Craig RG, Kamer AR (Eds.) - A Clinician's Guide To Systemic Effects of Periodontal Diseases. Springer. 2016

A Clinician’s Guide to
Systemic Effects of
Periodontal Diseases
Ronald G. Craig
Angela R. Kamer
Editors
123
A Clinician’s Guide to Systemic Effects
of Periodontal Diseases
Ronald G. Craig • Angela R. Kamer
Editors
A Clinician’s Guide to
Systemic Effects of
Periodontal Diseases
Editors
Ronald G. Craig Angela R. Kamer
Basic Sciences and Craniofacial Biology Department of Periodontology
New York University College of Dentistry and Implant Dentistry
New York, NY New York University College of Dentistry
USA New York, NY
USA
ISBN 978-3-662-49697-8 ISBN 978-3-662-49699-2 (eBook)

DOI 10.1007/978-3-662-49699-2
Library of Congress Control Number: 2016940199
© Springer-Verlag Berlin Heidelberg 2016

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Contents
1 Introduction and Overview of the Systemic Effects of Periodontal

Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Ronald G. Craig and Angela R. Kamer
2 Pathogenesis of Periodontal Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Ronald G. Craig
3 Periodontitis and Diabetes Mellitus: A Complex Relationship. . . . . . . 19
Maria Emanuel Ryan, Veena S. Raja, and Sherry K. Sussman
4 Atherosclerotic Vascular Disease and Periodontal Disease . . . . . . . . . . 39
Harmony R. Reynolds and Ronald G. Craig
5 Interactions Between Periodontal Disease and Chronic
Kidney Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Ronald G. Craig and Peter Kotanko
6 The Association Between Periodontitis and Preterm
Labor (PTL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Ananda P. Dasanayake and Frederick Naftolin
7 Oral Health and Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Frank A. Scannapieco and Keith Webb Harris
8 Peripheral Inflammation and Alzheimer’s Disease:
Periodontal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Angela R. Kamer, Ronald G. Craig, and Mony J. de Leon
9 Periodontal Infections and Rheumatoid Arthritis . . . . . . . . . . . . . . . . 107
Walter A. Bretz, Jose U. Scher, and Steven B. Abramson
10 Summary and Possible Future Directions . . . . . . . . . . . . . . . . . . . . . . 117
Angela R. Kamer and Ronald G. Craig
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
v
Contributors
Steven B. Abramson, MD Department of Medicine, New York University School

of Medicine, New York, NY, USA
Walter A. Bretz, DDS, PhD Department of Cariology and Comprehensive Care,
New York University College of Dentistry, New York, NY, USA
Ronald G. Craig, DMD, PhD Department of Basic Sciences and Craniofacial
Biology, New York University College of Dentistry, New York, NY, USA
Department of Periodontology and Implant Dentistry, New York University College
of Dentistry, New York, NY, USA
Ananda P. Dasanayake, BDS, MPH, PhD, FACE Department of Epidemiology
and Health Promotion, New York University College of Dentistry, New York,
NY, USA
Keith Webb Harris, DO Pulmonology, John T. Mather Memorial Hospital,
Port Jefferson, NY, USA
Angela R. Kamer, DMD, MS, PhD Department of Periodontology and Implant
Dentistry, New York University College of Dentistry, New York, NY, USA
Peter Kotanko, MD Private Corporation, Renal Research Institute, New York,
NY, USA
Mony J. de Leon, EdD, Professor Department of Psychiatry, Director Center for
Brain Health, New York University Langone Medical Center, New York, NY, USA
Frederick Naftolin, MD, PhD, FACOG, FRCOG Division of Reproductive
Biology Research, New York University School of Medicine, New York, NY, USA
Veena S. Raja, BDS, MS Graduate Program in Department of Oral Biology and
Pathology, The Graduate School, Stony Brook University, Stony Brook, NY, USA
Harmony R. Reynolds, MD Leon H. Charney Division of Cardiology, Department
of Medicine, New York University School of Medicine, New York, NY, USA
Maria Emanuel Ryan, DDS, PhD Department of Oral Biology and Pathology,
School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA
vii
viii Contributors
Frank A. Scannapieco, DMD, PhD Department of Oral Biology, State University

of New York at Buffalo, Buffalo, NY, USA
Jose U. Scher, MD Division of Rheumatology, New York University School of
Medicine, New York, NY, USA
New York University Langone Hospital for Joint Diseases, New York, NY, USA
Sherry K. Sussman, MD, FACE, ECNU Department of Medicine, Division of
Endocrinology, School of Medicine, Stony Brook University, Stony Brook,
NY, USA
Introduction and Overview
of the Systemic Effects of Periodontal 1
Diseases
Ronald G. Craig and Angela R. Kamer
There has been an exponential increase in the number of papers published within
the past decade on the association between periodontal diseases and a range of
seemingly non-related systemic diseases and conditions. These associations include
but are not limited to: diabetes mellitus, atherosclerosis, preterm low birth weight
infants, rheumatoid arthritis, chronic kidney disease, pneumonia, Alzheimer’s dis-
ease (all covered in this volume), some forms of cancer [1–4], and even erectile
dysfunction [5]. When confronted with this wide array of diseases and conditions
associated with periodontitis, one might ask if periodontitis contributes to the cause
and progression of these conditions or whether these conditions contribute to peri-
odontitis? Is the association due to a common underlying mechanism or mecha-
nisms, or is the association merely due to the presence of confounding factors? And
most importantly, can periodontal therapy decrease the risk or progression of these
systemic diseases and conditions? Surprisingly, the answer to all five questions
could be yes depending upon the disease or condition. Clearly what is needed by the
practicing healthcare professional to remain abreast of this rapidly advancing and
sometimes confusing field is a concise source that summarizes the current research
on the association between periodontitis and systemic disease.
R.G. Craig, DMD, PhD (*)

Department of Basic Sciences and Craniofacial Biology, New York University College of
Dentistry, New York, NY, USA
Department of Periodontology and Implant Dentistry, New York University College of
e-mail: ron.craig@nyu.edu
A.R. Kamer, DMD, MS, PhD
e-mail: angela.kamer@nyu.edu
© Springer-Verlag Berlin Heidelberg 2016 1

R.G. Craig, A.R. Kamer (eds.), A Clinician’s Guide to Systemic Effects of
Periodontal Diseases, DOI 10.1007/978-3-662-49699-2_1
2 R.G. Craig and A.R. Kamer
To meet this need, A Clinician’s Guide to Systemic Effects of Periodontal

Diseases is intended to be a quick reference for the healthcare professional that will
in one convenient volume:
1. Summarize the current research on the effects of periodontal diseases on

systemic health and disease.
2. Relate how the results of recent research in this area may impact clinical
practice, both now and in the future.
3. Assist in making evidence-based responses to questions posed by patients,
colleagues, and the media in this ever-expanding area.
The volume is not meant to be an exhaustive discussion on the systemic effects of

periodontal diseases but to provide a quick overview of the research findings in this
rapidly expanding field with an emphasis placed upon clinical applications.
Additional information on each topic may be accessed using the reference section
found in the conclusion of each chapter. The book has been designed to present each
topic as a collaborative narrative between a dental investigator and medical
colleague(s) active in the field of interest in an attempt to highlight the clinical rele-
vance of the topic from both the dental and medical perspectives. We felt this design
was important since effective management of several of the diseases presented in this
volume require interdisciplinary efforts between medical and dental practitioners.
Chapter 2 presents a discussion of the pathogenesis of periodontal diseases with
a focus on adult chronic periodontitis, the periodontal disease most often associated
with systemic effects. Our understanding of the pathogenesis of periodontitis has
extensively deepened over the past several decades, providing insight into possible
mechanisms through which a common oral disease such as periodontitis can have
diverse and often significant systemic effects. Along with type 2 diabetes mellitus,
atherosclerosis, Alzheimer’s disease, and rheumatoid arthritis, periodontitis is con-
sidered to be a complex disease that begins with a mild clinical presentation that
advances in severity with age. In addition, complex diseases exhibit multiple risk
factors both modifiable and innate (genetic), although in the case of periodontitis,
the genes involved and the roles they play in disease susceptibility and progression
have not yet been characterized. Periodontitis is also a polymicrobial disease.
Disease progression is associated with a predictable succession of microbial species
that climax in disease-susceptible individuals with the appearance of Gram-negative
anaerobic assacharolytic bacterial species. Several Gram-negative anaerobic spe-
cies associated with periodontitis have been shown to invade periodontal tissues and
gain access to the circulation to seed distant non-oral sites such as atheromas. The
presence of Gram-negative anaerobic species in moderate to severe periodontitis
has also been shown to elevate pro-inflammatory cytokines and initiate an acute
phase response which includes elevation in blood glucose levels, dyslipidemia, and
increase in systemic markers of inflammation. These and other systemic effects of
periodontopathic bacteria further detailed in this volume have been proposed as
mechanisms to link periodontitis with the systemic diseases and conditions described
in this volume.
1 Introduction and Overview of the Systemic Effects of Periodontal Diseases 3
The following Chaps. 3, 4, 5, 6, 7, 8, and 9 discuss the association of periodontal

diseases with diabetes mellitus, atherosclerosis, chronic kidney diseases, preterm
labor, pneumonia, Alzheimer’s disease, and rheumatoid arthritis. Each chapter
begins with a discussion of the prevalence, presentation, pathogenesis, and medical
management of the systemic disease/condition. Each chapter then discusses the
association with periodontal diseases, comments on possible mechanisms involved,
and concludes with a discussion of management concerns from both medical and
dental perspectives.
The final chapter discusses factors that are common among the systemic effects
of periodontal diseases with respect to underlying mechanisms. The chapter also
discusses some of the difficulties encountered when designing periodontal interven-
tion trials and possible reasons for the inconclusive results reported for intervention
trials to date. The chapter also discusses several clinical implications for disease
management and suggestions for further studies.
With the aging of the populations in industrialized nations and the advances
made in the prevention and treatment of oral diseases, more individuals will retain
teeth into old age and therefore be at risk for periodontal disease and its associated
systemic effects. An understanding of the mechanisms linking periodontal diseases
with systemic disease underscores the need for prevention and early intervention for
this manageable common oral disease.
Acknowledgments This work was supported by NIH DE023139-02, Alzheimer’s Association

NIRG-12-173937.
References
1. Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, Loree TR, Rigual NR,
Merzianu M, Hauck L, Lillis C, Wactawski-Wende J, Scannapieco FA. Chronic periodontitis
and the incidence of head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers
Prev. 2009;18:2406–12.
2. Ahn J, Segers S, Hayes RB. Periodontal disease, porphyromonas gingivalis serum antibody
levels and orodigestive cancer mortality. Carcinogenesis. 2012;33:1055–8.
3. Salazar CR, Francois F, Li Y, Corby P, Hays R, Leung C, Bedi S, Segers S, Queiroz E, Sun J,
Wang B, Ho H, Craig RG, Cruz G, Blaser MJ, Perez-Perez G, Hayes RB, Dasanayake A, Pei
Z, Chen Y. Association between oral health and gastric precancerous lesions. Carcinogenesis.
2012;33:399–403.
4. Wen B-W, Tsai C-S, Lin C-L, Chang Y-J, Lee C-F, Hsu C-H, Kao C-H. Cancer risk among
gingivitis and periodontitis patients: a nationwide cohort study. Q J Med. 2014;107:283–90.
5. Keller JJ, Chung S-D, Lin H-C. A nationwide population-based study on the association
between chronic periodontitis and erectile dysfunction. J Clin Periodontol. 2012;39:507–12.
Pathogenesis of Periodontal Diseases
2
Ronald G. Craig
2.1 Introduction
Our understanding of the pathogenesis of periodontal diseases has greatly pro-

gressed over the past three decades. Beginning with the observation that periodontal
diseases are associated with the presence of a bacterial plaque or biofilm, our under-
standing has evolved to the realization that specific bacterial profiles exist within
dental biofilms in association with specific periodontal diseases. This understanding
has in turn led to the emerging concept of immune subversion of the host by peri-
odontal pathogens with the attendant conversion of the periodontal biofilm/host
relationship from one of a symbiosis in health to a dysbiosis in disease. Currently,
periodontitis is viewed as a polymicrobial, complex disease that shares several char-
acteristics with other complex diseases including atherosclerosis, diabetes mellitus,
and Alzheimer’s disease. We presently recognize that individuals vary greatly in
disease susceptibility and that host genetic factors play a significant, although cur-
rently largely unspecified, role in determining disease susceptibility. Therefore, to
provide an understanding of periodontal diseases for the chapters that follow, this
chapter will present an overview of our current understanding of the pathogenesis
of periodontal diseases with the aim of providing a conceptual framework to help
address how a common oral inflammatory disease can contribute to the wide array
of systemic diseases and conditions described in this book.
R.G. Craig, DMD, PhD

Department of Basic Sciences and Craniofacial Biology, New York University College of

6 R.G. Craig
2.2 Classification and Prevalence of Periodontal Diseases
Periodontal diseases present a continuum of inflammatory conditions that afflict the

supporting tissues of the dentition. Both the initiation and progression of periodon-
tal disease requires the development of a microbial biofilm on the tooth surface.
Biofilm-induced periodontal diseases have been classified as (1) gingivitis or (2)
early onset, (3) chronic adult, and (4) aggressive periodontitis [1]. The inflamma-
tory lesion in gingivitis is limited to the soft tissues (gingiva) surrounding the tooth
which forms in response to the dental biofilm. Gingivitis is nearly universally pres-
ent in children and young adults and is essentially reversible with the removal of the
bacterial biofilm. In contrast, periodontitis is irreversible in that the inflammatory
lesion extends beyond the gingiva into the supporting tissues of the dentition result-
ing in their progressive destruction. Alveolar bone, dental cementum, and periodon-
tal ligament are the three tissues that support the dentition and their destruction in
periodontitis, termed attachment loss, is mainly the result of host-mediated innate
and adaptive immune response mechanisms. The most common form of periodon-
titis, chronic adult periodontitis, can become manifest as early as the second decade
of life and, if left untreated, can eventually culminate in tooth loss. Less common
forms of periodontitis appear considerably earlier (early onset) or progress at a
greatly accelerated rate (aggressive periodontitis) [2]. All forms of periodontitis are
currently believed to result from the interaction of specific oral bacterial species
with components of the host immune response in disease-susceptible individuals.
Therefore, although gingivitis precedes periodontitis, not all cases of gingivitis prog-
ress to periodontitis. In addition, considerable variability exists among individuals
with respect to disease severity.
Past attempts to determine the prevalence and severity of periodontal diseases in
various populations have been seriously hampered by a lack of consensus on the
clinical criteria used to define disease presence and severity. For example, the types
of clinical measurements recorded during the examination (e.g. probing depth, clin-
ical attachment level, bleeding upon probing, etc.) or whether all teeth or a partial
sampling within an individual need to be examined are just a few of the factors that
have varied among studies. To address this problem the Centers for Disease Control
(CDC) and the American Academy of Periodontology (AAP) recently developed a
set of case definitions for use in periodontitis prevalence and severity studies [3]. If
universally accepted, the use of the CDC/AAP case definitions will allow the stan-
dardized comparison of disease prevalence and severity across populations and for
populations over time.
A recent report was published on the prevalence and severity of periodontitis
using the United States National Health and Nutrition Examination Survey
(NHANES) that was conducted from 2009 to 2012 which examined 7,066 adults
≥30 years of age. Using full-mouth periodontal examinations and the CDC/AAP
case definitions, 46 % of the adult population were found to have periodontitis and
8.9 % had severe periodontitis. Both the prevalence and severity of periodontitis was
greater in males and was increased with age, smoking, and lower socioeconomic
status. Hispanic Americans had the highest prevalence of periodontitis, followed by
2 Pathogenesis of Periodontal Diseases 7
non-Hispanic blacks which were followed by Asian-Americans. Non-Hispanic

whites had the lowest prevalence of periodontitis [4]. Therefore, periodontitis is
highly prevalent in the United States adult population (46 %), although considerable
variance exists in disease severity among individuals, racial/ethnic groups, and sev-
eral demographic variables.
The disease prevalence and severity rates reported for the 2009–2012 NHANES
study are remarkably similar to those reported in a landmark 15-year longitudinal
study of 480 male Sri Lankan tea workers. Because the study population did not
receive any dental treatment or participate in any oral disease prevention programs
and was virtually free of dental caries, the Sri Lankan study essentially recorded the
natural progression of periodontal diseases in a human population. Complete peri-
odontal examinations were conducted in 1970 and the cohort was reexamined five
times, the last examination occurring in 1985. The study found gingivitis univer-
sally present in this population since no conventional oral hygiene procedures were
practiced by the workers. However, three groups emerged with respect to periodon-
titis susceptibility and progression. Approximately 8 % of the study population
exhibited rapid periodontitis progression as evidenced by attachment loss. A second
group, approximately 81 % of the study population, exhibited moderate periodonti-
tis progression while a third group, approximately 11 % of the study population,
exhibited no disease progression beyond gingivitis. In addition, the majority of the
333 teeth lost during the 15-year study period occurred within a limited number of
individuals [5]. It may be concluded from the combined results of the NHANES and
the Sri Lankan studies that not all adults are susceptible to periodontitis. In addition
considerable variability in the rates of disease progression exist, even in untreated
populations, with about 8–10 % of the population being susceptible to severe
periodontitis.
2.3 Susceptibility to Periodontal Diseases
The question therefore arises, what determines susceptibility to periodontal dis-

eases? It is clear that cessation of oral hygiene procedures and the subsequent devel-
opment of a tooth-borne biofilm universally results in gingivitis. However, as
demonstrated by the Sri Lankan study, not all individuals who develop gingivitis
progress to periodontitis. Since the Sri Lankan study, a large number of studies have
identified a series of risk factors associated with periodontitis initiation and progres-
sion. The most robust risk factors identified to date include: male gender, increased
age, smoking, colonization of the biofilm with specific anaerobic bacteria including
Porphyromonas gingivalis and Tannerella forsythia, diabetes mellitus, obesity, and
decreased socioeconomic status (reviewed in [6]). Almost all studies have reported
males to be at increased risk of periodontitis although this is usually attributed to
life style and not genetic factors [6]. The increased prevalence of periodontitis with
age is thought to reflect the cumulative exposure of periodontitis risk factors over
time in disease-susceptible individuals or to an alteration in host immune response
occurring with age. Smoking in particular has been strongly associated with
8 R.G. Craig
periodontitis as well as other chronic diseases including atherosclerosis. The num-

