanz M, Janket SJ. Oral health, atherosclerosis, and diabetes mellitus. J Periodontol. 2003;74(9):1361-1367. cardiovascular disease. Crit Rev Oral Biol Med. 2004;15(6):403-413. 51. Stewart JE, Wager KA, Friedlander AH, et al. The effect of 70. Briggs JE, McKeown PP, Crawford VLS, et al. Angiographically periodontal treatment on glycemic control in patients with type 2 confi rmed coronary heart disease and periodontal disease in middle- diabetes mellitus. J Clin Periodontol. 2001;28(4):306-310. aged males. J Periodontol. 2006;77(1):95-102. 52. Iwamoto Y, Nishimura F, Nakagawa M, et al. The effect of 71. Czerniuk MR, Górska R, Filipiak KJ, et al. C-reactive protein in antimicrobial periodontal treatment on circulating tumor necrosis patients with coexistent periodontal disease and acute coronary factor-alpha and glycated hemoglobin level in patients with type 2 syndromes. J Clin Periodontol. 2006;33(6):415-420. diabetes. J Periodontol. 2001;72(6):774-778. 72. Deliargyris EN, Madianos PN, Kadoma W, et al. Periodontal 53. Kiran M, Arpak N, Unsal E, et al. The effect of improved periodontal disease in patients with acute myocardial infarction: prevalence health on metabolic control in type 2 diabetes mellitus. J Clin and contribution to elevated C-reactive protein levels. Am Heart J. Periodontol. 2005;32(3):266-272. 2004;147(6):1005-1009.

Grand Rounds Supplement | September 2007 25

0709GRsupp_rev_25 25 9/24/07 10:31:22 AM Report of the Independent Panel of Experts of The Scottsdale Project