ber of pack years smoked has been correlated in a dose-dependent relationship with
the severity of periodontitis [7] and with the number of missing teeth lost to peri-
odontitis. Smoking cessation improves the outcome of periodontal therapy while
smokers have poorer wound healing outcomes after periodontal and oral surgical
procedures. A number of mechanisms have been proposed for the strong association
between smoking and periodontitis. These include, nicotine-induced local vaso-
constriction which may decrease oxygen tension favoring colonization with Gram-
negative periodontopathic anaerobic bacteria including P. gingivalis, T. forsythia,
depressed neutrophil function including phagocytosis and increased local expres-
sion of pro-inflammatory cytokines. Gingival vasoconstriction leading to decreased
oxygen tension may also depress rates of wound healing. In addition, colonization
with periodontal pathogens, obesity, and type 2 diabetes mellitus have all been asso-
ciated with increased systemic inflammatory burden and increased prevalence and
severity of periodontitis [8]. Therefore, some of the risk factors found associated
with periodontitis may not act independently but may interact with one another to
facilitate periodontitis initiation and progression.
The combination of multifactorial risk factors for disease initiation and progres-
sion, the variability in disease susceptibility within the population, and the chronic-
ity of disease progression suggest that periodontitis may be considered to be a
complex disease that shares features with other complex diseases such as type
2 diabetes mellitus, atherosclerosis, and Alzheimer’s disease. Most complex dis-
eases begin with a relatively mild clinical presentation, progress slowly over time,
and may result from several convergent biologic pathways. Most notably, not all
individuals within a population are equally susceptible to a complex disease even if
known risk factors are present [9]. The last feature strongly implicates a genetic
component to complex disease susceptibility. In addition several complex diseases
display subtle mutations in several genes that combine to promote disease initiation
and progression in the presence of appropriate environmental risk factors. It is
thought that the interaction between an individual’s unique set of genes with envi-
ronmental risk factors results in complex disease initiation and progression [10].
A number of studies using several experimental designs report that genetic fac-
tors strongly contribute to periodontitis susceptibility although the specific genes
responsible remain to be identified. One study from the United States examined a
group of largely African-American families in which an older sibling was diag-
nosed with localized early onset periodontitis. This study reported a 50 % chance of
a younger sibling also developing localized early onset periodontitis [11]. Similar
results have been reported in studies from other countries and racial groups.
However, the results of susceptibility studies of localized early onset periodontitis
may not be transferable to chronic periodontitis since localized early onset peri-
odontitis develops as the individual passes through puberty, a defined and limited
time period, as opposed to chronic periodontitis, which can begin and progress
across the entire adult life span. Nonetheless, studies from the Netherlands [12] and
Indonesia [13] also suggest that chronic adult periodontitis has a genetic basis for
disease susceptibility since a statistically significant clustering of periodontitis cases
were found within the families studied. But it is difficult using a familial study
design to distinguish between the relative contributions of genetic versus environ-
mental factors to disease susceptibility. A powerful experimental design to dissect
genetic from environmental factors is the twin study model. Michalowicz et al. [14]
reported the results of a cross-sectional study of 117 pairs of adult twins of which
64 were monozygotic and 53 were dizygotic. Periodontal disease status was deter-
mined using attachment loss and clinical measures of gingival inflammation. It was
concluded that, after controlling for smoking, oral hygiene, and the use of dental
services, approximately 50 % of the variance observed in periodontitis susceptibil-
ity was due to genetic factors. Unfortunately, the twin model has not been able to
identify the specific genes involved.
One approach to identify genes associated with complex disease susceptibility is
to analyze the prevalence of single nucleotide polymorphisms that associate with
the disease. A single nucleotide polymorphism is a variation in DNA sequence
found in greater than 1 % of the population. Many studies have sought to link gene
polymorphisms with aggressive or chronic periodontitis by targeting genes involved
in host responses to bacterial infections. The underlying assumption is that poly-
morphisms in DNA sequences may alter gene expression rendering the individual
more susceptible or resistant to periodontitis. The strength of the associations
reported between targeted gene polymorphisms and periodontitis has varied accord-
ing to the populations studied and has been confounded by the presence of other
disease-associated risk factors such as diabetes or smoking [10]. However, using
this approach several genes have emerged as having a possible contribution to peri-
odontitis susceptibly. The most promising gene polymorphisms identified thus far
include: interleukin 1α (IL1A) and interleukin 1β (IL1B), transforming growth fac-
tor β (TGFB), IL4, IL6, IL10, various leukocyte receptors for host antibody classes
(FcγR genes), the vitamin D3 receptor (VDR), and genes for several host cell recep-
tors to structural components displayed on bacteria [10]. Of this group of polymor-
phisms, the most studied has been the combined IL1A and IL1B genotype
polymorphism which has been found predictive of periodontitis susceptibility in
populations of Northern European descent [15]. As with several genes found associ-
ated with periodontitis in targeted polymorphism studies, the predictive value of the
combined IL1A and IL1B genotype polymorphism was abolished in individuals
that smoke [16].
A second approach to identify specific genes associated with disease suscepti-
bility is the use of genome-wide polymorphism studies which allows the mapping
of up to one million polymorphisms with complex diseases. This approach was
made possible due to advances in high-throughput DNA sequencing techniques
and data analysis software. An advantage of this approach over targeted gene
polymorphism studies is specific genes are not selected a priori; instead a wide
array of polymorphisms are screened for associations with complex diseases inde-
pendent of known biologic mechanisms. Genome-wide studies have been suc-
cessfully used to identify candidate susceptibility genes for atherosclerosis and
for type 2 diabetes and are just beginning to be used to study periodontal disease
susceptibility. One study using genome-wide screening identified a polymorphism
10 R.G. Craig
in the glucosyltransferase-6 gene as being associated with aggressive periodontitis

in a Dutch study [17]. Although in its infancy, the use of genome-wide analysis
holds promise for identification of specific genes responsible for periodontal disease
susceptibility in the future. The clinical significance of being able to identify
disease-susceptible genotypes is that preventive therapy could be directed to those
individuals at risk for disease initiation and progression which is a central objective
of personalized medicine. In addition, the identification of the genes responsible for
periodontitis susceptibility may also identify new therapeutic targets potentially
useful in the treatment of periodontitis [18].
2.4 A Microbial Profile Shift Occurs with the Transition

from Health to Disease
Regardless of an individual’s disease susceptibility, a dental biofilm is required for

periodontal disease initiation and progression. This realization has prompted an
extensive study of the oral microbial profile and the changes that occur in associa-
tion with various periodontal diseases. Bacteria that colonize the dentition exist
within a highly ordered biofilm. This is a biologically important concept since the
bacterial phenotype expressed when living in a biofilm radically differs from that
expressed in a free-living (planktonic) environment [19]. Within the biofilm discrete
associations can be established between species to promote cell attachment, antibi-
otic resistance, and nutrient exchange. Central to biofilm development is the synthe-
sis of an exopolysaccharide matrix that may comprise 50–90 % of the biofilm mass.
The exopolysaccharide matrix not only provides a scaffold for bacterial attachment
and growth but also provides protection against desiccation, inhibits the effective-
ness of applied antimicrobials and, due to the porosity of the biofilm, provides a
primitive form of circulation for nutrient and waste transfer. The biofilm also pro-
vides a scaffold for cell-cell communication including the sharing of plasmids
(transformation) or DNA sequences (conjugation) to aid in conferring antibiotic
resistance or the ability to utilize new energy sources. Species within biofilms may
also secrete growth factors and metabolites that assist other bacteria in fulfilling
nutritional requirements. Since the biofilm places a large and diverse bacterial popu-
lation in close approximation to host tissue, the opportunity also exists for the devel-
opment of host-biofilm interactions [19].
Due to the relative ease of sampling dental biofilms, the development and the
composition of the microbial profile associated with health and disease have been
extensively studied. However, only about half of the approximately 700 species that
may potentially colonize the oral cavity have been characterized to date [20]. As
more species become characterized, our understanding of the association between
the biofilm composition and periodontal diseases will undoubtedly deepen. With that
caveat in mind, the following summarizes our current understanding of the major
changes that occur in the microbial profile with the progression from periodontal
health to gingivitis to periodontitis.
Dental biofilm development begins with the absorption of salivary and bacterial
proteins as well as other oral compounds on to the tooth surface to form the acquired
salivary pellicle. The first bacterial species to colonize the acquired salivary pellicle
include various Streptococci, Staphylococci, and Actinomyces species whose adher-
ence is mediated through specific receptors for various molecular structures present
on components of the acquired salivary pellicle. The early bacterial biofilm profile
colonizing the acquired pellicle consists of Gram-positive aerobic or facultative sac-
charolytic species and is also the microbial profile associated with periodontal health.
Later colonizers of the dental biofilm include Gram-negative cocci and rods including
various Fusobacterium nucleatum species that adhere to the exopolysaccharide bio-
film matrix as well as to specific cell wall components displayed by the early biofilm
colonizers. The development of a more complex biofilm and the appearance of Gram-
negative species such as F. nucleatum elicits a local host inflammatory response that
is clinically observed as gingivitis. With continued biofilm maturation, additional spe-
cies including Gram-negative rods colonize the biofilm. Finally, in individuals suscep-
tible to periodontitis, biofilm development climaxes with the appearance of additional
asaccharolytic anaerobic species. Samples of biofilms from sites with periodontitis or
from sites resistant or refractory to periodontal therapy frequently contain P. gingiva-
lis, T. forsythia, and Treponema denticola, three species collectively known as the “red
complex” from landmark studies conducted at the Forsyth Institute using DNA-DNA
checkerboard hybridization and cluster analysis [21]. However, other presently non-
cultivatable anaerobic species belonging to the Firmicutes, Proteobacteria and
Spirochaete, and Bacteroides genera have of late also been associated with periodon-
titis in addition to the red complex. [22]
Bacterial species become highly stratified within the maturing biofilm, assuming
specific locations to most optimally fulfill metabolic and nutrient requirements.
Driving the stratification of bacterial species within the biofilm are gradients of
host-derived dietary carbohydrates, oxygen, and inflammatory exudates. The most
superficial portions of the biofilm are colonized by Gram-positive aerobic saccharo-
lytic bacteria while deep within in the biofilm in close approximation to the gingival
epithelium Gram-negative anaerobic asaccharolytic bacteria, such as the red com-
plex, are found [22]. Asaccharolytic bacteria such as P. gingivalis are unable to
utilize carbohydrates for energy metabolism and require peptides and amino acids
for both carbon and energy sources as well as iron and porphyrin for growth [23].
These essential factors are provided as sequelae of the host inflammatory
response. It was based on these findings that the concept of microbial subversion
of the host immune response by members of the red complex was developed and is
further described below.
Periodontal diseases are therefore associated with discreet microbial profile
shifts that occur with the development and maturation of the biofilm. The acquired
salivary pellicle is initially colonized by Gram-positive aerobic cocci and is associ-
ated with periodontal health. The appearance of Gram-negative cocci and rods such
as various F. nucleatum species within the biofilm is associated with gingivitis.
Finally, in disease-susceptible individuals, the appearance of the red complex and
12 R.G. Craig
other Gram-negative anaerobic asaccharolytic species is associated with periodon-

titis. It should be noted that the appearance of Gram-negative anaerobic bacteria
such as the red complex is necessary but not sufficient for periodontitis initiation
and progression since these species have also been isolated from periodontally
healthy individuals, although at greatly reduced frequencies [21].
2.5 Host Response to Dental Biofilm Development
Within the gastrointestinal tract, the presence of teeth presents an anatomically

unique non-shedding structure for biofilm development. Most areas of the gut are
continuously lined by epithelium which secretes a layer of mucous that partially
segregates the biofilm from the epithelial surface and, through its continuous pas-
sage through the gut, assists in controlling the biofilm mass. The gut epithelium also
secretes innate immune host defense molecules such as defensins to help control the
biofilm mass. In addition the gut epithelium actively monitors the composition of the
biofilm by continuously sampling and transporting bacteria and their products to
Peyer’s patches for development of an appropriate adaptive immune response to con-
trol biofilm growth and composition.
In contrast to the rest of the gastrointestinal tract, teeth pierce the continuity of
the oral epithelium. Periodontal tissues do not secrete a protective layer of mucous
and are consequently placed in direct contact with bacteria of the dental biofilm.
Gingival epithelial cells, in response to the development of the dental biofilm, mobi-
lize multiple innate immune mechanisms which generate an inflammatory response
clinically observed as gingivitis. Recognition of microbial pathogen-associated
molecular patterns by membrane bound toll-like receptors (TLRs) and by intracel-
lular nucleotide-binding oligomerization domain receptors (Nod receptors) elicit a
local inflammatory response that includes the expression of pro-inflammatory cyto-
kines including IL-1β, IL-6, and TNF-α that signal endothelial cells of the micro-
vasculature to generate tissue edema. The arachidonic acid cascade is also activated
and generates factors including prostaglandins, leukotrienes, and thromboxanes that
promote edema. Bacterial activation of the complement cascade serves to further
focus and amplify inflammation through the generation of tissue edema, the produc-
tion of recruitment factors for neutrophil migration from the vasculature into the
area of inflammation, the covalent tagging of bacteria for leukocyte phagocytosis,
and the generation of the membrane attack complex to directly lyse bacterial cell
membranes. Gingival epithelial cells, as with their gut counterparts, secrete various
bactericidal proteins such as defensins to control the adjacent biofilm but also
express Il-8 that recruits neutrophils to the site of inflammation. Many of the
recruited neutrophils do not remain resident in the periodontal connective tissues
but migrate out of the junctional epithelium into the biofilm to help control the bio-
film mass. The remaining neutrophils within the gingival connective tissue in effect
form a protective barrier, walling off the biofilm from deeper periodontal tissues.
Therefore a series of multiple overlapping innate immune mechanisms become acti-
vated during gingivitis in response to the adjacent biofilm.
In disease-susceptible individuals, the emergence within the biofilm of Gram-

negative anaerobic bacteria is associated with a further intensification of the local
innate and adaptive immune response and the progression from gingivitis to peri-
odontitis. Host matrix metalloproteinase and bone resorption pathways become
activated leading to the destruction of the periodontal connective tissues support-
ing the dentition. Gingival epithelium migrates into the area of periodontal con-
nective tissue and alveolar bone loss creating a periodontal pocket that centrally
consists of the biofilm surrounded by the newly exposed root surface and ulcerated
pocket epithelium. Subjacent to the ulcerated gingival epithelium, an intense
immune/inflammatory cell infiltration is generated consisting of dendritic cells,
neutrophils, monocytes, macrophages, and antigen-specific T- and B-cells. As
attachment loss progresses and the periodontal pocket deepens, it becomes increas-
ingly difficult for the patient or healthcare professional to effectively debride the
biofilm and its products from the site thereby promoting further disease progres-
sion. With the onset of moderate to severe periodontitis, local and systemic levels
of pro-inflammatory cytokines including TNF-α, IL-1, Il-6, and Il-8 become ele-
vated and a systemic acute phase response ensues that includes elevation of
C-reactive protein, pentraxin-3, fibrinogen, serum glucose, and dyslipidemia.
Serum endotoxin levels may also become elevated depending on the severity of
periodontitis. The total epithelial pocket surface area for an individual with mod-
erate to severe periodontitis has been estimated to range from 8 to 20 cm [2]
depending upon disease severity and the number of teeth involved [24]. Therefore
with increasing disease severity, periodontitis can become a significant source of
systemic inflammation.
2.6 Subversion of the Host Response in Periodontitis
The Gram-negative assacharolytic anaerobic bacteria residing within the periodon-

tal pocket face a difficult challenge. They must survive in a hostile inflammatory
environment that contains an array of host-generated bactericidal molecules and
innate immune effector cells. But they also require the by-products of the host
inflammatory response, namely, peptides and amino acids arising from neutrophil
and macrophage-mediated destruction of host tissues as well as iron and porphyrins
from blood, to meet nutrient requirements. Therefore the option of suppressing the
host immune response for bacterial survival is not possible. An alternate strategy to
resolve this challenge is the recently proposed subversion of the host response by
keystone pathogens associated with periodontitis [25]. Although this hypothesis
addresses many previously unanswered questions regarding the pathogenesis of
periodontitis, it must be kept in mind that the majority of the evidence that supports
this hypothesis has been largely derived from mouse experimental models. However,
the use of transgenic mice, whose genes can be readily manipulated, coupled with
infection by defined bacterial species, whose genomes can also be experimentally
manipulated, is a very powerful experimental model to study the pathogenesis of
periodontitis.
14 R.G. Craig
Early studies using germ-free mice demonstrated that infection with P. gingivalis
alone produced gingival inflammation but little alveolar bone loss. The introduction
of P. gingivalis into gnotobiotic animals resulted in an overgrowth of the commensal
species and loss of alveolar bone although the numbers of P. gingivalis within the
biofilm remained relatively modest. The observation that the introduction of a rela-
tively minor component of the biofilm can change the host-biofilm relationship
from symbiotic, associated with health, to dysbiotic, associated with disease, has
been called the keystone pathogen hypothesis. Activities of the keystone species
subvert the host response, in this case blunt several host mechanisms active in bacte-
rial killing, while leaving intact or amplifying host mechanisms that promote
inflammation, thereby supplying host-derived peptides, iron, and porphyrins
required for survival by the keystone species. Bystander bacteria in the absence of
the keystone species coexist with the host in health. With the introduction of key-
stone species, bystander species are partially freed from host bactericidal pressure,
increase in mass, and tip the balance toward disease. Such commensal species
whose overgrowth is associated with disease have been termed pathobionts [25].
Evidence for host subversion in periodontitis thus far largely hinges on the role of
neutrophils and complement in controlling the periodontal biofilm. For example P.
gingivalis expresses a protease (gingipain) that cleaves complement component C5
releasing the neutrophil chemotactic fragment C5a but inactivating fragment C5b.
Without C5b the complement membrane attack complex cannot assemble thus pre-
venting complement-mediated bacterial cell lysis. P. gingivalis also inhibits TLR2
signaling and neutrophil phagocytosis through intracellular signaling pathways. The
result is recruitment of increased numbers of neutrophils within the periodontal
pocket whose ability to bind with and kill P. gingivalis is compromised. The recruit-
ment of additional neutrophils result in the increased expression of matrix metallo-
proteinases that degrade host periodontal connective tissues releasing peptides and
amino acids required by P. gingivalis for nutritional needs. With depressed bacteri-
cidal activity, pathobionts proliferate, enhancing inflammation and promoting alveo-
lar bone loss. As a consequence, the periodontal pocket progressively deepens in an
effort to wall off the advancing biofilm front from the host and, if left untreated,
eventually culminates in tooth loss [26].
A major question not addressed by the keystone pathogen hypothesis is the reason
for the wide variation in disease susceptibility observed within human populations.
Differences in bacterial virulence factors for keystone species have been proposed
[26], but as described earlier, a substantial portion of the variance in susceptibility to
periodontitis (up to 50 %) has been attributed to host genetic factors. It is therefore
possible that mutations in host genes, possibly those involved in the generation of an
innate or adaptive immune response, may confer resistance or susceptibility to host
subversion by keystone pathogens such as P. gingivalis. It may also be possible that
some individuals have evolved pathways to circumvent microbial subversion strate-
gies. To determine whether these possibilities are correct, studies are being con-
ducted to determine the role of host genetic factors in determining susceptibility to
keystone pathogens and to determine whether results from mouse transgenic models
can be extrapolated to human periodontitis.
2.7 Management of Periodontal Diseases
Strategies for disease management arise from our understanding of the pathogenesis
of the disease. As our understanding of the pathogenesis of periodontal diseases
increases in the future, therapeutic approaches will most likely become increasingly
focused on the patients at risk for disease and on the specific biologic pathways
involved. At present, it is clear that the initiation and progression of periodontal
diseases is dependent upon the presence of a dental biofilm and that a microbial
profile shift predictably occurs during the transition from periodontal health to gin-
givitis to periodontitis. It is the shift in the microbial profile from health to disease
that provides the rationale for the current main objective of periodontal therapy: to
convert the biofilm from one associated with disease to one associated with health.
Although we are beginning to understand the roles that specific bacterial species
and host response mechanisms play in the pathogenesis of periodontitis, our most
effective therapies currently rely on relatively nonspecific approaches that physi-
cally disrupt the biofilm and decrease the oral bacterial load.
Periodontitis is associated with the appearance of Gram-negative anaerobic
assacharolytic species, such as the red complex, within the mature biofilm. These
species have evolved to exploit, or perhaps promote, the harsh conditions of the
periodontal pocket for survival becoming in the process metabolically fastidious
requiring low oxygen tensions and the presence of peptides, iron, and porphyrins
derived from the host inflammatory response. The physical disruption of the biofilm
through oral hygiene procedures or by mechanical debridement by a healthcare pro-
fessional (e.g., “scaling and root planing”) has proven to be an extremely effective
treatment strategy in controlling periodontal diseases by removing the growth and
metabolic requirements of this group of disease-associated bacteria. Removal of the
biofilm not only destroys the anaerobic environment required by the red complex
but necessitates the reformation of the dental biofilm beginning with the absorption
of the acquired salivary pellicle. Removal of the biofilm allows the resolution of
gingival inflammatory response and the reinstatement of a symbiotic biofilm rela-
tionship with the host. However, the effectiveness of both oral hygiene and profes-
sional debridement procedures decrease as pocket depths increase. Therefore in
sites with deep pocket depths, surgical intervention, either resective or regenerative,
is presently required to decrease pocket depths to a level that can be adequately
maintained by the patient.
Without continued oral hygiene by the patient and regular professional mainte-
nance, the biofilm will eventually reform and, in disease-susceptible individuals,
Gram-negative anaerobic assacharolytic bacteria will reappear promoting the reoc-
currence of periodontitis. Therefore, the success of this approach in the manage-
ment of periodontitis largely predicated upon both the patient’s level of manual
dexterity and commitment to daily remove the biofilm. This approach also requires
regular professional care to insure adequate levels of oral hygiene are being main-
tained and to remove any calcified biofilm (dental calculus) that has formed.
Although the success of this approach in managing periodontitis is well documented
[27], it also presents two major requirements that limit its effectiveness as a public
16 R.G. Craig
health intervention. The high prevalence of periodontitis within the population

requires a large professional work force to effectively manage the disease. In addition,
this approach is dependent upon achieving long-term patient compliance in perform-
ing effective oral hygiene procedures. Both limitations have prompted the search for
alternate approaches in the management of periodontitis.
Since a biofilm is required for periodontitis initiation and progression, the use of
both systemic and locally applied antibiotics as well as oral antimicrobial rinses
have been used in the management of periodontal diseases. Systemic antibiotics
have proven useful when combined with local debridement procedures in cases of
aggressive periodontitis where bacteria have been shown to invade host tissue,
thereby creating a reservoir for reinfection that may not be accessed by local
debridement procedures. However, the use of systemic antibiotics alone in the treat-
ment of chronic periodontitis has shown limited efficacy since the bacteria reside
within a biofilm in the periodontal pocket and are not in direct contact with the
patient’s circulation. In addition, the chronicity of the disease necessitates long-term
antibiotic administration and the associated complications of disease resistance and
emergence of disease-associated microbial species. The use of locally applied antibi-
otics in various vehicles (e.g., Arestin® or Atridox®) in selected sites of disease recur-
rence has shown efficacy as an adjunct to traditional debridement procedures. The use
of antimicrobial rinses such as 0.12 % chlorhexidine gluconate have also shown effi-
cacy in decreasing biofilm mass and gingival inflammation but has shown limited
effectiveness in the management of periodontitis perhaps due to the physical proper-
ties of biofilms and undesirable side effects such as staining with chronic use.
More recent disease management strategies that target the host response rather
than the biofilm, collectively called host response modification, have appeared. The
rationale for this strategy is that most tissue destruction in periodontitis is due to the
host response to the pathogenic biofilm and not to activities of the bacteria them-
selves. One of the earliest host response modifications targeted a class of host matrix
metalloproteinases (MMPs) expressed in inflammatory lesions. In particular, MMP-8
has been associated with connective tissue collagen breakdown in inflammatory
lesions such as periodontitis. All MMPs require divalent zinc as an enzyme cofactor
at their active site for activity but vary in cofactor affinity. Periostat® (20 mg doxy-
cycline hyclate) competitively binds with the active site of MMP-8 and inhibits its
collagen lytic activity. Periostat® has been shown to decrease periodontal connective
tissue destruction especially when combined with scaling and root planning [28].
Also attempted have been various non-steroidal anti-inflammatory medications
such as flurbiprofen to depress inflammation in periodontitis. Although the host
inflammatory response is largely responsible for connective tissue destruction, damp-
ening the overall inflammatory response may compromise the recruitment and antimi-
crobial activities of host innate and adaptive immune cells during the early phases of
the inflammatory response. An alternate approach that holds promise is the discovery
of a group of arachidonic acid metabolites (termed resolvins, protectins, and lipoxins)
that are synthesized by the host late in the inflammatory response to actively resolve
inflammation. The topical application of lipoxin in a rabbit model of periodontitis
halted the progression of periodontitis without any attempts to remove the pathogenic
biofilm. With resolution of the active inflammatory response, metabolic and nutri-
tional requirements of the assacharolytic anaerobic bacteria were not met, and in the
absence of keystone pathogens, periodontal health was reinstated [29]. The advan-
tages of host response modification strategies include less reliance on patient compli-
ance to perform effective oral hygiene procedures and the possible large scale use of
pharmacologic approaches for disease management.
2.8 Summary
Periodontitis is currently viewed as a polymicrobial complex disease possibly

resulting from the subversion of host defense mechanisms by keystone species of
the biofilm in disease-susceptible individuals. Although a number of modifiable
environmental risk factors for periodontitis susceptibility have been identified, host
genetic factors play a major, although at present unspecified, role in conferring dis-
ease susceptibility or resistance. A biofilm is required for periodontal disease initia-
tion and progression and a predictable succession of microbial species within the
maturing biofilm is associated with the progression from periodontal health to gingi-
vitis and periodontitis. Therefore, the main objective of periodontal therapy is to
convert the periodontal microbial profile from one associated with disease to one
associated with health. At present, this is accomplished through relatively nonspe-
cific means. Most importantly, the Gram-negative assacharolytic anaerobic bacterial
species associated with periodontitis can be systemically disseminated and can elicit
an intense innate and adaptive immune response that can elevate systemic levels of
inflammation. Both of these features of periodontitis can have significant systemic
consequences as described in the following chapters.
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Periodontitis and Diabetes Mellitus:
A Complex Relationship 3
Maria Emanuel Ryan, Veena S. Raja, and Sherry K. Sussman
3.1 Introduction
This chapter explores the complex relationship between diabetes mellitus and
periodontal diseases. When either disease is undiagnosed or poorly managed, risk
for the other disease increases. In addition, the optimal management of both diseases
is essential to prevent adverse sequelae that can occur in a bidirectional manner.
Studies in this area have been confounded by variability in the type of diabetes
studied, diabetes treatment regimens, the level of diabetic control, the presence or
absence of diabetic complications, periodontal disease severity, the periodontal
therapy used, and the numbers of subjects enrolled with vastly different inclusion
and exclusion criteria. Despite these challenges, the preponderance of evidence
supports a bidirectional relationship requiring collaboration between medical and
dental practitioners for the provision of optimal healthcare services to the growing
population of patients with both diabetes and periodontal diseases. A better
understanding of the mechanisms involved in these disease processes would enable
a multidisciplinary team of healthcare providers including the dentist and hygienist
to provide optimal therapy for this complex patient population. In addition, the
challenges faced in interprofessional management of patients with diabetes and
periodontal diseases will also be addressed.
M.E. Ryan, DDS, PhD (*)

Department of Oral Biology and Pathology, School of Dental Medicine,
Stony Brook University, Stony Brook, NY, USA
e-mail: Maria.Ryan@stonybrookmedicine.edu
V.S. Raja, BDS, MS
Graduate Program in Department of Oral Biology and Pathology, The Graduate School,
S.K. Sussman, MD, FACE, ECNU
Department of Medicine, Division of Endocrinology, School of Medicine,

20 M.E. Ryan et al.
3.2 Diabetes: Presentation, Prevalence, Diagnosis,

and Management
Diabetes mellitus is a systemic endocrine disorder driven primarily by a dysregula-

tion of carbohydrate metabolism. The hallmark of this chronic disease is elevated
blood glucose levels, which must be monitored regularly by the patient and practi-
tioner. Elevated blood glucose or hyperglycemia is due to defects in insulin secre-
tion and/or impaired insulin action. Alterations in lipid and protein metabolism are
also seen. Numerous therapeutic approaches have been developed to address defi-
cits in insulin secretion and improve insulin sensitivity to reduce blood glucose
levels. Chronic hyperglycemia can lead to long-term dysfunction and damage to
numerous organs throughout the body making diabetes the 7th leading cause of
death in the USA, which is most likely an underestimate since diabetes is not often
noted as the primary cause of death.
Estimates from 2012 report diabetes affected 29.1 million adults and children in
the USA (21 million diagnosed and 8.1 million undiagnosed) or 9.3 % of the popu-
lation [1]. The majority have type 2 diabetes, with approximately 1.25 million
American children and adults presenting with type 1 diabetes. Worldwide more than
387 million people have diabetes; by 2035, this will rise to 592 million [2].
Worldwide the prevalence of diabetes is 80 % type 2 diabetes, 10 % type 1 and 10 %
with gestational diabetes or other forms. In addition, there are 86 million Americans
age 20 and older who have prediabetes, an increase from 79 million in 2010. Without
changes in diet and physical activity, 15–30 % will develop type 2 diabetes within
5 years. The percentage of Americans age 65 and older with diabetes remains high,
at 25.9 % or 11.8 million seniors. About 208,000 Americans under age 20 are esti-
mated to have diagnosed diabetes, approximately 0.25 % of the population. US
adults have a 40 % lifetime risk of developing diabetes [3], and $245 billion was
spent in 2012 in treatment. For these reasons, the Centers for Disease Control con-
sider diabetes the epidemic of our time.
The rapid rise in diabetes is attributed to increased longevity, rising urbanization,
and changes in lifestyle including less physical activity and dietary changes. Obesity
worldwide and in the USA, where more than one-third (34.9 % or 78.6 million) of
US adults are obese, has had a tremendous impact on a number of people with dia-
betes [4]. The term “diabesity” has been used to highlight the link between diabetes
and obesity [5]. In addition, changes in demographics and genetic predisposition
have added to the worldwide growth in prevalence with Asia having the greatest
prevalence of diabetes patients (60 %) worldwide. Type 2 diabetes was formally
termed adult-onset diabetes, but the dramatic rise in type 2 diabetes in children,
which has paralleled the increase in childhood obesity in Western societies, has
resulted in modification of disease terms accepted by the American Diabetes
Association [6]. In the USA, type 2 diabetes is more prevalent in obese Hispanic,
Black, and Native American communities. The risk of developing the long-term
complications of diabetes at a younger age is significant and will potentially increase
morbidity and mortality from this chronic condition.
3 Periodontitis and Diabetes Mellitus: A Complex Relationship 21
Table 3.1 Diabetes mellitus Type 1 diabetes

classification by the ADA Insulin-dependent diabetes
(1997) Type 2 diabetes
Non-insulin-dependent diabetes
Gestational diabetes
Other types of diabetes
Genetic defects in B-cell function or in insulin action
Pancreatic diseases or injuries
Infections
Drug-induced or chemical-induced diabetes
Endocrinopathies
Other genetic syndromes associated with diabetes
Table 3.1 outlines the types of diabetes. Gestational diabetes mellitus (GDM) is
usually diagnosed about the 24th week of pregnancy and affects ~14 % of all preg-
nancies. GDM has a similar pathophysiology to type 2 diabetes requiring intensive
monitoring and treatment with most women returning to normal after delivery.
However, it is important to note that 30–50 % of all pregnant women who had ges-
tational diabetes will develop type 2 diabetes within 10 years [7].
Type 1 diabetes is associated with pancreatic autoimmune β-cell destruction. As
a result endogenous insulin is not produced to enable cellular glucose storage or
use. Treatment includes either subcutaneous insulin, recently developed inhaled
insulin, or pancreatic transplants which are currently not widely available. Diet and
exercise are always part of the treatment plan for diabetes management. Type 1
diabetes is more common in whites and those with thin or normal stature and are
<30 years of age. The onset of type 1 diabetes frequently occurs at <20 years of age
and thus was initially called juvenile-onset diabetes. A family history may exist, but
often an initial presentation of an abrupt onset with a rapid decrease in insulin
resulting in cellular starvation and life-threatening ketoacidosis leads to a diagnosis
of type 1 diabetes. Ketoacidosis occurs when body fat is broken down for energy
and the resulting fatty acids are converted to ketones. Ketones are eliminated in the
urine leading to dehydration and, if left untreated, can lead to coma and death. Signs
and symptoms of ketoacidosis include nausea, vomiting, abdominal pain, frequent
urination, dehydration, dry mucous membranes, abnormal skin turgor, tachycardia,
hypotension, Kussmaul’s respiration, altered mental state, and possible coma.
Confirmatory laboratory findings include hyperglycemia, increased BUN, creati-
nine and anion gap, decreased serum potassium and phosphorus, and acidosis.
In contrast, patients with type 2 diabetes or gestational diabetes continue to
secrete insulin, which may be at normal, elevated, or diminished serum levels. In
addition, ketoacidosis is not as common as in type 1 diabetes. Type 2 diabetes may
remain undetected for many years and exhibit insulin resistance and other patho-
physiologic abnormalities contributing to hyperglycemia referred to as the “omi-
nous octet” shown in Fig. 3.1 [8]. In both type 1 and 2 diabetes, chronic hyperglycemia
results in similar long-term complications. Type 2 diabetes is more prevalent in
22 M.E. Ryan et al.
Fig. 3.1 The ominous octet. Multiple defects contribute to the development of glucose intolerance
in type 2 diabetes, HGP, hepatic glucose production [8]
Table 3.2 Classic signs and Polydipsia, polyuria, nocturia, polyphagia

symptoms of diabetes Unexplained weight loss
mellitus General fatigue
Increased infections
Leg cramps
Numbness in the extremities
Impotence
Blurred vision
Cuts/bruises that are slow to heal
African Americans, Latinos, Asian Americans, Pacific Islanders, and Native

Americans, and in some groups almost half of adults from age 30 to 64 have type 2
diabetes. Type 2 diabetes has a very strong genetic predisposition and most often
develops in adulthood (>45 years), therefore was termed adult-onset diabetes. Also
important to risk assessment is a history of gestational diabetes mellitus, prediabe-
tes, hypertension (HTN), and dyslipidemia. Type 2 diabetes usually does not sud-
denly appear and may have no noticeable symptoms or only mild symptoms for
years before diagnosis as outlined in Table 3.2. Three-fourths of all people with type
2 diabetes are or have been obese (>20 % ideal body weight) and have increased
central body obesity and decreased physical inactivity. Consequently initial therapy
frequently consists of diet counseling and exercise, followed by oral and/or inject-
able drugs to increase endogenous insulin secretion or enhance tissue sensitivity to
glucose as described in Fig. 3.2. But for many, insulin therapy is initiated as endog-
enous insulin production diminishes and/or insulin resistance increases.
Screening is very important due to the prevalence of undiagnosed diabetes.
Screening procedures for diabetes in nonpregnant adults are essentially the same
Fig. 3.2 Pathophysiological abnormalities targeted by currently available antidiabetic medica-

tions. DPP4i dipeptidyl peptidase-4 inhibitor, GLP1RA glucagon-like peptide-1 receptor agonist,
HGP hepatic glucose production, MET metformin, SGLT2i sodium-glucose co-transporter 2 inhib-
itor, TZD thiazolidinedione [8]
Table 3.3 Criteria for the diagnosis of diabetes [9]

HbA1C ≥6.5 %. The test should be performed in a laboratory using a method that is NGSP
certified and standardized to the DCCT assaya
OR
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 ha
OR
Two-hour PG ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as
described by the WHO, using a glucose load containing the equivalent of 75 g anhydrous
glucose dissolved in watera
OR
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma
glucose ≥200 mg/dL (11.1 mmol/L)
a
In the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing
and include elevated casual or random plasma glucose (≥200 mg/dL), fasting
plasma glucose (FPG ≥126 mg/dL), the oral glucose tolerance test (OGTT), and
elevated hemoglobin A1c (HbA1c ≥6.5 %) outlined in Table 3.3 [9]. FPG continues
to be the preferred test to diagnose diabetes in children as HbA1c data was collected
from nonpregnant adults. HbA1c has several advantages to the FPG and OGTT,
including greater convenience (fasting not required), greater stability, and less day-
to-day variation due to stress and illness.
24 M.E. Ryan et al.
Table 3.4 Categories of FPG 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L)
increased risk for diabetes (IFG)
(prediabetes) [9] OR
2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/
dL (11.0 mmol/L) (IGT)
OR
A1C 5.7–6.4 %
For all three tests, risk is continuous, extending below the lower
limit of the range and becoming disproportionately greater at
higher ends of the range
Table 3.5 Criteria for testing for diabetes in asymptomatic adult individuals [9]
1. Testing should be considered in all adults who are overweight (BMI ≥25 kg/m2a) and have
additional risk factors:
(a) Physical inactivity
(b) First-degree relative with diabetes
(c) High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian
American, Pacific Islander)
(d) Women who delivered a baby weighing >9 lb or were diagnosed with GDM
(e) Hypertension (≥140/90 mmHg or on therapy for hypertension)
(f) HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level >250 mg/dL
(2.82 mmol/L)
(g) Women with polycystic ovarian syndrome
(h) A1C ≥5.7 %, IGT, or IFG on previous testing
(i) Other clinical conditions associated with insulin resistance (e.g., severe obesity,
acanthosis nigricans)
(j) History of CVD
2. For all patients, particularly those who are overweight or obese, testing should begin at age
45 years
3. If results are normal, testing should be repeated at least at 3-year intervals, with
consideration of more frequent testing depending on initial results (e.g., those with
prediabetes should be tested yearly) and risk status
a
At-risk BMI may be lower in some ethnic groups
Early diagnosis facilitates optimal management and a significant reduction in long-

term complications. In addition, identification of the prediabetic can lead to effective
preventive strategies. Categories of increased risk for diabetes or prediabetes are out-
lined in Table 3.4 and include impaired glucose tolerance (IGT), impaired fasting
glucose (IFG), a significant family history of diabetes, or a history of vascular disease
or hypertension [9]. Metabolic syndrome, a widely prevalent and multifactorial disor-
der, may be a prediabetic state since it is predictive of type 2 diabetes and cardiovas-
cular disease. Metabolic syndrome is defined as insulin resistance plus two or more of
the following: central obesity, dyslipidemia, HTN, and a FPG ≥110 mg/dL. A pro-
inflammatory state contributes to the increasing prevalence of this syndrome [10].
Diabetic screening is usually conducted in asymptomatic adults every 3 years in
those >45 years of age and with other risk factors such as HTN, high cholesterol, or a
first-degree relative with diabetes in those >30 years of age as outlined in Table 3.5 [9].
Table 3.6 Testing for type 2 diabetes in asymptomatic children [9]