73. Desvarieux M, Demmer RT, Rundek T, et al. Relationship between 90. Seinost G, Wimmer G, Skerget M, et al. Periodontal treatment periodontal disease, tooth loss, and carotid artery plaque: the Oral improves endothelial dysfunction in patients with severe periodontitis. Infections and Vascular Disease Epidemiology Study (INVEST). Am Heart J. 2005;149(6):1050-1054. Stroke. 2003;34(9):2120-2125. 91. Daly CG, Mitchell DH, Highfi eld JE, et al. Bacteremia due to 74. Desvarieux M, Demmer RT, Rundek T, et al. Periodontal microbiota periodontal probing: a clinical and microbiological investigation. and carotid intima-media thickness: the Oral Infections and J Periodontol. 2001;72(2):210-214. Vascular Disease Epidemiology Study (INVEST). Circulation. 2005;111(5):576-582. 92. Forner L, Larsen T, Kilian M, et al. Incidence of bacteremia after chewing, tooth brushing and scaling in individuals with periodontal 75. Dorfer CE, Becher H, Ziegler CM, et al. The association of infl ammation. J Clin Periodontol. 2006;33(6):401-407. gingivitis and periodontitis with ischemic stroke. J Clin Periodontol. 2004;31(5):396-401. 93. Kinane DF, Riggio MP, Walker KF, et al. Bacteremia following periodontal procedures. J Clin Periodontol. 2005;32(7):708-713. 76. Engebretson SP, Lamster IB, Elkind MS, et al. Radiographic measures of chronic periodontitis and carotid artery plaque. Stroke. 94. Hujoel PP, White BA, Garcia RI, et al. The dentogingival epithelial J Periodont Res 2005;36(3):561-566. surface area revisited. . 2001;36(1):48-55. Ann 77. Grau AJ, Becher H, Ziegler CM, et al. Periodontal disease as a risk 95. Zambon JJ. Periodontal diseases: microbial factors [review]. Periodontol factor for ischemic stroke. Stroke. 2004;35(2):496-501. . 1996;1(1):879-925. 78. Holmlund A, Holm G, Lind L. Severity of periodontal disease 96. Feng Z, Weinberg A. Role of bacteria in health and disease of and number of remaining teeth are related to the prevalence of periodontal tissues [review]. Periodontol 2000. 2006;40:50-76. myocardial infarction and hypertension in a study based on 4,254 97. Haraszthy VI, Zambon JJ, Trevisan M, et al. Identifi cation of J Periodontol subjects. . 2006;77(7):1173-1178. periodontal pathogens in atheromatous plaques. J Periodontol. 79. Lee HJ, Garcia RI, Janket SJ, et al. The association between 2000;71(10):1554-1560. cumulative periodontal disease and stroke history in older adults. 98. Fiehn NE, Larsen T, Christiansen N, et al. Identifi cation of J Periodontol. 2006;77(10):1744-1754. periodontal pathogens in atherosclerotic vessels. J Periodontol. 80. Lopez R, Oyarzun M, Naranjo C, et al. Coronary heart disease 2005;76(5):731-736. and periodontitis – a case control study in Chilean adults. J Clin 99. Padilla C, Lobos O, Hubert E, et al. Periodontal pathogens Periodontol. 2002;29(5):468-473. [Erratum in: J Clin Periodontol. in atheromatous plaques isolated from patients with chronic 2002;29(8):788.] periodontitis. J Periodont Res. 2006;41(4):350-353. 81. Persson GR, Ohlsson O, Pettersson T, et al. Chronic periodontitis, a 100. Zaremba M, Górska R, Suwalski P, et al. Evaluation of the incidence signifi cant relationship with acute myocardial infarction. Eur Heart of periodontitis-associated bacteria in the atherosclerotic plaque of J. 2003;24(23);2108-2115. coronary blood vessels. J Periodontol. 