Criteria:
Overweight (BMI >85th percentile for age and sex, weight for height >85th percentile, or
weight >120 % of ideal for height)
Plus any two of the following risk factors:
(a) Family history of type 2 diabetes in first- or second-degree relative
(b) Race/ethnicity (Native American, African American, Latino, Asian American, Pacific
Islander)
(c) Signs of insulin resistance or conditions associated with insulin resistance (acanthosis
nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome, or small-for-
gestational-age birth weight)
(d) Maternal history of diabetes or GDM during the child’s gestation
Age of initiation: age 10 years or at onset of puberty, if puberty occurs at a younger age
Frequency: every 3 years
Persons aged 18 years and younger
Table 3.7 Classic complica- Macrovascular disease (accelerated atherosclerosis)

tions of diabetes mellitus Peripheral
Cardiovascular (coronary artery disease)
Cerebrovascular (stroke)
Nephropathy
Renal failure
Neuropathy
Sensory (peripheral is most common)
Autonomic (dysrhythmias, alterations in BP, genitourinary,
gastroparesis)
Retinopathy
Blindness, blurred vision
Altered wound healing
Periodontitis
Testing to assess risk for diabetes should be considered in adults of any age who are
overweight or obese determined by body mass index (BMI ≥25 kg/m2 or ≥23 kg/m2 in
Asian Americans) and who have one or more additional risk factors for diabetes. For
all patients, testing should begin at age 45 years. Testing to detect prediabetes should
be considered in children and adolescents who are overweight or obese and who have
two or more additional risk factors for diabetes as outlined in Table 3.6 [9]. If tests are
normal, repeat testing carried out at a minimum of 3-year intervals is reasonable.
Hyperglycemia is known to cause tissue injury and lead to diabetic complica-
tions outlined in Table 3.7. Hyperglycemia not only glycates proteins such as hemo-
globin and collagen and produces advanced glycation end products (AGEs) but also
leads to the accumulation of sorbitol and fructose in the nerves and the lens of the
eye leading to neuropathy, retinopathy, and cataract formation. Hyperglycemia can
also lead to the activation of protein kinase C (PKC) impacting vascular cells and
contributing to micro- and macrovascular complications. The tissue changes that
ensue are a result of altered protein function and turnover as well as cytokine activa-
tion. Osmotic and oxidative stress within tissue is also associated with
26 M.E. Ryan et al.
Table 3.8 Factors Duration of diabetes

accentuating periodontal Degree of metabolic control
disease in patients with Co-occurrences of complications
diabetes [13]
Angiopathy (heart disease and stroke)
Delayed wound healing
Nephropathy (kidney disease)
Neuropathy
Retinopathy (eye disease)
Concurrent risk factors
Hormonal variations (e.g., adolescence, pregnancy,
menopause)
Medications
Plaque
Smoking
Stress
hyperglycemia. Reduced motor and sensory nerve conduction velocity associated

with neuropathy and an increased glomerular filtration rate and renal plasma flow
associated with nephropathy occur. Complications that significantly increase the
risk for mortality in people with diabetes include heart attacks, strokes, and kidney
disease. The leading cause of blindness in adults is related to diabetic retinopathy,
with cataracts also being very common. Neuropathy, wound healing issues, and
periodontitis are other common complications of diabetes. People with diabetes are
at an increased risk for developing infections, which can lead to impaired diabetic
control.
The two main techniques available for health providers and patients to assess the
effectiveness of the management plan on glycemic control are patient self-
monitoring of blood glucose (SMBG) and HbA1c. HbA1c is the gold standard for
diabetic monitoring by integrating the levels of control over the past 2–3 months.
The Diabetes Control and Complications Trials (DCCT) in patients with type 1
diabetes demonstrated that tight control of blood glucose as assessed by HbA1c
levels reduced the risk of multiple long-term complications [11]. The absolute risk
of retinopathy in the DCCT was significantly decreased with tighter control estab-
lishing 7 % HbA1c as an optimal level [12]. The American Diabetes Association
(ADA) recommends an HbA1c of <7.0 % with a goal of <6.5 % in select individuals
to reduce the risk and slow down the progression of the long-term complications of
diabetes as described in Table 3.7. Large trials in type 2 diabetes subjects were con-
ducted in the United Kingdom Prospective Diabetes Study (UKPDS) to assess the
influence of intensive versus conventional (diet alone) glycemic control on both
microvascular and macrovascular complications [14]. Microvascular and macrovas-
cular complications were reported to increase once HbA1c >6.5 %. Intensive con-
trol with diet and sulfonylurea, or insulin, or metformin significantly reduced the
risk of microvascular complications. A 6-year follow-up data showed progression
of retinopathy increased more than fourfold with HbA1c of 6.2–7.5 % as compared
to those with <6.2 %. HbA1c >7.5 % had little progression of retinopathy beyond
that seen from 6.2 to 7.5 %. A few smaller cohort trials corroborate the significance
of HbA1c of >6.5 % with no differential effect between type 1 and type 2 diabetes
mellitus. Based on these and other data, the American Association of Clinical
Endocrinologists (AACE) recommends an HbA1c goal of <6.5 %. Epidemiologic
analysis of all those subjects receiving intensive therapy in the UKPDS showed a
14 % reduction in macrovascular and a 37 % reduction in microvascular complica-
tions for every 1 % decrease in HbA1c [15].
The goal of diabetes management is the prevention of acute and chronic complica-
tions with macrovascular complications being the most prevalent and the major cause
of disability and death. The reality is that the HbA1c goals are unmet in many patients
with diabetes with 48 % of adult Americans with diabetes having a HbA1c >7 % [16].
Fasting glucose targets have also been established from the UKPDS data with a treat-
ment target glucose level of <108. The NHANES III database showed retinopathy
increased with fasting glucose from 110 to 119. Fasting levels of >110 were associ-
ated with substantial cardiovascular risk. In the CARE study which consisted of 3500
patients without diabetes, the rates of recurrence of cardiovascular events increased in
those with FPG >90 and doubled in those with FPG of 110–115 [17]. Based on these
studies, the ADA goal for fasting plasma glucose is 90–130 and the AACE recom-
mends FPG <110. HbA1c has less intraindividual variation and better predicts both
micro- and macrovascular complications [18]. Although the cost of HbA1c monitor-
ing is higher than FPG, the additional benefits in predicting costly preventable clinical
complications may make this a cost-effective choice.
3.3 Common Ground Between Periodontal Diseases

and Diabetes
Periodontal disease is the most common chronic inflammatory disease worldwide with
recent reports indicating that the prevalence of periodontitis US adults is 47 % [19]. As
described in Chap. 2 of this volume, periodontal pathogens are essential for the initia-
tion of the disease process yet insufficient by themselves to cause significant disease. It
is recognized that periodontitis, an often silent disease if left untreated, can present a
significant challenge to the entire body resulting from bacteremias, endotoxemia, and
elevated levels of systemic inflammation as measured by elevations in high-sensitivity
C-reactive protein (hsCRP) levels [20]. CRP may be a stronger predictor for heart
attacks than cholesterol which is why most physicians now measure both hsCRP and
cholesterol for the most accurate risk assessment for cardiovascular disease [21]. The
2000 Surgeon General’s Report on Oral Health in America recognizes “the mouth as a
mirror of health or disease, as a sentinel or early warning system, as an accessible
model for the study of other tissues and organs, and as a potential source of pathology
affecting other systems and organs” [22]. This is particularly true of diabetes and oral
health where significant oral changes may be indicative of undiagnosed or poorly con-
trolled diabetes. Oral changes may be reflective of changes to other tissues and organs
throughout the body which are not as accessible. Poor oral health may have a negative
impact on diabetes control, increasing the risk for other complications of diabetes and
may even place people with prediabetes at risk for developing diabetes.
28 M.E. Ryan et al.
Diabetes and periodontal disease are both chronic diseases that can progress if
not well controlled. Neither can be cured but are treatable and may even be pre-
vented if high-risk individuals are identified. Early detection of prediabetes and
gingivitis would allow for early intervention. These diseases have common risk
factors such as obesity estimated to be 30–40 % of the population, metabolic syn-
drome believed to exist in 24 % of the population, and genetics. Both diabetes and
periodontal diseases can occur during pregnancy, yet they generally occur in older
individuals >45 years of age. Diabetes and periodontitis are risk factors for each
other. Both can lead to elevated hsCRP levels and often remain silent for extended
periods of time. The underlying chronic inflammation seen in diabetes as a result of
the AGE-RAGE interactions and in periodontal disease as a result of bacterial chal-
lenge and in both diseases as a result of genetic predispositions may explain their
associated increased risk for cardiovascular diseases, adverse pregnancy outcomes,
and the development of certain cancers.
In prediabetes acute infections may induce a temporary diabetic state requiring
short-term insulin therapy. The Insulin Resistance Atherosclerosis Study (IRAS)
demonstrated that inflammation as measured by CRP levels is associated with insu-
lin sensitivity even in nondiabetics [23]. Serum CRP levels and other markers of
inflammation were significantly related to the development of type 2 diabetes in
1047 nondiabetic subjects followed for 5 years. The investigators concluded that
chronic inflammation was a new risk factor for type 2 diabetes. Our group reported
a correlation of periodontal disease status in ten subjects with varying degrees of
insulin resistance [24]. Insulin resistance was measured using a hyperinsulinemic
euglycemic clamp to determine RD values, a measure of glucose uptake and insulin
sensitivity. A clinical periodontal examination determined the number of sites with
attachment loss of ≥5 mm, and DNA analysis was performed to determine variation
in interleukin-1 [25]. The findings showed 50 % of the subjects testing positive for
the IL-1 polymorphism and the same subjects with the greatest number of sites with
attachment loss of ≥5 mm were also very insulin resistant with RD values of <8.
Evaluation of all ten subjects revealed that those with the most attachment loss had
the greatest insulin resistance and those with the least number of sites with attach-
ment loss were more insulin sensitive. An epidemiologic study found that in sub-
jects followed for over two decades, those with periodontal disease were more likely
to develop type 2 diabetes later in life [26]. The risk of developing diabetes over the
next 20 years was twice as likely in people with varying degrees of periodontitis.
3.4 The Impact of Diabetes on Periodontal Tissues
Diabetes has long been associated with the increased prevalence and severity of
periodontitis, and periodontitis is recognized as one of the major diabetic complica-
tions. Persistent poor glycemic control has been associated with the incidence and
progression of gingivitis, periodontitis, and alveolar bone loss. The degree of meta-
bolic control and the duration of diabetes are closely associated with the severity of
periodontal disease [13]. Diabetics are known to be at an increased risk of infection.
Fig. 3.3 Poor glycemic Hyperglycemia

Hyperglycemia
control in diabetes induces
Insulin resistance/
and worsens oral
antagonism
inflammation, gingivitis, Bacterial
Bacterialinfection
infection Advanced glycation
Advanced glycation
and periodontal disease. Oral
Oral inflammation
inflammation end-products
end-products(AGEs)
(AGEs)
These conditions trigger a
host-mediated inflammatory
response, which further Cytokines Matrix
Prostanoids
hinders glycemic control. (IL-1β, IL-6, TNF-α) metalloproteinases
The resulting vicious cycle
of events enhance the
severity of periodontal
Bone
Bone Connective tissue
disease (Adapted from resorption breakdown
resorption breakdown
Ryan et al. [13])
Clinical attachment loss

Tooth mobility and loss
Periodontitis initiated by infection and driven by inflammation is a known compli-

cation of diabetes mellitus. In a meta-analysis including 3500 adults with diabetes,
Papapanou found a significant association between diabetes and periodontitis [27].
A classic cross-sectional study showed type 1 diabetes was associated with a five-
fold increased prevalence of periodontitis in teenagers [28]. Epidemiologic studies
support an increased prevalence and severity of attachment loss and bone loss in
adults with diabetes mellitus. A multivariate risk analysis showed that subjects with
type 2 diabetes had a three times greater odds of having periodontitis compared with
subjects without diabetes (after adjusting for confounding variables including age,
sex, and oral hygiene measures) [29]. These results were supported by the NHANES
III study which included thousands of American adults with poorly controlled dia-
betes. Diabetics had a threefold increased risk of having periodontitis compared
with nondiabetics (after adjusting for age, sex, and oral hygiene measures) [30].
Poor glycemic control in diabetes is associated with an increased risk of periodontal
attachment and alveolar bone loss over time, comparable to other long-term diabetic
complications such as retinopathy. Some of the factors that can accentuate peri-
odontitis in diabetes are outlined in Table 3.8.
Figure 3.3 outlines some of the mechanisms through which diabetes can affect
periodontal tissues [13]. Many of these mechanisms share characteristics with those
involved in the classic complications of diabetes such as retinopathy, neuropathy,
nephropathy, macrovascular diseases, and altered wound healing. The function of
neutrophils, monocytes, and macrophages is altered in diabetes. These cells are the
first line of defense, and inhibition of their function may prevent destruction of bac-
teria in the periodontal pocket, thereby increasing periodontal destruction. The pri-
mary reparative cell in the periodontium, the fibroblast, does not function properly in
high-glucose environments. Periodontal wound healing may be impaired in those
with sustained hyperglycemia. Diabetics, especially those with poor glycemic con-
trol, accumulate high levels of glycated proteins. Collagen the most prevalent protein
30 M.E. Ryan et al.
in the body will become glycated, eventually leading to the accumulation of advanced
glycation end products (AGEs) which accumulate in tissues throughout the body,
including the periodontium. AGE-enriched gingival tissue changes are seen due to
altered protein function and turnover impacting the wound healing process.
AGEs are a primary link between many diabetes complications. AGE accumula-
tion will result in osmotic and oxidative stress contributing to tissue changes through-
out the body. Interactions between AGEs and their receptors (RAGEs) on inflammatory
cells result in an increased production and activation of pro-inflammatory cytokines,
prostanoids, and enzymes such as matrix metalloproteinases (MMPs). There is also
increased macrophage migration and immobilization at AGE-rich sites. A monocytic
hypersecretory phenotype has been observed responding dramatically to Gram-
negative LPS, elevated lipid levels, and the presence of AGEs exacerbated by
HLA-DR3/4 or HLA-DQ genotypes. Fourfold increases in gingival crevicular fluid
(GCF) levels of the pro-inflammatory mediators have been noted in the GCF of peo-
ple with type 1 diabetes as compared to those without diabetes with equivalent pocket
depths [31]. Engebrettson and colleagues found that IL-1α GCF levels were twice as
high in poorly controlled type 2 subjects with diabetes with HbA1c levels greater than
8 % compared with subjects whose hemoglobin A1c levels were less than or equal to
8 %. This same group also found that the severity of periodontitis was correlated with
plasma TNF-α levels in subjects with type 2 diabetes [32]. Chronic periodontal
inflammation can contribute to systemic inflammation facilitating insulin resistance.
In addition, activation of the cells lining the blood vessels through endothelial RAGE
increases permeability and the production of adhesion molecules. These changes in
diabetic vasculature may create an even greater portal to the systemic circulation for
bacterial products and host-produced local inflammatory mediators. AGEs will induce
abnormal endothelial cell function, capillary growth, and vessel proliferation. The
presence of AGEs has been linked to thickening of the basement membrane and
altered vasculature. Degenerative vascular changes may interfere with nutrient and
leukocyte migration to gingival tissue, decreasing oxygen diffusion, and elimination
of metabolic waste, thereby increasing the severity of periodontitis by decreasing den-
tal healing capacity [13]. Activation of fibroblast RAGE results in decreased collagen
production and increased MMP levels. The risk and rate of periodontal disease are
impacted by AGE-enriched gingival tissues.
Collectively, diabetes creates specific conditions leading to enhanced oral inflam-
mation coupled with overproduction of inflammatory mediators and degradation
enzymes, all of which participate in periodontitis progression. People with diabetes
are at significant risk for periodontitis due to excessive inflammation with equiva-
lent bacterial burden not proportionate to plaque and calculus levels. Diabetes
induces an exaggerated response to periodontal pathogens resulting in accelerated
destruction of periodontal tissues.
3.5 The Impact of Periodontitis on Diabetes
While a systemic disease such as diabetes can affect oral health, there is growing
evidence that oral infections can also have systemic effects. This bidirectional rela-
tionship is especially important for diabetic control. Studies of active inflammatory
connective tissue diseases have shown that inflammation can trigger insulin resis-
tance [33]. TNF-α has been reported to interfere with lipid metabolism and cause
insulin resistance, while IL-1β and IL-6 antagonize insulin action. A host-mediated
inflammatory response can thus hinder glycemic control in patients with diabetes,
in turn creating a vicious cycle of events that compromises glycemic control and
further stimulates periodontal disease. Prevention and control of oral inflammation
and periodontal disease are essential for appropriate prevention and management of
diabetes complications. It is known that systemic infections result in increased sys-
temic inflammation which increases insulin resistance and makes it difficult for
patients to control their glucose levels. Bacterial infections decrease insulin-
mediated glucose uptake by the skeletal muscle leading to a whole-body insulin
resistance. Acute endotoxemia and cytokine production (TNF-α, IL-1β, IL-6)
induce insulin resistance and decrease insulin action. Chronic periodontal diseases
can exacerbate insulin resistance and worsen glycemic control increasing the risk
for the development of other long-term diabetic complications such as cardiovascu-
lar disease and kidney disease.
A 2-year longitudinal trial demonstrated a sixfold increased risk of decreased
glycemic control in patients with type 2 diabetes who had severe periodontitis com-
pared to periodontally healthy patients [34]. Thorstensson et al. reported that in up
to an 11-year follow-up of people with diabetes who had severe periodontitis com-
pared to those with mild periodontitis or gingivitis, there was a greater prevalence
of proteinuria, a sign of kidney disease, and a greater number of cardiovascular
complications including stroke and myocardial infarction [35]. Another study
reported that periodontal disease (60 % of subjects had severe periodontitis) is
strongly predictive of mortality from ischemic heart disease and diabetic nephropa-
thy in Pima Indians with type 2 diabetes [36]. 204/628 subjects greater than 35 years
of age died in an 11-year follow-up with 44/54 CVD-related deaths attributed to
ischemic heart disease and 28/35 diabetes-related deaths attributed to nephropathy.
The age- and sex-adjusted death rates were 3.7 for no or mild periodontitis, 19.6 for
moderate periodontitis, and 28.4 for severe periodontitis. This is supported by
another report that periodontitis predicts development of overt nephropathy and
end-stage renal disease (ESRD) in individuals with type 2 diabetes [37]. During a
22-year follow-up of 529 subjects, 193 developed macroalbuminuria, and 68
developed ESRD with a correlation in the severity of periodontal disease with the
risk for developing kidney dysfunction. Chronic periodontitis may potentiate insu-
lin resistance increasing the risk for the development of multiple long-term
complications of diabetes.
3.6 Therapeutic Strategies
Periodontitis is often referred to as the world’s most common chronic inflamma-

tory disease. Since systemic infections can result in increased systemic inflamma-
tion, insulin resistance, and poor glycemic control, the need to manage this oral
condition is evident. Patients with diabetes or at risk for diabetes should be seen
by oral healthcare providers to assess their oral status and to develop a treatment
plan for managing oral infection and inflammation followed by an appropriate
32 M.E. Ryan et al.
maintenance regimen. As oral healthcare providers will see increasing numbers of

patients with diabetes, they should be knowledgeable and equipped for the man-
agement of hypoglycemic episodes which are common in this patient
population.
Poorly controlled patients with diabetes are at greater risk for developing peri-
odontitis, and for this reason, the patient’s physician should be contacted to deter-
mine the level of glycemic control and, if poorly controlled, consider how to
achieve better glycemic control to facilitate an optimal response to periodontal
therapy. Poorly controlled diabetics are more difficult to manage periodontally
and may require the use of adjunctive therapeutics in addition to traditional
mechanical therapy, such as systemic or local administration of antimicrobials
and/or host modulatory therapy.
Numerous studies have been conducted to determine if periodontal therapy can
improve on metabolic control. The first case series published in 1960 reported that
patients with type 1 diabetes and periodontitis had a reduction in insulin dosage fol-
lowing periodontal therapy that included scaling and root planing, localized gingi-
vectomy, and selected tooth extractions combined with penicillin and streptomycin
administration [38]. Iwamoto et al. found that periodontal treatment in type 2 dia-
betes resulted in a significant reduction in serum levels of TNF-α and mean HbA1c
levels (8.0–7.1 %) [39]. A meta-analysis of 10 intervention trials including 456
patients indicated that nonsurgical periodontal therapy can decrease absolute HbA1c
values by ~0.4 %. The addition of systemic antibiotics has been reported to result in
an average absolute reduction of ~0.7 % [40]. Recent systematic reviews and meta-
analyses also report that nonsurgical periodontal treatment improves metabolic con-
trol [41–43]. However, these findings were not supported by a large multicenter
randomized clinical trial of the effect of nonsurgical periodontal therapy on HbA1c
levels. Subjects with moderate to advanced periodontitis and type 2 diabetes with
HbA1c levels between 7 and 9 % were randomized into treatment (scaling and root
planing plus chlorhexidine oral rinse and supportive periodontal care at 3 and
6 months post therapy) (N = 257) or control (no treatment for 6 months) (N = 257).
No difference between the treatment and control groups were found at 6 months
[44]. Findings reported in this study may support the need for adjunctive therapies,
in addition to mechanical therapy, in the management of periodontitis in poorly
controlled patients with diabetes.
Doxycycline has been found to be an effective adjunct to scaling and root planing
even when administered at non-antimicrobial levels (20 mg bid known as Periostat
or sub-antimicrobial dose doxycycline (SDD)) for 3 months on a daily basis. Studies
indicate that host modulatory properties of doxycycline, reducing MMP and cyto-
kine levels as well as the nonenzymatic glycation of proteins and the development
of AGEs, may prove doxycycline to be an optimal adjunctive periodontal treatment
for people with diabetes. SDD decreases HbA1c in patients who are taking hypo-
glycemic agents [45]. SRP and adjunctive Periostat significantly improved pocket
depth and clinical attachment levels, reduced reactive oxygen species, reduced IL-2,
and reduced HbA1c [46].
3.7 Clinical Management of the Diabetic Patient