2007;78(2):322-327. 82. Slade G, Ghezzi EM, Heiss G, et al. Relationship between periodontal 101. Kozarov EV, Dorn BR, Shelburne CE, et al. Human atherosclerotic disease and C-reactive protein among adults in the Atherosclerosis plaque contains viable invasive Actinobacillus actinomycetemcomitans Risk in Communities study. Arch In Med. 2003;163(10):1172-1179. and Porphyromonas gingivalis. Arterioscler Thrombo Vasc Biol. 2005;25(3): 83. Spahr A, Klein E, Khuseyinova N, et al. Periodontal infections and e17-e18. coronary heart disease: role of periodontal bacteria and importance of total pathogen burden in the Coronary Event and Periodontal 102. Geerts SO, Nys M, De MP, et al. Systemic release of endotoxins Disease (CORODONT) study. Arch Int Med. 2006;166(5):554- induced by gentle mastication: association with periodontitis severity. J Periodontol 559. . 2002;73(1):73-78. 84. Tabrizi F, Buhlin K, Gustafsson A, et al. Oral health of monozygotic 103. Ioannidou E, Malekzadeh T, Dongari-Bagtzoglou A. Effect of peri- twins with and without coronary heart disease: a pilot study. J Clin odontal treatment on serum C-reactive protein levels: a systematic re- J Periodontol Periodontol. 2007;34(3):220-225. view and meta-analysis [review]. . 2006;77(10):1635-1642. 85. Khader YS, Albashaireh ZS, Alomari MA. Periodontal disease and the 104. Ebersole JL, Machen RL, Steffen MJ, et al. Systemic acute-phase risk of coronary heart and cerebrovascular disease: a meta-analysis reactants, C-reactive protein and haptoglobin, in adult periodontitis. [review]. J Periodontol. 2004;75(8):1046-1053. Clin Exp Immunol. 1997;107(2):347-352. 86. Howell TH, Ridker PM, Ajani UA, et al. Periodontal disease and risk 105. Glurich I, Grossi S, Albini B, et al. Systemic infl ammation in of subsequent cardiovascular disease in U.S. male physicians. J Am cardiovascular and periodontal disease: comparative study. Clin Coll Cardiol. 2001;37(2):445-450. Diagn Lab Immunol. 2002;9(2):425-432. 87. Nakib SA, Pankow JS, Beck JD, et al. Periodontitis and coronary 106. Slade GD, Offenbacher S, Beck JD, et al. Acute-phase infl ammatory artery calcifi cation: the Atherosclerosis Risk in Communities (ARIC) response to periodontal disease in the US population. J Dent Res. study. J Periodontol. 2004;75(4):505-510. 2000;79(1):49-57. 88. Mercanoglu F, Ofl az H, Oz O, et al. Endothelial dysfunction in 107. Meurman JH, Janket SJ, Quarnstrom, et al. Dental infections and patients with chronic periodontitis and its improvement after initial serum infl ammatory markers in patients with and without severe periodontal therapy. J Periodontol. 2004;75(12):1694-1700. heart disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96(6):695-700. 89. Elter JR, Hinderliter AL, Offenbacher S, et al. The effects of periodontal therapy on vascular endothelial function: a pilot trial. 108. Lalla E, Cheng B, Lal S, et al. Diabetes-related parameters and Am Heart J. 2006;151(11):47. periodontal conditions in children. J Periodont Res. 2007;42(4):345-349.

26 September 2007 | Grand Rounds Supplement

0709GRsupp_rev_26 26 9/24/07 10:31:45 AM Report of the Independent Panel of Experts of The Scottsdale Project

109. Lalla E, Kaplan S, Yang J, et al. Effects of periodontal therapy on 123. Haffner SM, Lehto S, Rönnemaa T, et al. Mortality from coronary serum C-reactive protein, sE-selectin and tumor necrosis factor-alpha heart disease in subjects with type 2 diabetes and in nondiabetic secretion by peripheral blood-derived macrophages in diabetics. A subjects with and without prior myocardial infarction. N Engl J Med. pilot study. J Periodont Res. 2007;42(3):274-282. 1998;339(4):229-234. 110. Lalla E, Cheng B, Lal S, et al. Periodontal changes in children 124. Beck JD, Eke P, Heiss G, et al. Periodontal disease and coronary heart and adolescents with diabetes: a case-control study. Diabetes Care. disease: a reappraisal of the exposure. Circulation. 2005;112(1):19-24. 2006;29(2):295-299. 125. Shimazaki Y, Saito T, Kiyohara Y, et al. Relationship between 111. Taylor GW, Burt BA, Becker MP, et al. Severe periodontitis and risk electrocardiographic abnormalities and periodontal disease: the for poor glycemic control in patients with non-insulin-dependent Hisayama study. J Periodontol. 2004;75(6):791-797. diabetes mellitus. J Periodontol. 1996;67(10 Suppl):1085-1093. 126. Renvert S, Pettersson T, Ohlsson O, et al. Bacterial profi le and 112. Genco RJ, Grossi SG, Ho A, et al. A proposed model linking burden of periodontal infection in subjects with a diagnosis of acute infl ammation to obesity, diabetes and periodontal infections. coronary syndrome. J Periodontol. 2006;77(7):1110-1119. J Periodontol. 2005;76(11 Suppl):2075-2084. 127. Iwamoto Y, Nishimura F, Soga Y, et al. Antimicrobial periodontal 113. Engebretson S, Chertog R, Nichols A, et al. Plasma levels of tumour treatment decreases serum C-reactive protein, tumor necrosis necrosis factor-_ in patients with chronic periodontitis and type 2 factor-alpha, but not adiponectin levels in patients with chronic diabetes. J Clin Periodontol. 2007;34(1):18-24. periodontitis. J Periodontol. 2003;74(8):1231-1236. 114. Grossi SG, Skrepcinski FB, DeCaro T, et al. Response to periodontal 128. Ide M, McPartlin D, Coward PY, et al. Effect of treatment of chronic therapy in diabetics and smokers. J Periodontol. 1996;67(10 periodontitis on levels of serum markers of acute-phase infl ammatory Suppl):1094-1102. and vascular responses. J Clin Periodontol. 2003;30(4):334-340. 115. Aldridge JP, Lester V, Watts TL, et al. Single-blind studies of the 129. Talbert J, Elter J, Jared HL, et al. The effect of periodontal therapy effects of improved periodontal health on metabolic control in type on TNF-alpha, IL-6 and metabolic control in type 2 diabetics. J Dent 1 diabetes mellitus. J Clin Periodontol. 1995;22(4):271-275. Hyg. 2006;80(2):7. 116. Christgau M, Palitzsch KD, Schmalz G, et al. Healing response to 130. Paquette DW. The periodontal infection-systemic disease link: non-surgical periodontal therapy in patients with diabetes mellitus: a review of the truth or myth [review]. J Int Acad Periodontol. clinical, microbiological, and immunological results. J Clin Periodontol. 2002;4(3):101-109. 1998;25(2):112-124. 131. Vlachopoulos C, Dima I, Aznaouridis K, et al. Acute systemic 117. Faria-Almeida R, Navarro A, Bascones A. Clinical and metabolic infl ammation increases arterial stiffness and decreases wave refl ections Circulation changes after conventional treatment of type 2 diabetic patients with in healthy individuals. . 2005;112(14):2193-2200. J Periodontol chronic periodontitis. . 2006;77(4):591-598. 132. Schillinger M, Exner M, Mlekusch W, et al. Infl ammation and Circulation 118. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone Carotid Artery–Risk for Atherosclerosis Study (ICARAS). . treatment on nontraditional makers of cardiovascular disease in patients 2005;111(17):2203-2209. Circulation with type 2 diabetes mellitus. . 2002;106(6):679-684. 133. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1- N Engl J Med 119. Hanley AJ, Karter AJ, Williams K, et al. Prediction of type 2 receptor antagonist in type 2 diabetes mellitus. . diabetes mellitus with alternative defi nitions of the metabolic 2007;356(15):1517-1526. syndrome the insulin resistance atherosclerosis study. Circulation. 134. Bogaty P, Brophy JM, Noel M, et al. Impact of prolonged 2005;112(24):3713-3721. cyclooxygenase-2 inhibition on infl ammatory markers and 120. Howard BV, Best LG, Galloway JM, et al. Coronary heart disease endothelial function in patients with ischemic heart disease and risk equivalence in diabetes depends on concomitant risk factors. raised C-reactive protein: a randomized placebo-controlled study. Circulation Diabetes Care. 2006;29(2):391-397. . 2004;110(8):934-939. 121. Grundy S, Balady GJ, Criqui MH, et al. Primary prevention of 135. D’Aiuto F, Parkar M, Nibali L, et al. Periodontal infections cause coronary heart disease: guidance from Framingham: a statement for changes in traditional and novel cardiovascular risk factors: Am Heart J healthcare professionals from the AHA Task Force on Risk Reduction. results from a randomized controlled clinical trial. . American Heart Association. Circulation. 1998;97(18):1876-1887. 2006;151(5):977-984. 136. American Diabetes Association. Standards of Medical Care in 122. Grundy SM, Howard B, Smith S Jr, et al. Prevention Conference VI: Diabetes – 2007. Diabetes Care. 2007;30(Suppl 1):S4-S41. Diabetes and Cardiovascular Disease: executive summary: conference proceeding for healthcare professionals from a special writing group 137. Borrell LN, Kunzel C, Lamster I, et al. Diabetes in the dental offi ce: of the American Heart Association. Circulation. 2002;105(18):2231- using NHANES III to estimate the probability of undiagnosed 2239. disease. J Periodont Res. 2007; Epub ahead of print.

Grand Rounds Supplement | September 2007 27

0709GRsupp_rev_27 27 9/24/07 10:32:06 AM What makes Colgate Total ® the #1 most recommended toothpaste?1* Proven 12-hour antibacterial, plus anti-inflammatory protection 2

The Only Toothpaste With Clinically Proven 12-Hour Antibacterial, plus Anti-inflammatory Protection

Better Oral Health for Better Overall Health

Visit colgateprofessional.com for free patient samples.

0709GRsupp_rev_28 28 9/24/07 10:23:58 AM