with Periodontitis
3.7.1 Dental Considerations
Review of the patient’s medical history should include the date of the patient’s last
medical evaluation, current medications, disease history including the occurrence of
any diabetic complications, and the level and history of glycemic control. A consult
letter can be sent to the patient’s physician of record, informing the physician of the
patient’s dental status. In patients suspected to be diabetic or in those with previ-
ously diagnosed diabetes but not followed by the physician for diabetes, a dentist
may consider screening for non-fasting blood glucose, fasting blood glucose, or
HbA1c and referring positive patients for medical management.
We have included periodontal disease in risk assessment for diabetes. The CDC
has suggested that dental professionals can aid in identifying the nearly 50 % of
people with type 2 diabetes that remain undiagnosed. Early identification and diag-
nosis of diabetes are of paramount importance, since more than 60 % of Americans
see a dentist at least once per year, often returning for multiple visits; the dental
office can be an effective screening site. Dental management of patients with diabe-
tes has been discussed [47, 48]. Recognition of diabetes symptoms as well as modi-
fication of treatment plans according to the level of metabolic control and related
diabetes complications including cardiovascular disease, neuropathy, and impaired
wound healing should be considered. The dentist should advise the patient of their
risk for oral diseases, assess their oral status, and check for xerostomia, caries, peri-
odontal disease, abscesses, and yeast infections.
3.7.2 Medical Considerations
Many physicians have yet to acknowledge the impact of poor oral health on their
patients with diabetes. They can assist in assessing if their patients are being evalu-
ated by oral healthcare providers, and if not, they should make the appropriate refer-
ral. When hyperglycemia has been difficult to control, the physician might consider
asking patients when they last saw their dentist, whether periodontitis has been
diagnosed, and, if so, whether treatment has been completed. A consultation with
the dentist may be appropriate, to discuss whether periodontal treatment has been
successful or whether a more intensive approach with systemic or locally applied
antimicrobials and/or host modulatory therapy is in order because, just as it is dif-
ficult to control diabetes while the patient has an infected leg ulcer, the same applies
when there’s infection and inflammation of the periodontium. The physician may
perform a cursory oral evaluation looking for signs of inflammation or asking the
patient if they have red, swollen, or bleeding gums, gingival recession, mobile teeth,
bad breath, oral pain, or discomfort. Whether this evaluation is done through a ver-
bal patient self-report or through a cursory dental examination by the physician,
34 M.E. Ryan et al.
they should refer all people suspected to have oral disease to the dentist. At a mini-
mum, the physician should determine the date of the last dental examination, and in
those people with or at risk for diabetes, they should be referred to a dentist for an
oral examination if they have not been seen by the dentist within the past year.
Future point of care diagnostics aiding in the identification of oral inflammation and
infection may help to guide physicians and other healthcare providers in providing
dental referrals. Physicians should also recommend biannual exams and necessary
dental treatment and oral hygiene compliance. Physician referrals should be accom-
panied with either an assessment of prediabetes or if diabetic the current level of
metabolic control. Recent results from blood glucose testing, HbA1c, hsCRP, and
cholesterol as well as reports that may indicate increased risk for diabetic complica-
tions should be provided by the physician to the dentist.
Conclusions
Diabetes mellitus has a significant impact on all tissues throughout the body,
including the oral cavity. A reciprocal relationship exists in that poorly con-
trolled diabetes increases the risk of periodontitis and periodontal infection/
inflammation and treatment can alter glycemic control. Common to both peri-
odontal diseases and diabetic complications is elevation in systemic
inflammation.
This chapter emphasized the importance of early detection and intervention in
both diabetes and periodontitis and the important role that oral healthcare provid-
ers can play. Current data suggests that a customized treatment plan for manag-
ing oral disease, particularly periodontitis, may not only optimize dental
management while indirectly yielding improvements in glycemic control but
that some adjuncts used to manage periodontitis may directly impact glycemic
control. Prevention and control of periodontal disease must be considered an
integral aspect of metabolic control, since improved oral health can lead to
improvements in the overall health of patients with diabetes.
A team effort is truly necessary for the proper management of the diabetic
patient: the physician, nurse, diabetes educators, dieticians, dentists, hygienists,
and a number of other specialists. There is a great need for dental and medical
practitioners to communicate and partner to facilitate the care of patients with
diabetes. Oral health should never be considered an option or elective, and the
current evidence regarding the links between oral and overall health in people
with diabetes certainly supports an increased primary and preventive role for
dental care providers.
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Atherosclerotic Vascular Disease
and Periodontal Disease 4
Harmony R. Reynolds and Ronald G. Craig
4.1 Overview
Cardiovascular diseases (CVD) are the world’s leading cause of mortality, claiming
over 17 million lives per year [1]. In the United States alone, over 800,000 individu-
als died from CVD in 2013, or about one-third of all deaths that year, making CVD
the leading cause of death in the nation [2, 3]. Coronary heart disease accounts for
just under half of CVD deaths, and with cerebrovascular disease and peripheral vas-
cular disease, comprises the atherosclerotic vascular diseases (ASVD). The annual
incidence of global ASVD mortality is expected to rise to an estimated 23.6 million
deaths by the year 2030. As a comparison, ASVD annually accounts for more deaths
in the United States than all forms of cancer combined [2]. However, progress is
being made to moderate the high rate of ASVD mortality through risk reduction
strategies and improvements in therapy.
Underlying ASVD is the process of atherosclerosis, a complex and still incom-
pletely understood vascular disorder. Some atherosclerotic lesions ultimately lead to
vascular occlusion via plaque rupture or erosion with superimposed thrombosis,
resulting in myocardial infarction, stroke, and in some cases, death. Atherosclerotic
lesions begin to develop in the teenage years but the vast majority of cardiovascular
events occur in middle and older age. Therefore prevention needs to begin as early as
H.R. Reynolds, MD (*)

Leon H. Charney Division of Cardiology, Department of Medicine,
New York University School of Medicine, New York, NY, USA
e-mail: Harmony.Reynolds@nyumc.org
Department of Basic Sciences and Craniofacial Biology,
Department of Periodontology and Implant Dentistry,

40 H.R. Reynolds and R.G. Craig
possible in life to reduce the risk of cardiovascular events, for example, by following
a healthy diet and exercise plan and with screening for risk factors. Risk for athero-
sclerosis is a combination of both non-modifiable (genetics, age, sex, family history)
and modifiable risk factors. Prospective epidemiologic studies, such as the Framingham
risk for cardiovascular disease study, have identified a set of modifiable atheroscle-
rotic risk factors that include cigarette smoking, dyslipidemia, hypertension, diabetes
mellitus, obesity, and physical inactivity. These factors interact in a multiplicative
fashion such that two risk factors present simultaneously within an individual roughly
increase risk by a factor of four [4]. Fortunately reduction in an individual’s risk factor
profile can mitigate risk for atherosclerotic progression. Hypercholesterolemia, for
example, is a very robust atherosclerotic risk factor that can be lowered through statin
administration and lifestyle changes, which also results in a decreased incidence of
subsequent ASVD events [5]. However, not all patients who experience ASVD events
present with traditional risk factors as those identified by the Framingham study. With
the realization that atherosclerosis is an inflammatory disease [6] and that increased
systemic inflammation is associated with ASVD progression, systemic inflammation
has also become recognized as a risk factor for ASVD. Therefore, means to decrease
systemic inflammation have become a major focus of ASVD research.
Periodontitis is highly prevalent in adult populations, can contribute to systemic
inflammation, and is associated with ASVD. In addition, both ASVD and periodon-
titis share several common risk factors including increased age, cigarette smoking,
and diabetes mellitus. To explore whether periodontitis contributes to risk for athero-
sclerosis and, perhaps more importantly, whether periodontal therapy can decrease
ASVD risk, this chapter will begin with a discussion of the pathogenesis of athero-
sclerosis and then focus on the association between ASVD and periodontitis.
Specifically addressed in this chapter are the following questions:
• What is the strength of the association between ASVD and periodontitis?

• What are the biologic mechanisms for the association?
• Is periodontitis a risk factor for ASVD?
• Can periodontal therapy decrease risk for ASVD?
4.2 Atherosclerosis, an Inflammatory Disease
Atherosclerosis is currently thought to result from the persistent presence of inflam-

mation overlaid by repeated attempts at healing and repair within the arterial wall in
response to injury. This view, termed the response to injury hypothesis, embraces
most of the established atherosclerotic risk factors [4]. Atheroma formation is the
characteristic lesion of atherosclerosis. Present within the atheroma are endothelial
cells, smooth muscle cells, macrophages, and T-cell lymphocytes with each cell type
performing a specific role in atherosclerotic progression. Of interest, inflammation is
present at each stage of atherosclerotic disease progression [7].
Endothelial cells lining the arterial wall perform several essential functions
including the regulation of local blood flow and the selective migration of fluid and
4 Atherosclerotic Vascular Disease and Periodontal Disease 41
cells from the vascular to extravascular compartments. Local vascular tone is regu-
lated in part through endothelial cell expression of nitric oxide, a vasodilator, and
endothelin, a vasoconstrictor, in addition to other vasoactive mediators. In health
the luminal surface of the endothelial cell presents a non-thrombogenic surface
that facilitates blood flow. However, endothelial cells dramatically change their
phenotype when injured or stimulated by a wide array of pro-inflammatory media-
tors that include:
1. Proinflammatory cytokines, including tumor necrosis factor-α, (TNF-α), inter-

leukin 1 (IL-1), or IL-6
2. Components of the complement and coagulation cascades
3. Lipid metabolites such as prostaglandins
4. Reactive oxygen species generated by inflammatory cells
5. Bacterial or viral products such as endotoxin
6. Components of tobacco smoke
Under pro-inflammatory conditions, endothelial cells become activated and

assume a key role in the initiation and regulation of local inflammatory events.
These activities include endothelial cell contraction that exposes the underlying
endothelial basement membrane thus allowing the passage of fluid from the circula-
tion into the surrounding tissues to generate tissue edema. Endothelial cells also
express cell adhesion molecules that recruit specific innate and adaptive immune
cells from the circulation into the intimal layer of the artery. In addition, endothelial
cells express procoagulants that facilitate intravascular platelet adhesion, activation,
and the release of growth factors to aid in tissue repair. Usually these endothelial
activities result in the removal of the inflammatory stimulus and the restoration of
healthy vascular tissue. However, under some conditions, such as hyperlipidemia,
hemodynamic disturbances in blood flow or an increase in systemic inflammation,
endothelial activation inappropriately persists, a condition called endothelial dys-
function. Endothelial dysfunction is one of the earliest cellular events observed in
atherosclerosis.
Atherosclerosis continues to progress via the migration and proliferation of
smooth muscle cells from the arterial medial wall into the intima, where the recruited
smooth muscle cells proliferate and express extracellular matrix proteins including
type I and III collagens that increase the thickness of the intimal layer. The thick-
ened intimal layer, termed the neointima, is the characteristic response of the arte-
rial wall to injury. Smooth muscle cells of the neointima are distinct from contractile
smooth muscle cells of the media from which they were derived in that they migrate,
proliferate, and actively express extracellular matrix proteins. Therefore within the
neointima, smooth muscle cells assume functions that are analogous to fibroblasts
activated during injury and wound healing within other connective tissues.
Lipid accumulation is a key feature of atherogenesis. Persistent endothelial dys-
function facilitates entry of cholesterol and cholesterol esters into the neointima [8].
Cholesterol is a vital structural component of cell membranes and is both synthe-
sized de novo and obtained from the diet. Cholesterol is transported to peripheral
tissues by serum transport proteins such as low-density lipoprotein (LDL) and from
peripheral tissues to the liver by high-density lipoproteins (HDL) to be metabolized
into bile and other end products of metabolism. Lipoproteins accumulate in the
intima, where they are more susceptible to oxidation. The presence of cholesterol
deposits within the intima is itself pro-inflammatory and stimulates the recruitment
of monocytes into the neointima by the expression of cell adhesion molecules on the
luminal surface of endothelial cells [8]. Within the neointima, monocytes become
macrophages that ingest extracellular deposits of LDL-cholesterol, cholesterol
esters, and oxidized cholesterol. However, the ingested cholesterol deposits are not
totally degradable by the macrophage. The intracellular lipid persists within the
macrophage as lipid vesicles transforming the macrophages into foam cells. Foam
cell formation is one of the earliest histologic events observed in atherosclerosis.
Foam cells are innately pro-inflammatory, even in the absence of exogenous anti-
gens. Additional monocyte recruitment and cell death (apoptosis) results in local
concentrations of foam cells, extracellular cholesterol, and cellular debris within the
intima. These small discrete lesions, termed fatty streaks, may or may not coalesce
to form atheromas. Fatty streaks are nearly universally present as early as adoles-
cence in populations of industrialized nations. It is thought the interplay of addi-
tional atherosclerotic risk factors, both innate and modifiable, over time promote the
progression of fatty streaks into atheromas.
Of interest, atheromas are not randomly distributed within the arterial tree but
tend to develop in areas of naturally disrupted or turbulent hemodynamic flow such
as arterial bifurcations and the ostia of branch vessels. As a result, the most common
sites of atheroma formation are in order of prevalence: the posterior wall of the
abdominal aorta, coronary, popliteal, and internal carotid arteries and the arteries of
the circle of Willis at the base of the skull [4]. It is thought that the disruption of
hemodynamic flow at these anatomical sites plays a central role in maintaining
endothelial dysfunction and thus promoting atherosclerotic progression.
The presence of cholesterol crystals and intracellular non-degraded cholesterol
within macrophages can also bind intracellular NOD-like receptors and activate
inflammasome signaling leading to further inflammation and/or apoptosis [9]. With
the progression of atherosclerosis, T-cell lymphocytes are recruited into the lesion
that express cytokines such as interferon γ that further focus and amplify the inflam-
matory response [9]. Over time, interior portions of the necrotic atheroma may also
calcify. Additional smooth muscle cells are recruited that express type I and III col-
lagens that form a fibrous cap to cover the thrombogenic interior of the atheroma
and sequester it from the circulation. The integrity of the overlying fibrous cap is a
function of both extracellular matrix protein synthesis and degradation. Maintenance
of the integrity of the fibrous cap is essential since cap rupture can expose the lipid
rich thrombogenic interior of the atheroma to the circulation precipitating intravas-
cular coagulation and thrombus formation.
Atheroma enlargement is a nonlinear process with slow increases in size over
time, punctuated by sudden increases in size relating to rupture of the fibrous cap
with resulting thrombosis and/or intraplaque hemorrhage, followed by a healing
process which may include further smooth muscle cell proliferation and deposition
of extracellular matrix. Atheromas at risk for these events are called unstable athero-
mas and frequently exhibit inflammatory cells within the peripheral or “shoulder
regions” of the atheroma. These inflammatory cells express inflammation-associated
matrix metalloproteinases (MMPs) that can degrade the protein extracellular matrix
of the fibrous cap. Excessive MMP expression can lead to erosion and destabiliza-
tion or possible rupture of the fibrous cap thereby precipitating an atherosclerotic
event such as myocardial infarction or stroke [10]. Stenosis of the artery results in
symptoms such as chest pain (angina) or leg pain with exertion (claudication),
among others. If the lumen of the artery is decreased in size to a point where perfu-
sion of tissues distal to the atheroma becomes compromised, infarction (necrosis) of
tissues distal to the stenosis will occur. Other outcomes may include thrombus for-
mation (embolism) and possible distal vascular occlusion by the thrombus or arte-
rial wall weakening leading to arterial aneurysms and/or rupture [11].
Increased systemic inflammation has been correlated with an increased risk of
ASVD. Increase in the systemic inflammatory biomarker C-reactive protein (CRP)
in particular has been found to complement lipid profiles as a risk factor for athero-
sclerotic events, as it predicts risk even among individuals with low LDL-cholesterol
[12]. CRP is synthesized mainly in the liver under IL-1 regulation as part of the
acute phase response. The acute phase response is a primitive response to infection
or trauma that predates the innate and adaptive immune response. CRP can bind
with the cell membrane component lysophosphatidylcholine exposed on dead or
dying host cells and with phosphocholine present on bacterial cell membranes.
Once bound, CRP can initiate the complement cascade via the antibody-dependent
“classical arm” of complement activation and is therefore analogous to pentameric
IgM complement activation. In addition, both macrophages and neutrophils express
receptors for bound CRP to facilitate phagocytosis (opsonization). Both comple-
ment activation and opsonization serve to focus and amplify the ensuing inflamma-
tory response. Of interest, reduction in CRP levels below 2 mg/L with statin therapy
has been found to decrease both the incidence of cardiovascular events and mortal-
ity [5]. However, it is not clear whether increased CRP levels merely reflect increased
inflammation present in the shoulder regions of unstable atheromas or whether
increased systemic levels of CRP can amplify inflammation within the atheroma
and thus precipitate an ASVD event. Certainly other inflammatory biomarkers are
also associated with vascular risk. Examination of the effects of sources of systemic
inflammation on ASVD independent of the atheroma, such as periodontitis, may help
address this question.
4.3 What Is the Strength of the Association Between ASVD

and Periodontitis?
One of the earliest reports of an association between ASVD and periodontitis

came from Scandinavia in 1989. Mattila [13] reported that patients with a recent
myocardial infarction tended to have an increased incidence of oral disease such
as dental caries, periodontitis, periapical lesions, and pericoronitis. In the same
year, Syrajanen [14] reported poor oral health was more frequently found in
patients with recent strokes than in stroke-free individuals. Since 1989, an ever
increasing number of studies have been published on the relationship between
ASVD and periodontitis. However, as a group, the results of these studies have not
been consistent. This may be due in part, to differing criteria used to define peri-
odontal status and ASVD events, efforts to control for confounding variables com-
mon to both diseases, differing study designs, and the magnitude of the effect size
between periodontitis and ASVD.
The use of systematic reviews and meta-analyses attempts to account for these
variables by combining results across studies that are designed to answer a common
question. Perhaps one of the more insightful studies on the strength of the associa-
tion between ASVD and periodontitis was a meta-analysis that included five cohort
prospective studies, five cross-sectional studies, and five case–control studies. Over
86,000 subjects were included in the prospective cohort study meta-analysis.
Subjects with periodontitis had a 1.14 times greater adjusted risk (95 % CI 1.07–
1.21, P < .001) of a subsequent cardiovascular event than those without periodonti-
tis. Over 17,000 subjects were included in the cross-sectional study meta-analysis.
Those with chronic periodontitis had a 1.59 greater adjusted risk (95 % CI 1.14–
1.21, P < .001) of also having had a cardiovascular event than those without peri-
odontitis. Over 1400 subjects were included in the five case–control studies
meta-analysis. Those with periodontitis were at a greater adjusted risk (OR = 2.22,
95 % CI 1.59–3.11, P < .001) of having had a cardiovascular event than those with-
out periodontitis [15]. A follow-up analysis, sponsored by the American Heart
Association, reviewed the results of observational studies on the association between
ASVD and periodontitis. This study concluded that an association between the two
diseases existed independent of known confounders including smoking but that the
data to date do not support causality [16]. Another systematic review and meta-
analysis undertaken for the United States Preventive Services Task Force similarly
found that periodontal disease was associated with coronary heart disease, indepen-
dent of traditional risk factors. Risk estimates ranged from 1.24 to 1.34 depending
on the type of periodontal disease and were similar for both genders [17]. Taken
together, these studies suggest an association exists between ASVD and periodonti-
tis however the association appears relatively modest with an increased risk of
approximately 1.14–2.2 times to fold.
4.4 What Are the Biologic Mechanisms for the Association?
Several mechanisms have been forwarded to account for the association between
ASVD and periodontitis. The following briefly discusses three of the more popular
proposed mechanisms: infection, molecular mimicry, and systemic inflammation. It
should be noted that many of the proposed mechanisms may not be mutually exclu-
sive and it is entirely possible that several mechanisms may coexist to link these two
common diseases.
4.5 Infection
One of the earliest associations between oral diseases and heart diseases was the
observation that oral infection can cause infective bacterial endocarditis. Starting in
the early twentieth century, this observation was expanded into the focal infection
theory in which sepsis originating from oral sources including periodontitis, peri-
apical pathology, and defective dental restorations was thought to cause many medi-
cal conditions including bacterial endocarditis and ASVD. As a consequence, belief
in the focal infection theory led to massive numbers of dental extractions, many of
which may not have been necessary. The focal infection theory gradually fell out of
favor by the mid-twentieth century due to the lack of supporting scientific evidence.
However, the concept that oral bacteria and systemic disease were associated was
revived in 1989 by the aforementioned Scandinavian reports of the association
between periodontitis and ASVD.
The mouth is richly colonized with microorganisms and it should be noted that
within the gastrointestinal tract, teeth uniquely present a non-shedding structure for
biofilm development. The dental biofilm is estimated to contain up to 700 bacterial
species although only about half of the species have been fully characterized to date
[18]. As noted in chapter 2 of this volume, viable bacterial counts from subgingival
periodontal sites can range from 10 3 in periodontally healthy sites to >10 8 in sites
with periodontitis. In addition, it has been estimated that the total epithelial surface
area in contact with the bacterial biofilm in periodontal pockets can be as large as
8–20 cm [2] depending upon the number of teeth involved and the severity of peri-
odontitis present within an individual. Since the epithelial surface within a periodon-
tal pocket is frequently ulcerated, periodontitis places a large and diverse bacterial
biofilm in close approximation to the circulation. It has been well documented that
periodontal bacteria can enter the circulation after routine events such as chewing or
dental procedures. Such transient bacteremias are usually effectively cleared by the
individual’s innate immune system. But the possibility also exists that periodontal
pathogens or their products can infiltrate distant sites such as atheromas via the cir-
culation and thus promote atherosclerotic progression.
Many studies have reported that oral bacteria can gain access to the circulation
and colonize distant sites. P. gingivalis, a Gram-negative anaerobic bacterium
closely associated with periodontitis initiation and progression, has been reported to
adhere to and invade several cell types including endothelial cells. In addition,
P. gingivalis cell wall components such as endotoxins and intact, viable P. gingivalis
as well as other periodontitis associated bacteria such as T. forsythus and A. actino-
mycetemcomitans have also been isolated from atheromas [19]. However, the asso-
ciation between microorganisms and ASVD has not been limited to oral bacterial
species. Helicobacter pylori, Chlamydophila pneumoniae, and several viruses
including cytomegalovirus and hepatitis A virus among others have also been found
in atheromas and their presence has been proposed as a precipitating factor in ASVD
events. The observation of non-oral bacteria within arterial walls and atheromas
led to the AZACS, WIZARD, and ACADEMIC clinical trials in which long-term
antibiotic therapy was tested as a preventive intervention against subsequent coro-

nary vascular disease events. All three trials found no benefit at 6, 14, or 24
months of antibiotic therapy (reviewed in [20]). Finally a meta-analysis that included
11 trials enrolling >19,000 subjects with end points of all-cause mortality, myocar-
dial infarction, or unstable angina combined with myocardial infarction reported no
benefit of long-term antibiotic therapy [21]. It should be noted that since periodon-
topathic bacteria exist in a biofilm within the periodontal pocket and not within the
host tissues per se, systemic antibiotics may not be totally effective in decreasing
the oral load of these bacterial species within an individual.
4.6 Molecular Mimicry
Molecular mimicry is a second mechanism proposed for the association between

periodontitis and ASVD. Molecular mimicry or immune cross-reactivity occurs
when an immune response to antigenic structures (epitopes) present on a pathogenic
species cross-react with host cell epitopes. The immune response generated there-
fore targets both the pathogen and host cells that display the cross-reacting epitope.
Molecular mimicry occurs since the strategies to remove T- and B-cells that are
self-reactive during immune cell development are imprecise. For example, patients
suffering recent ASVD events have been reported to have a greater total burden of
P. gingivalis, A. actinomycetemcomitans, and T. forsythia [22]. These patients also
have an elevated serum antibody to human heat shock protein 60, one of several
proteins expressed by host cells when injured or under conditions of metabolic
stress. Of interest, under conditions of endothelial dysfunction, endothelial cells
express heat shock protein 60. Human heat shock protein 60 shares epitopes with
GroEL, a protein expressed by P. gingivalis and other periodontopathic bacteria.
Therefore an adaptive immune response generated to bacterial GroEL could also
cross-react with human heat shock protein 60. The cross-reactive immune response
could result in continued injury to the intima, facilitating endothelial dysfunction
and atherosclerotic progression [23].
4.7 Inflammation
Systemic inflammation from moderate to severe periodontitis has been forwarded

as a third biologic mechanism linking ASVD and periodontal disease. This mecha-
nism is particularly attractive since the pathogenesis of both atherosclerosis and
periodontitis have strong inflammatory components. The local periodontal genera-
tion of the pro-inflammatory cytokines TNF-α, Il-1, and Il-6 in moderate to severe
periodontitis has been shown to elevate systemic levels of these cytokines which in
turn induce an acute phase response. Elevated CRP, fibrinogen, blood glucose,
white blood cell counts, total cholesterol, triglycerides, and LDL and depressed
HDL are all components of the acute phase response, are recognized ASVD risk
factors, and all have been reported in patients with moderate to severe periodontitis,
albeit with considerable variability among reports. As discussed earlier, elevated

CRP in particular has been shown to be a risk factor for ASVD. However, since
many sources of systemic inflammation exist, and none of the inflammatory mark-
ers characterized to date are specific to periodontitis, attempts to link ASVD and
periodontitis through increased systemic inflammation have been complicated by
the need to control for an array of confounding variables. In addition, periodontal
intervention studies have also been complicated by the modest degree of association
between the two diseases. As a consequence, it has been difficult to definitively
demonstrate that increased systemic inflammation from moderate to severe peri-
odontitis directly contributes to ASVD or ASVD events.
4.8 Is Periodontitis a Risk Factor for ASVD?
The association between periodontitis and ASVD is clear. However, the strength of
the association is modest and it remains unknown whether the relationship is causal.
Certainly a causal relationship is plausible, because periodontal diseases can contrib-
ute to systemic inflammation, and systemic inflammation has been closely correlated
with increased ASVD risk. The role of periodontal disease could relate to progression
of atherosclerosis and/or triggering of events. In an effort to improve risk assessment
for ASVD, a systematic review was conducted that assessed most of the recognized
global ASVD risk factors and indicators with both hard and surrogate endpoints of
cardiovascular disease. This review found periodontitis to be an independent although
modest risk factor for cardiovascular disease outcomes [16]. Unfortunately, available
data are limited by confounding, since the two diseases share risk factors, and do not
presently support causality [20]. Therefore the available evidence suggests that peri-
odontitis is a risk factor for ASVD but no evidence exists that periodontitis directly
contributes to ASVD events. This leads to a question of perhaps greater clinical
importance; could periodontal therapy decrease the incidence of ASVD events?
4.9 Could Periodontal Therapy Decrease Risk of ASVD

Events?
Strategies that mitigate ASVD risk are intensively sought in view of the large impact
of ASVD mortality on the world population. The facts that periodontal diseases are
treatable and associated with ASVD suggest that periodontal diseases could be a
modifiable risk factor for ASVD. A relatively large number of periodontal interven-
tion studies have been conducted over the past decade. It is important to point out
that at present no reports have been published that periodontal therapy can decrease
the incidence of “hard” endpoints such as ASVD events or mortality. Rather peri-
odontal intervention trials to date have reported the effects of periodontal therapy on
secondary outcomes such as ASVD risk factors and surrogate endpoints. In addi-
tion, the assessment of periodontal intervention trials is complicated by the large
heterogeneity of reported results, study designs, subject populations, and duration
of follow-up (usually not greater than 6–12 months). An additional challenge is how
to ethically design a control (nontreatment) population for an interventional trial.
Given these challenges, three recent systematic reviews and meta-analyses have
attempted in detail to address whether periodontal therapy can improve ASVD risk
profiles and intermediate outcomes related to vascular health [24–26]. The follow-
ing briefly summarizes the findings.
Both measurements of carotid intima-media thickness (CIMT) and endothelial
dysfunction have been used as surrogate measures of atherosclerotic progression.
These measurements are each predictive of future ASVD events. Tonetti in 2007
published the results of a 121-subject randomized clinical trial of supragingival
scaling versus aggressive periodontal therapy consisting of extraction of hopeless
teeth, scaling and root planing, and the local application of antibiotics. After
6 months there was a 2.0 % difference in flow-mediated dilation, a clinical measure-
ment of endothelial function, between treatment and control groups (95 % CI
1.2–2.8, P < 0.001) [27]. Others have replicated this effect of periodontal therapy on
endothelial dysfunction in patients with moderate to severe periodontitis. A meta-
analysis of three studies that included 71 subjects reported a 6.64 % (95 % confi-
dence interval of 2.83–10.44, P =0.011) improvement in flow-mediated dilation
with periodontal therapy [26]. One trial has reported the effect of periodontal ther-
apy on CIMT. A reduction in CIMT was reported 6 and 12 months after the peri-
odontal intervention; however the reduction was modest, within the range of
measurement error, over the relatively short timeframe of 1 year and in a small
sample [28]. Nonetheless, these studies raise interesting questions about the poten-
tial for periodontal therapy to affect intermediate measures of vascular health in
patients with moderate to severe periodontitis.
Traditional, modifiable risk factors for ASVD include lipid profiles, hyperten-
sion, diabetes, systemic inflammation, obesity, and smoking. A systematic review
and meta-analysis by Teeuw [25] that included 25 trials with a total of 1748 subjects
found that periodontal therapy up to 12 months post therapy improved hsCRP,
hemoglobin A1C, IL-6, and TNF-α, fibrinogen with additional statistically signifi-
cant but small effects on total and HDL cholesterol. These effects were greater for
subjects with comorbidities such as preexisting coronary artery disease, abnormali-
ties of glucose metabolism such as diabetes or the metabolic syndrome, or both. The
presence of other risk factors including obesity or tobacco smoking tended to blunt
the effects of periodontal therapy. However, it should be stressed that the large het-
erogeneity in individual study results limits conclusions about the role of periodon-
tal therapy in ASVD risk factor reduction.
Conclusions
Based upon the current evidence, an association exists between ASVD and mod-
erate to severe periodontitis even after controlling for known confounders includ-
ing smoking, although the strength of the association is relatively modest. Several
biologic mechanisms have been proposed to account for this association with
increased systemic inflammation from moderate to severe periodontitis being
one of the more attractive and actively investigated mechanisms. Effective
periodontal therapy in patients with moderate to severe periodontitis has been

shown to decrease systemic inflammation as well as several other components of
the acute phase response, most notably hsCRP levels. But most importantly, to
date, no periodontal intervention trial has been sufficiently powered to detect an
effect of periodontal therapy on hard end points such as ASVD events or
mortality.
Aside from the considerable challenges faced in designing periodontal inter-
vention trials, both atherosclerosis and periodontitis are inflammatory diseases
that require years to develop clinically significant lesions. It is not clear that
providing periodontal therapy would alter the time course of atherosclerosis
development because by the time periodontal disease is manifest, atherosclerosis
is likely already present. For this reason, it is important to make patients aware
of increased cardiovascular risk among individuals with periodontal disease and
to encourage ASVD screening. It is hoped that periodontal therapy might prevent
rupture of atherosclerotic plaques resulting in events, but this remains to be
definitively tested. It may be hypothesized that periodontal intervention may
need to be applied early in life to have the greatest potential effect. In addition,
several other sources of systemic inflammation are associated with ASVD risk
including obesity, diabetes mellitus, and smoking. Their presence during inter-
vention trials have frequently swamped the reduction in systemic inflammation
achieved from providing effective periodontal therapy. Therefore, it is entirely
possible that effective periodontal therapy may never be definitively shown to
decrease ASVD events in patients with moderate to severe periodontitis. But
since periodontitis is readily treatable, has benefits of its own regarding quality
of life, and is a reversible source of systemic inflammation, consideration of the
contribution of periodontitis to overall ASVD risk appears clinically warranted
in the management of the ASVD patient.
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13. Mattila KJ, Nieminen MS. Association between dental health acute myocardial infarction.
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14. Syrjanen J, Peltola J. Dental infections in association with cerebral infarction in young and
middle-aged me. J Intern Med. 1989;225:179–84.
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Interactions Between Periodontal
Disease and Chronic Kidney Diseases 5
Ronald G. Craig and Peter Kotanko
5.1 Introduction
An increasing number of patients with chronic kidney disease (CKD) including

those with end-stage renal disease (ESRD) on renal replacement therapy present
each year for dental care. This increase is due, in part, to the rising prevalence of
type 2 diabetes and the aging population demographics of industrialized nations.
However, advances in renal replacement technologies have also greatly increased
the life expectancies for ESRD patients thereby increasing the size of this patient
population. In addition, not only will the dental profession be asked to care for an
increasing number of CKD patients, but recent studies suggest that periodontitis
may affect the medical management of the CKD patient. Adverse outcomes includ-
ing mortality have been associated with increased systemic inflammation in both the
CKD and the general population making means to decease systemic inflammation
an emerging medical concern [1, 2]. For patients receiving hemodialysis mainte-
nance therapy, for example, increased systemic inflammation has been closely asso-
ciated with atherosclerotic complications including myocardial infarction and
R.G. Craig, DMD, PhD (*)

Department of Basic Sciences and Craniofacial Biology,
Department of Periodontology and Implant Dentistry,
P. Kotanko, MD
Private Corporation, Renal Research Institute, New York, NY, USA
e-mail: Peter.Kotanko@RRINY.COM

54 R.G. Craig and P. Kotanko
stroke, which are among the most frequent causes of mortality in this patient popu-
lation [3].
In the general population, a growing number of studies have reported that moder-
ate to severe periodontitis can contribute to systemic inflammation and that peri-
odontitis is associated with atherosclerotic complications including myocardial
infarction and stroke [4, 5] (see Chap. 4 in this volume). This is especially relevant
since several studies suggest that periodontitis is more prevalent and severe in the
renal hemodialysis than in the general population [6]. In addition, recent interven-
tion studies suggest that aggressive periodontal therapy may decrease systemic
inflammation as well as endothelial dysfunction, an early vascular event common to
several chronic diseases, including atherosclerosis, diabetes, and possibly some
forms of chronic renal disease [1, 2]. At the present time, a periodontal examination
is usually not performed as part of the medical assessment of the CKD patient.
Since periodontitis is readily amendable to treatment, it may be possible that for
some CKD patients periodontitis may be a covert but reversible source of systemic
inflammation [7]. This possibility implies that a periodontal examination and appro-
priate periodontal therapy may become a medical management concern for this
population in the future.
In view of the medical complexity of CKD management, especially for those
patients receiving renal replacement therapy, and in anticipation of the increased role
that dentistry may play in their health-care management in the future, the intent of
this chapter is to present an overview of CKD and renal replacement therapies, sum-
marize the research linking increased systemic inflammation, chronic kidney dis-
ease, and periodontitis, and provide suggested guidelines for the dental management
of the CKD patient.
5.2 CKD Progression and Renal Replacement Therapies
The kidneys perform several diverse but essential functions including:
• The metabolism and excretion of the end products of metabolism such as urea
• Regulation of blood fluid volume and electrolyte concentration
• Secretion of erythropoietin to help regulate erythrocyte production in the bone
marrow
• The maintenance of calcium homeostasis through the hydroxylation of vitamin
D3 into active or inactive metabolites [8]
Therefore, the loss of kidney function for ESRD patients presents an array of medi-
cal management challenges.
Renal function is assessed, in part, by measurement of the glomerular filtration
rate (GFR). Normal adult GFR varies between 100 and 200 mL min−1/1.73 m2 body
surface area. As kidney function decreases with the progression of glomerular or
interstitial renal disease, a large number of toxic compounds that are normally
cleared by the kidneys are retained producing a condition termed the uremic
5 Interactions Between Periodontal Disease and Chronic Kidney Diseases 55
syndrome [9]. In addition, disturbances in blood electrolyte concentration such as

hyperphosphatemia, acid/base balance (metabolic acidosis), sodium retention (hyper-
kalemia), increased blood volume (hypertension), anemia, and renal osteodystrophy
may also develop. During the early stages of CKD, the remaining functional kidney
glomeruli are able to compensate through hypertrophy and increased filtration rates.
Also if CKD is detected early, additional interventions can be prescribed including
diet modifications, the use of phosphorus binding compounds, the administration of
1,25 dihydroxy vitamin D3, human recombinant erythropoietin, and antihypertensive
medications. However, once the GFR falls below 10–20 mL min−1/1.73 m2 body sur-
face area and blood urea nitrogen levels rise above 100–150 mg/dL, renal compensa-
tory mechanisms fail marking the beginning of ESRD and making the initiation of
renal replacement therapy necessary to maintain life [8].
The most common cause of ESRD is diabetes mellitus with hypertension, glo-
merulonephritis, and cystic kidney disease also major contributors. Of note, approx-
imately 44 % of patients receiving renal dialysis replacement therapy also have type
2 diabetes mellitus. In 2012, 114,813 new cases of ESRD were reported in the
United States and on December 31, 2012 636,905 patients were actively receiving
treatment for ESRD [10]. Since the 1980s until 2010, the incidence of ESRD has
been steadily increasing and is mostly attributed to the rising prevalence of type
2 diabetes (see Fig. 5.1). The incident rate of ESRD for both 2011 and 2012 were
less than 2012 hopefully signaling a decrease in incident rates for ESRD in the
United States [10].
ESRD is fatal without renal replacement therapy, which can be provided by renal
dialysis, peritoneal dialysis, or kidney transplantation [8]. Renal hemodialysis is by
far the most common form of renal replacement therapy (see Fig. 5.2). As depicted
in Fig. 5.3, access to the patient’s circulatory system is typically achieved via a sur-
gically created arteriovenous fistulae typically sited in the forearm. The patient’s
blood is then circulated from the fistulae to the hemodialysis machine. Within the
dialysis machine, a membrane dialyzes low molecular weight substances from the
blood via a diffusion process against a large volume of a pH and electrolyte-balanced
dialysis solution. Typically 120–150 L of dialysis solution are required per dialysis
session. Heparin is administered during the dialysis session to inhibit blood clotting.
The dialyzed blood is then returned to the patient, completing the dialysis circuit.
(See Fig. 5.1.) Renal hemodialysis sessions typically last for 3–5 h and are con-
ducted three times per week at specialized hemodialysis units.
In contrast to hemodialysis, peritoneal dialysis uses the patient’s peritoneal cav-
ity to dialyze urea and other small molecular weight compounds from the blood.
Access to the peritoneal cavity is provided by a surgically implanted catheter
through which a sterile dialysis fluid is intermittently infused and removed.
Peritoneal dialysis can be performed throughout the day (continuous ambulatory
dialysis) or overnight using an automated machine (automated continuous cyclic
peritoneal dialysis). A major advantage of peritoneal dialysis for the patient is peri-
toneal dialysis can be performed in the home and removes the need to travel to a
specialized regional dialysis facility. However, peritoneal dialysis presents the addi-
tional risk of peritoneal infections which can be difficult to manage. It should be
Counts
50
Number of patients (in thousands)

Diabetes
Hypertension
40
Glomerulonephritis
30 Cystic kidney
20
10
0
Rates
160
Rate per million population
120
80
40
0
82 86 90 94 98 02 06 10
Fig. 5.1 Annual incident counts and adjusted rates of ESRD by primary diagnosis (US Renal
Data System)
Incident Prevalent
200 400
Hemodialysis (2010: 105,923)
Number of patients (in thousands)
Hemodialysis (2010: 383,992)

Peritoneal dialysis (7,703) Peritoneal dialysis (29,733)
150 300
Total dialysis (114,083) Transplant (179,361)
Transplant (2,863) OPTN transplant
wait list (87,932)
100 200
50 100
0 0
78 82 86 90 94 98 02 06 10 78 82 86 90 94 98 02 06 10
Fig. 5.2 Hemodialysis is the most common form of renal replacement therapy. Incident and prev-
alent patient counts on December 31, 2010 by renal replacement therapy (US Renal Data System)
Blood Arterial
Anticoagulant
pump pressure
From the patient

Dialysis
fluid pump Dialyzer
Outlet
Vencus
Water pressure
Balancing
chamber
Ultrasonic
air detector
Heater
Concentrate
pump
Blood lines
To the patient
Concentrate
Fig. 5.3 The hemodialysis circuit and a typical clinical hemodialysis session
kept in mind that at best, both renal hemodialysis and peritoneal dialysis are only
able to provide approximately 10 % of the clearance of metabolic end products of a
healthy kidney. As a consequence, dialysis patients remain in a continuous state of
chronic renal failure and accompanying uremic syndrome.
Far greater kidney function is provided by renal transplantation. Successful renal
transplantation is dependent upon closely matching the patient and donor ABO blood
type and major human histocompatibility leukocyte antigen (HLA) complexes.
Achieving an identical match of HLA complexes is nearly impossible without a
kidney donor who is also an identical twin. Therefore immune suppression is required
to prevent graft rejection [8]. Immune suppression is usually provided by the combi-
nation of corticosteroids, calcineurin inhibitors, such as cyclosporine A or tacroli-
mus, to suppress interleukin two production, and lymphocyte proliferation inhibitors,
such as azathioprine or mycophenolate mofetil (CellCept®, Hoffmann-La Roche
Inc., Nutley, NJ). Transplant survival rates of 83 % for 1 year and 65 % for 5 years
have been reported for cadaver donor kidneys. For live donor kidneys, transplant
survival rates increase by about 10–15 % for each time period [11]. The disadvan-
tages of renal transplantation include the need for constant immune suppression that
may result in increased susceptibility to opportunistic infections, decreased kidney
function with increasing transplant age, and the development of hypertension [8].
5.3 Systemic Inflammation Is Associated with Adverse

Outcomes in CKD Patients
ESRD patients on renal hemodialysis maintenance therapy face a greatly increased

mortality rate when compared to the general population, especially among the
younger age groups. In 2012 the United States Renal Data System reported a 22.3 %
annual mortality rate; a rate that was 6.1–7.8 times greater than that of the age-
matched Medicare population (see Fig. 5.4). Cardiovascular disease was the most
common cause of mortality followed by infection and stroke [10]. Mortality is
highly associated with increased systemic inflammation because C-reactive protein
(CRP), an acute phase protein and systemic marker of inflammation, is a major risk
factor for both cardiac and all-cause mortality in renal hemodialysis patients [12–
14]. In the general population, CRP has been identified along with other acute phase
proteins as a major risk factor for atherosclerotic complications [15] and supple-
ments more traditional atherosclerotic risk factors, such as serum lipoprotein pro-
files, as predictors of cardiac events [16]. As discussed in Chaps. 2 and 4 of this
Deaths per 1,000 patient years at risk
300
ESRD
Dialysis
200 Transplant
General medicare
100
0
<20 20–44 45–64 65+
Fig. 5.4 Hemodialysis populations face a disproportionate rate of mortality. Adjusted all-cause
and mortality in the ESRD and general populations by age in the United States (US Renal Data
System)
volume, moderate to severe periodontitis has been shown to contribute to systemic

inflammation and effective periodontal therapy has been shown to decrease serum
markers of inflammation including CRP and early events associated with athero-
sclerosis including endothelial dysfunction and carotid media intima thickness.
5.4 Periodontitis Is More Prevalent and Severe in CKD

Populations
Not only is periodontitis a potential source of systemic inflammation but an

increased prevalence and severity of periodontitis has been globally reported for
CKD patients, most notably for renal dialysis patients. A Taiwanese study of 128
adult hemodialysis patients reported an increased incidence of periodontitis and
periodontal treatment needs [17]. A second study from Taiwan of 253 hemodialysis
patients reported increased prevalence and severity of periodontitis when compared
to national data on periodontal disease. After controlling for confounding variables
by multivariate analysis, the best predictors of periodontitis in this population were
increased age, presence of diabetes mellitus, smoking, and dialysis duration.
Decreased serum albumin was also found associated with periodontitis implying
that periodontitis is also associated with malnutrition and protein energy wasting, a
major predictor of adverse outcome in this population [18]. A cross-sectional study
from Poland found a successive increase in the incidence and severity of periodon-
titis across the four groups of health, early CKD, CKD-receiving peritoneal dialysis,
and CKD-receiving hemodialysis, suggesting that chronic uremia may facilitate
periodontitis initiation and progression [19]. A Brazilian study divided patients into
healthy, pre-dialysis and dialysis groups and reported an increased incidence and
severity of periodontitis in the dialysis group [20]. A Swedish cross-sectional study
examined 68 pre-dialysis, 19 peritoneal dialysis, and 15 hemodialysis subjects, all
matched with age and gender controls, and reported that uremic subjects had signifi-
cantly more dental disease including decayed, missing, or filled teeth and periodon-
tal and periapical disease than controls. These results imply that dental pathology
may begin to develop before CKD patients have progressed to hemodialysis [21].
Finally, radiographic alveolar bone loss, used as a cumulative measure of past peri-
odontitis activity, was reported to be greater in hemodialysis patients than in pre-
dialysis CKD patients or in healthy controls in retrospective studies from the United
States [22] and from China [23].
If periodontitis is indeed more prevalent and severe in hemodialysis than in the
general population as the above studies suggest, what mechanism (s) may account
for this finding? Almost all studies have reported increased levels of factors associ-
ated with periodontitis initiation and progression including plaque [18, 24–28],
calculus [18, 24, 26, 28], and gingival inflammation [24, 26, 28, 29], in hemodialy-
sis populations. It is probable that the 3–5 h, thrice-weekly dialysis sessions and
psychological stress that the hemodialysis procedure places on patients may decrease
the priority of seeking oral health care and maintaining oral health. In support,
several studies have reported decreased use of dental care services in hemodialysis
populations [24, 26, 27, 29]. The use of anti-coagulants during the hemodialysis
session, such as heparin, has been suggested to promote gingival bleeding and
thereby facilitate subgingival colonization with Gram-negative periodontal patho-
gens leading to increased gingival inflammation [19]. The high incidence of diabe-
tes mellitus in hemodialysis populations and the strong association between diabetes
mellitus and periodontitis in the general population has also been proposed [30]. In
addition, hemodialysis patients also suffer several nutritional deficiencies arising
from the dialysis procedure including severe vitamin C deficiency and deficiencies
of several essential amino acids [31].
However, since gingival inflammation and periodontitis have been reported to
increase with hemodialysis duration [17] and in hemodialysis compared to pre-
dialysis CKD populations and non-CKD populations [19–21], it is also possible that
immune dysfunction secondary to chronic uremia may also contribute to the increased
prevalence and severity of periodontitis observed in hemodialysis populations [32].
Defects in both innate and adaptive immunity have been reported in hemodialysis
populations [33–36] and suggest an impaired patient response to Gram-negative bac-
teria associated with periodontitis occurs in the uremic state that may result in the
increased prevalence and severity of periodontitis observed in this population.
5.5 Periodontitis as a CKD Risk Factor and Its Association

with Adverse ESRD Outcomes
Not only is periodontitis more prevalent and severe in CKD patients but several
studies suggest that periodontitis is a risk factor for chronic kidney disease. A
22-year study of Pima Native Americans reported that subjects at study entry with
moderate, or severe periodontitis, or who were edentulous, presumably due to peri-
odontitis, were 2.3, 3.5, and 4.9 times more likely, respectively, to develop end-
stage renal disease than subjects that were periodontally healthy or who had mild
periodontitis [37]. A series of retrospective analyses of the third National Health
and Nutrition Survey have reported periodontitis to proceed and be a risk factor for
CKD [38–40]. A cross-sectional study of 5537 patients in the Atherosclerosis Risk
in Communities study reported patients with severe periodontitis were twofold
more likely to present with renal insufficiency than periodontally healthy patients
[41]. However, both periodontitis and CKD and ESRD share several risk factors
including increasing age, smoking, and obesity which raises the question of whether
inflammation from periodontitis actually contributes to CKD or are the two diseases
merely linked by confounding factors? A cohort study from Taiwan attempted to
address this question. Using the Taiwan National Health Insurance Database, 35,496
patients who underwent surgical periodontal therapy were compared to 141,824
patients who did not. Both groups were free of any claims data for ESRD at study
entry. From the period of 1997–2009, patients in the periodontal therapy group were
found to be 37 % less likely to report codes for ESRD compared to the nontreatment
group. These results suggest that periodontal therapy may be able to decrease risk
for ESRD [42].
Several studies report that periodontitis is associated with adverse outcomes

including mortality in ESRD populations. In addition, additional studies suggest
that effective periodontal therapy can reduce the risk of adverse outcomes. A 6-year
longitudinal study of 253 Taiwanese hemodialysis patients who received a peri-
odontal examination at study entry reported frequencies of all-cause mortality in
24 % of patients who were periodontally healthy or with mild periodontitis, 41.8 %
in those with moderate periodontitis and 70.6 % with severe periodontitis [43].
A prospective study from 2 sites in the United States reported a fivefold increase in
cardiac mortality 18 months after study entry for hemodialysis patients that had
moderate to severe periodontitis compared to those who had mild periodontitis or
were periodontally healthy [44]. A periodontal intervention study of 30 hemodialy-
sis subjects from Thailand reported a decrease in CRP and erythropoietin dosage
and an increase in serum albumin and hemoglobin after periodontal therapy that
included both nonsurgical and surgical periodontal therapy [45]. A prospective
study from Brazil of 122 patients on hemodialysis therapy were given periodontal
examinations and divided into patients who were periodontally healthy (N = 49),
had chronic periodontitis without periodontal care (N = 30) and had periodontitis
and received nonsurgical periodontal care (N = 43). The primary outcome variable
was mortality. Periodontitis was defined as clinical attachment loss of ≥5 mm in at
least 3 teeth in at least 2 quadrants. Patients were then followed for up to 60 months.
The prevalence of periodontitis using this study’s disease criteria was 59 %.
A Kaplan-Meier survival analysis found patients with periodontitis to be at a higher
risk of mortality than those without periodontitis (OR 2.65 95 % CI 1.06–5.59,
P = 0.036) and periodontal therapy partially decreased this risk (OR 2.36.CI 1.01–
5.59, P = 0.0470). However, significant differences between groups were not main-
tained after multivariate analysis [46]. A multinational study of oral health practices
and mortality in 4205 ESRD patients on hemodialysis maintenance therapy reported
that poorer oral health was associated with earlier death while preventative oral
health practices were associated with longer survival [47]. Taken together, the above
studies highlight the importance of periodontal health in the management of the
ESRD patient and the need for periodontal intervention trials in CKD/ESRD patient
populations to determine whether periodontal therapy can decrease systemic inflam-
mation and mortality in CKD populations.
5.6 Periodontal Management of the CKD Patient
Patients receiving renal hemodialysis maintenance therapy are medically complex

and present the dental practitioner with several challenges in the management of
their periodontal condition. Infection and medical complications requiring hospital-
ization frequently occur. Accordingly, close communication between the dentist and
nephrologist is essential to safely treat the patient being given renal hemodialysis
and to optimize management of the periodontal condition.
Due to the increased prevalence of plaque, calculus, and gingival inflammation
in CKD populations, the patient should be carefully instructed in the importance
of effective oral hygiene procedures and examined at regular maintenance inter-

vals to ensure optimal compliance. The effectiveness of regular recall and mainte-
nance visits for periodontal patients in the general population has been well
documented and may be of even more importance in the renal hemodialysis popu-
lation. A primary objective of periodontal therapy is the local elimination of
Gram-negative bacteria and their products. In patients with moderate to severe
periodontitis, decreased Gram-negative bacterial load through periodontal ther-
apy will also decrease systemic inflammation in patients with moderate to severe
periodontitis. Because invasive dental procedures such as root planning and
extractions can result in transient bacteremia, antibiotic prophylaxis before the
dental appointment may be considered during consultation with the patient’s
nephrologist to protect vascular access sites. Anemia and possible clotting defi-
ciencies should be evaluated in consultation with the patient’s physician, and den-
tal appointments should be scheduled the day after hemodialysis sessions in view
of the heparin used during hemodialysis. Because fluid retention and resulting
hypertension increases during intervals between hemodialysis sessions, dental
appointments should be avoided on the day of dialysis prior to the hemodialysis
session. Also, because of the high prevalence of hypertension in the ESRD popu-
lation, care should be used with local anesthetics containing vasoconstrictors. The
patient’s current vascular access site should be determined and avoided during
dental treatment. For example, care should be exercised not to physically impinge
on the site when monitoring blood pressure. The dosage and administration of
drugs cleared by the kidneys may need to be altered with respect to decreased or
absent kidney function. For example, care should be used in the administration of
local anesthetics to minimize the total dosage because serum albumin contains a
low-affinity but high-capacity binding site [48] and serum albumin may be
reduced in some patients using renal hemodialysis. Among analgesics, postopera-
tive use of acetaminophen is considered safe but nonsteroidal anti-inflammatory
drugs should be avoided [48]. The half-life of oxycodone is prolonged in renal
failure so the dose should be reduced and the dosage interval prolonged.
Meperidine HCl (Demerol®, Sanofi Aventis, Bridgewater, NJ), which is metabo-
lized to normeperidine, is dependent on kidney function for elimination and
should be avoided. Lastly, codeine and dihydrocodeine half-lives are significantly
prolonged; therefore, dosages and dosage intervals should be adjusted accord-
ingly [48].
Conclusions
Moderate-to-severe periodontitis and atherosclerotic complications are prevalent
in the renal hemodialysis population. Periodontitis has been associated with
increased markers of systemic inflammation, including elevated CRP levels, and
endothelial dysfunction, an early predictor of atherosclerotic complications, in
the general population. Some recent studies suggest effective periodontal ther-
apy may decrease systemic inflammation and endothelial dysfunction and may
even decrease the incidence of CKD/ESRD. Therefore, periodontitis in renal
hemodialysis populations may be a reversible source of systemic inflammation
that can be managed through effective periodontal therapy.
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The Association Between Periodontitis
and Preterm Labor (PTL) 6
Ananda P. Dasanayake and Frederick Naftolin
6.1 Overview
Pregnancy is a time when periodontitis is commonly diagnosed and treated.

Periodontal disease has been raised as a possible cause of preterm labor (PTL).
There have been many studies testing for this association directly or by assessing
the effects of periodontal treatment on PTL. In this chapter we review the literature
with special attention to studies on the effects of periodontal treatment on rates of
PTL. We point out a number of design problems regarding single-use scaling and
root planning of teeth as a method of testing the hypothesized relationship that
could explain why these treatments did not forestall PTL. We also describe positive
studies that tested mechanical cleaning and/or antibacterial treatment and showed
promising results against PTL. Finally, we describe a recent finding of genetic
abnormality that appears to link PTL and periodontitis.
We conclude that the hypothesized relationship between poor oral health/peri-
odontitis and PTL has not been ruled out and that further studies are in order, includ-
ing gestational antibacterial prophylaxis and evaluation of the link between
abnormality of the prostaglandin E3 receptor gene and inflammatory conditions
such as periodontitis and PTL.
A.P. Dasanayake, BDS, MPH, PhD, FACE (*)

Department of Epidemiology and Health Promotion, New York University College of
e-mail: anandanyu@gmail.com
F. Naftolin, MD, PhD, FACOG, FRCOG
Division of Reproductive Biology Research, New York University School of Medicine,
New York, NY, USA
e-mail: naftof01@nyu.edu

68 A.P. Dasanayake and F. Naftolin
6.2 Introduction
Although there have been many advances, pregnancy outcomes continue to

account for significant morbidity and mortality. This is especially true for preterm
labor (PTL), which continues to be the leading cause of prematurity, and its atten-
dant ills. Globally, PTL accounts for the greatest number of perinatal deaths, enor-
mous cost, and untold morbidity. In most cases the cause of PTL remains unknown
and despite progress with both hormonal prophylaxis and medical and surgical
treatment, PTL remains among the highest priorities for research, prevention, and
treatment [1].
6.3 Evidence for the Association Between Periodontitis

and Pregnancy Outcomes
Inflammation, either infectious or noninfectious, has been accepted as a primary

element in PTL. Many attempts at documentation of the infectious origins have
been reported, but actual microbial infections have only been documented in the
minority of cases. Rather, inflammatory markers of unknown origin are commonly
present in sterile amniotic fluid and maternal blood of women undergoing PTL [1].
While they are indicative, the timing and sources of the appearance of these markers
remain unresolved [2].
Results from observational studies [3, 4], clinical explorations [5], and animal
studies [6] suggest a role of periodontal disease in adverse pregnancy outcomes.
However, studies on humans have only revealed “an association” rather than a
causal relationship [7]. With few exceptions, randomized controlled trials utilizing
periodontal treatment during pregnancy have failed to definitively reduce PTL or
low birth weight [8, 9]. However, these investigations have major limitations in their
design, which we discuss later. In any case, since the failure to show an effect (nega-
tive findings) does not rule out such an effect, before proceeding to discuss the
results of various studies, it is important to reconsider the biological plausibility of
the periodontitis hypothesis of PTL.
Inflammatory gum disease is common during pregnancy. Generally, this is a
bland form of inflammation and not accompanied by frank pus or massive cellular
infiltrates in the gingiva or periodontium. The inflammatory reaction is marked by
the presence of inflammatory cytokines, growth factors, and prostaglandins in the
fluid at the juncture of the gingiva and tooth and in the blood. The same or similar
inflammatory markers are found in tissues and amniotic sac of the uterus during
PTL and are associated with the cascade that results in uterine contractions.
Interestingly, these inflammatory markers may be found regardless of the presence
of infection. Despite a lack of knowledge of the time they appear, before or during
PTL, the presence of these inflammatory markers has led to the hypothesis of a
relationship of oral inflammation and PTL.
6 The Association Between Periodontitis and Preterm Labor (PTL) 69
6.4 Testing the Hypothesis of a Link Between Periodontitis

and Preterm Labor
Ideally, the way to establish an association between two conditions is to follow their
presence during the evolution of both conditions and show a parallelism in the
changes. If this is the case, one can attempt to disrupt the evolution of the markers
of disease and prepare prospective interventions. But, in the case of diseases of
pregnancy the presence of the embryo-fetus might be affected so it is often not fea-
sible to practice interventions, especially during human pregnancy. As well, human
pregnancies last about ten lunar months and the offspring goes through several pro-
grammatic periods during gestation, further complicating the experimentalists’ task
by adding issues of timing and possible need for repeated interventions/testing.
Finally, since the actual moment at which PTL begins is not known, the problems of
using a prospective approach have been insurmountable.
Therefore, in the case of human pregnancy, the usual path is to begin with
observational studies testing clinical, bacteriological, immunological, and inflam-
matory mediator parameters, relating them to documented periodontal disease
and evaluating their independent effects on poor pregnancy outcomes. Prospective,
case–control, or cross-sectional designs using adequate numbers of subjects and
taking into account the potential confounding factors are the usual ways that this
is done [7]. These studies employ the measurement of periodontal disease, relat-
ing it to local, systemic, utero placental, and fetal measurements related to preg-
nancy outcomes. Since this is very difficult to determine in the case of PTL, which
begins without symptoms and is almost always diagnosed after its effects have
become clinically evident, completely interpretable observational studies do not
exist in the literature. Further, preconception evaluation of risk for PTL and pro-
phylactic treatment with systemic or intravaginal progesterone has become stan-
dard of practice. This adds another major variable to observational studies since
the start of treatment is usually remote to the occurrence of clinical PTL and there
is only a ~60 % success rate, that is, 60/100 women so diagnosed and treated will
deliver at 37 or more weeks. Since it is not yet known which of the treated women
will be protected, the number of subgroups for study and analysis dramatically
rises [10].
An alternative to striving for developing the perfect study is to pool the results
from available observational studies. This requires a sorting out of studies to be sure
that the comparison and grouping of relevant and comparable data can be per-
formed. When the subject studies are performed to the standards required to ensure
homogeneity and quality, the comparison is known as meta-analysis. However, it is
difficult to eliminate confounding factors. For example, based on 17 observational
studies, Vergnes et al. [11], concluded that the overall association between peri-
odontal disease and preterm low birth weight was statistically significant (overall
Odds Ratio = 2.83; 95 % Confidence Interval = 1.95–4.10). A summary of results of
meta-analyses of observational studies are found in Table 6.1.
Table 6.1 Meta-analysis results from observational studies

Author Year Outcomes Number of studies (N) Pooled estimate I2
Khader 2005 Preterm birth Case–control studies [2]; OR = 4.28a (95 % –
et al. [34] regardless of birth Prospective cohort CI = 2.62–6.99)
weight studies [2]
Preterm birth Case- control studies [1]; OR = 4.32a (95 % –
regardless Prospective cohort CI = 2.50–7.44)
of birth weight studies [2]
excluding
the study with the
lowest
quality score
Preterm birth Prospective cohort OR = 3.87a (95 % –
studies [2] CI = 2.14–7.02)
Preterm birth and Case–control studies [2] OR = 5.28a (95 % –
low birth weight CI = 2.21–12.62)
Preterm birth or Prospective cohort OR = 2.30a (95 % –
low birth weight studies [2] CI = 1.21–4.38)
Vergnes 2007 Preterm birth and/ Case–control studies [9]; OR = 2.83a (95 % –
et al. or low birth Cross-sectional studies CI = 1.95–4.10)
[11] weight [2]; Prospective cohort
studies [4]; Unknown [2]
Corbella 2012 Preterm low birth Case–control studies [17] OR = 3.00a (95 % 89 %
et al. weight CI = 1.93–4.68)
[35] Preterm birth Case–control studies [17] OR = 1.78a (95 % 82 %
CI = 1.58–2.01)
Low birth weight Case–control studies [17] OR = 1.82a (95 % 66 %
CI = 1.51–2.20)
a
Significant at p < 0.05
Unfortunately, meta-analysis could not exclude potential confounding due to

inadequately controlled factors, such as smoking. One way to remove this “threat to
validity” is to conduct a study within a population where pregnant women do not
engage in behaviors such as smoking, alcohol consumption, and drug use. Since
these behaviors are causally related to poor pregnancy outcomes and are also related
to periodontal disease, by removing the effect of such factors within the study
design, one can enhance the credibility of the findings. Therefore, we studied Sri
Lankan women who did not engage in these behaviors due to economic and cultural
barriers. The cohorts were relatively small and even though the odds ratios for PTL
and lower birth weight favored an effect of periodontal disease on PTL, the differ-
ence was short of statistical significance [12]. Before it can be interpreted, this study
should be repeated with a larger sample size.
An alternative means of testing for a causal association between periodontal dis-
ease and poor pregnancy outcomes is to conduct clinical trials that test the appropri-
ate treatment regimens in relevant populations. For maximal value, these trials
should randomize subjects and have appropriate control groups. Unfortunately, in
addition to the variables mentioned above, most of the presently available studies
approached the prevention/treatment of periodontal disease along differing lines,
which has obscured the conclusions that can be drawn. For example, while inflam-
mation and gum swelling may be associated with the presence of dental plaque,
periodontitis is a chronic inflammatory condition that can exist without plaque [13].
This could explain why simple plaque removal, as was used in many clinical studies
on the effect of periodontitis, might not have shown the full impact of periodontal
inflammation on the presence of inflammatory markers or on prematurity during
affected pregnancies. Moreover, these studies performed the plaque removal only
once, usually leaving the gums available for new colonies to form plaque and
inflammation. There is little information on the effect of plaque removal on the
inflammatory markers during the above trials.
All in all, the results from randomized trials to-date are equivocal. Some studies
conducted in Chile [5, 14, 15] suggest that periodontal treatment (root planning and
scraping of teeth) applied as clinically indicated to pregnant women with gingivitis
or periodontitis results in a reduction of preterm low birth weight. A US study
showed that pregnant women who were refractory to periodontal treatment given
during pregnancy were significantly more likely to deliver preterm infants [16].
Larger randomized trials conducted in the United States [8, 9] and other countries
[17–20] also have failed to observe similar results. It is unlikely that these contrast-
ing findings are due only to population differences. While the Chilean studies pro-
vided mechanical periodontal treatment as needed during pregnancy, the US studies
were restricted to a limited number of scaling and root planning sessions during the
second trimester of pregnancy. One of the US studies suggests that other pregnancy
outcomes such as spontaneous abortion and stillbirth were significantly reduced in
the treatment group [9].
Among the potential explanations for these discrepancies are inadequate sample
sizes, inappropriate timing of treatment, inadequacy of treatment, and limitations in
the selected outcomes. Despite these concerns, when data from seven of these ran-
domized trials were pooled using meta-analysis, Polyzos et al. [21], showed that peri-
odontal treatment during pregnancy significantly reduced preterm birth (OR = 0.55;
95 % CI = 0.35–0.86) but not low birth weight (OR = 0.48, 95 % CI = 0.23–1.0).
In a more robust meta-analysis using 12 randomized controlled trails, Polyzos
et al. [22], further observed a statistically significant reduction in preterm birth as a
result of scaling and root planning, but only among high-risk women for poor preg-
nancy outcomes (pooled risk ratio [RR] = 0.66; 95 % confidence interval [CI] = 0.54–
0.80). Studies conducted among high-risk women also showed a statistically
significant reduction in low birth weight incidence (RR = 0.48; 95 % CI = 0.30–0.78).
High risk was defined as having a higher incidence of preterm birth (>22 %) based
on the combined preterm birth incidence in treatment and control groups within
each study. Only four studies were included in this analysis, with 88/280 events in
the treatment group and 130/275 events in the control group. When both high- and
low-risk studies were combined, reduction in preterm birth missed statistical sig-
nificance (RR = 0.81; 95 % CI = 0.64–1.02). Results were similar for deliveries
occurred before 35 weeks, low birth weight incidence, and mean low birth weight.
They concluded that for the general population, there is insufficient evidence to sup-
port the need for periodontal disease treatment to reduce preterm birth but
periodontal treatment may be beneficial for populations in which the incidence of

preterm birth is high.
George et al. in their meta-analysis of randomized trials have also shown signifi-
cant reductions in preterm birth and low birth weight among women who were
given periodontal treatment during pregnancy [23] while Kim et al. [24], in their
meta-analysis found a significant reduction in preterm birth only among groups who
were at high risk for preterm birth. However, the meta-analysis done by Uppal et al.,
using ten randomized trials failed to observe a significant reduction in preterm birth
or low birth weight in the treatment group [25]. Summary results of meta-analyses
of clinical trials are found in Table 6.2.
Outside of the above considerations, testing of other approaches to improving
oral hygiene as a way of avoiding PTL may have promise. This includes the use of
antibacterials/antiseptics. While one group found that systemic metronidazole
caused increased risk of preterm birth in the treatment group [26], the same group
found a significant decrease in PTL after the repeated topical use of nonalcoholic
antiseptic mouthwash [27].
If one were to find the “truth” about the efficacy of periodontal treatment in
reducing preterm birth, one must consider a number of issues:
1. A standard and unified definition of periodontal disease should be used in all

studies. There is much variability in the definition used in extant studies.
2. Treatment should be standardized, given during a biologically meaningful
timeframe and applied in adequate “doses.” Scaling and root planning, the most
commonly used treatment in the previous trials, was given at different gesta-
tional periods, by different individuals, and in different frequencies. This treat-
ment variation makes drawing valid inferences difficult.
3. Treatment should be shown to be effective against periodontal disease; it is the
inflammation and infection that is associated with periodontal disease that
might threaten the feto-placental unit. Only a few studies have shown the effec-
tiveness of scaling and root planning actually reduces periodontal disease dur-
ing pregnancy. It is naïve to assume that scraping teeth once or twice during
pregnancy will eliminate this chronic disease. If the underlying condition or
remnants of it remain after scaling and root planning, it is unrealistic to expect
this treatment to reduce preterm birth.
4. Outcome measures should be based on unified criteria. Gestational age is not
always based on sonograms, and some studies may have used the last menstrual
period in addition to sonograms to measure gestational age. If the potential
error related to this measure is random or non-differential (i.e., equal amounts
of this measurement error in treatment and control groups), the risk ratios will
be biased toward the null value (i.e., investigators will underestimate the true
effect). In addition, preterm birth and low birth weight may not be the only
outcomes that might be related to periodontal disease. Spontaneous abortion,
stillbirth, and neonatal complications can also be related, at least in theory, to
the infection and inflammation associated with periodontal disease. There was
some evidence for that in one study [9].
Table 6.2 Meta-analysis results from randomized controlled trials

Number of
Author Year Outcomes studies (N) Pooled estimate I2
Polyzos et al. 2009 Preterm birth (N = 7) OR = 0.55a (95 % 50.7 %
[21] CI = 0.35–0.86)
Low birth weight (N = 5) OR = 0.48 (95 % 57.6 %
CI = 0.23–1.00)
Abortions/stillbirths (N = 6) OR = 0.73 (95 % 22.2 %
CI = 0.41–1.31)
Polyzos et al. 2010 Preterm birth Low quality trials OR = 0.52a (95 % 0%
[22] (<37 weeks of (N = 6) CI = 0.38–0.72)
gestation) High quality OR = 1.15 (95 % 1%
trials CI = 0.95–1.40)
(N = 5)
Low birth weight Low quality trials OR = 0.44a (95 % 16 %
(<2500 g) (N = 5) CI = 0.30–0.66)
High quality OR = 1.07 (95 % 11 %
trials CI = 0.85–1.36)
(N = 3)
Spontaneous Low quality trials OR = 1.00 (95 % 0%
abortions/stillbirths (N = 6) CI = 0.51–1.97)
High quality OR = 0.79 (95 % 35 %
trials CI = 0.51–1.22)
(N = 5)
Overall adverse Low quality trials OR = 0.55a (95 % 12 %
pregnancy outcomes (N = 6) CI = 0.41–0.73)
(preterm birth High quality OR = 1.09 (95 % 21 %
<37 weeks of trials CI = 0.91–1.30)
gestation and (N = 5)
spontaneous
abortions/stillbirths)
Spontaneous preterm Low quality trials OR = 0.38 (95 % 75 %
birth <37 weeks of (N = 3) CI = 0.13–1.13)
gestation High quality OR = 1.05 (95 % 0%
trials CI = 0.74–1.50)
(N = 2)
Uppal et al. 2010 Preterm birth (N = 10) OR = 0.59a (95 % 75.8 %
[25] CI = 0.40–0.88)
Low birth weight (N = 8) OR = 0.72 (95 % 79.9 %
CI = 0.44–1.17)
Fogacci et al. 2011 Preterm birth (N = 3) Relative –
[36] (controlled for Risk = 0.63 (95 %
multiparity, previous CI = 0.32–1.22)
preterm birth, and
genitourinary
infections)
Low birth weight (N = 2) Relative –
(controlled for Risk = 0.52 (95 %
multiparity, previous CI = 0.10–2.60)
preterm birth, and
genitourinary
infections)
(continued)
Table 6.2 (continued)

Number of
Author Year Outcomes studies (N) Pooled estimate I2
George et al. 2011 Preterm birth (N = 10) OR = 0.65a (95 % 66 %
[23] CI = 0.45–0.93)
Low birth weight (N = 7) OR = 0.53a (95 % 69 %
CI = 0.31–0.92)
Abortions/stillbirths (N = 8) OR = 0.55a (95 % 19 %
(Sample size >500) CI = 0.31–0.99)
Kim et al. 2012 Preterm birth (N = 11) Risk ratio = 0.81 59 %
[24] (<37 weeks of (95 %
gestation) CI = 0.64–1.02)
High-risk group Risk ratio = 0.66a 3%
(N = 4) (95 %
CI = 0.54–0.80)
Moderate-risk Risk ratio = 0.97 37 %
group (95 %
(N = 7) CI = 0.75–1.24)
Preterm birth (N = 3) Risk ratio = 0.90 0%
(<35 weeks of (95 %
Low birth weight (N = 8) Risk ratio = 0.72 75 %
(95 %
CI = 0.48–1.07)
High-risk group Risk ratio = 0.48a 57 %
(N = 3) (95 %
CI = 0.30–0.78)
Moderate-risk Risk ratio = 1.08 24 %
group (95 %
(N = 5) CI = 0.83–1.42)
Rosa et al. 2012 Preterm birth (N = 13) Risk ratio = 0.90 74 %
[37] (<37 weeks of (95 %
(95 %
CI = 0.71–1.20)
Boutin et al. 2013 Preterm birth (N = 12) Risk ratio = 0.89 52 %
[38] (95 %
CI = 0.73–1.08)
Preterm birth (N = 5) Risk ratio = 1.00 22 %
(<35 weeks of (95 %
(95 %
CI = 0.60–1.16)
a
Significant at p < 0.05
5. Subject selection criteria also should be unified. If we include high-risk as well

as low-risk subjects, it will be difficult to evaluate the true effect of the peri-
odontal treatment on pregnancy outcomes. Rather than defining high- and low-
risk groups based on the combined incidence of preterm birth in treatment and
control group subjects, we need to focus on population data.
6. Concomitant medication and other dental treatment during the periodontal
treatment trial may influence the outcomes. It is unclear how the variability in
antibiotic use for other purposes, additional dental treatment outside of the trial,
and even the variability in personal hygiene practices during the previous trials
influenced the outcomes.
7. Is scaling and root planning the preferred treatment? Some studies have shown
a statistically significant reduction in preterm birth and low birth weight when
high-risk women were asked to rinse their mouth twice daily with a medicated
mouthwash [27].
8. Power analyses should precede all clinical trials and trial size should be appro-
priately weighed when considering the outcomes. Meta-analyses should also
weigh sample size so that unusually large study groups do not swamp the out-
comes of smaller groups.
9. Treatment trials should use proper analytic techniques. If randomized, data for
those subjects should be analyzed on an intent-to-treat basis to maintain the
integrity of the randomization. It is unclear how the analyses were conducted in
some trials and how the differential attrition rates within treatment and control
groups have influenced the results.
10. If there are enough studies in the literature, it is not difficult to perform additional
subgroup analyses to take into account the variations in at least some of the fac-
tors mentioned above and to see the effect of those factors on the outcome.
Unfortunately, we only have a handful of randomized controlled trails this area.
Uniform goals of clinical trials are necessary to avoid confounding. Subjects

should have preconceptual risk evaluation. Progesterone treatment, by whatever
route, should be applied equally. The most efficacious and safest modes of peri-
odontal treatment (either singly or combined) should be applied uniformly to high-
and low-risk subjects. Single treatments are probably not ever definitive. Data
collection should be blinded to the classification of the gravida.
In summary, the hypothesis linking periodontal disease to inflammation is based
on two possibilities: infection from the gum bacteria and the effect of gum inflam-
mation on the length of pregnancy. A major role for the former appears to have been
ruled out by bacteriological studies. The latter remains to be exhaustively and con-
vincingly tested, including the effect of the treatments on inflammatory signals [9].
The latter is important since medical intervention against periodontal disease in
pregnancy appears to result in lowering of the general inflammatory marker
C-reactive protein [28]. Also, two studies that utilized medical anti-infectious
agents showed prevention of preterm labor [16, 27], while a study from the same
group failed to show an effect of localized treatment of periodontal lesions on pre-
term birth [29].
Finally, clinicians should not misinterpret the existing evidence to indicate that
good oral health is not important during pregnancy. The mother’s oral health is sig-
nificantly related to downstream events in the baby, such as mutant streptococci
transmission and tooth decay [30]. It is important to maintain proper oral health
before, during, and after pregnancy regardless of whether it may or may not reduce
preterm birth.
6.5 Possible Linkage of PTL and Oral Disease to Systemic

Effects of Genetic Abnormalities
The apparent link between two systems, e.g., oral health and reproductive health,
could indicate a shared mechanism that is maybe more generalized. This could
explain the difficulty in showing a strict and direct relationship between periodonti-
tis and PTL. In such a case, the commonality could be inflammation brought on by
a fundamental abnormality or dysregulation. In this context, recent studies may
have exposed such a link by demonstrating abnormality of the prostaglandin E3
receptor gene in women with both periodontitis and PTL [31]. This genetic abnor-
mality would be expected to affect many actions of the prostenoid family, including
both periodontal disease and PTL [32, 33]. While it is too early to advance this
explanation for the link, the discovery of such abnormalities is a plausible explana-
tion that requires pursuit. In addition, such a finding implies the presence of other
inflammation and non-inflammation-associated abnormalities that could be associ-
ated with PTL in the affected population. For example, it has recently been shown
that pregnancies in women with polycystic ovarian syndrome have an increased
incidence of hospital admission for PTL. It will be interesting to know whether
there is an abnormality of the PGE3 receptor and increased periodontal disease in
this population [33].
Conclusions
Much progress has been made over the past decade to determine the impact of peri-
odontal diseases on various systemic diseases. However, the “jury is still out” on the
role of periodontal disease in PTL. Definitive, adequately powered, clinical studies
are required to demonstrate that the conversion of poor periodontal status to health
for the duration of pregnancy will result in a reduction of adverse pregnancy out-
comes. Until then, periodontal prophylaxis/treatment is warranted for pregnant
women in order that they maintain good periodontal health during pregnancy.
However, since such treatment has not undergone satisfactory long-term evaluation
of effects on the offspring, pharmacovigilance should be a part of this approach.
The recent report of a key gene abnormality in women at risk for PTL is
intriguing and could explain some of the apparent peculiarities in the results of
research regarding periodontal disease and PTL. This possibility and the proba-
bility of other inflammation-related problems militate toward a systems biology
approach to abnormalities of the prostaglandin E receptor, including a linkage
between periodontitis and PTL.
Acknowledgment Priyanka Taribagil and Gauri Panday, two graduate students in the clinical
research program, assisted the first author (APD) with conducting the literature search, obtaining
the relevant articles, and creating the reference libraries. Their help is much appreciated. We appre-
ciate the comments of Dr. Ashley Roman, Head of the Maternal and Fetal Medicine Unit of the
New York University School of Medicine on the final manuscript.
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Oral Health and Pneumonia
7
Frank A. Scannapieco and Keith Webb Harris
7.1 Introduction
The oral cavity can serve as a source of infection of the lungs. Aspiration of bacteria
from the oral cavity into the lower airway is possible since the surfaces of the oral
cavity are contiguous with those of the trachea and lower airway. Aspirated bacteria,
either normal inhabitants of the oral cavity that serve as opportunistic pathogens in
susceptible patients or exogenous pathogens that are not normal members of the
oral flora and that transiently colonize the oral cavity, can cause lung infections. In
addition, biological mediators, such as cytokines and hydrolytic enzymes, released
from the periodontium as the result of periodontal inflammation are aspirated into
the airway and may stimulate inflammation and increase susceptibility to infection.
This chapter reviews recent evidence implicating the oral microflora and oral
inflammation in the etiology of pneumonia.
7.2 Definitions and Disease Classifications
7.2.1 Community-Acquired Pneumonia
Community-acquired pneumonia (CAP) is an important cause of morbidity and

mortality in individuals who have not recently been admitted to a hospital or other
healthcare facility (e.g., nursing home). Bacterial pneumonia often occurs in an
individual with a suppressed immune system. Causes of immunosuppression include
F.A. Scannapieco, DMD, PhD (*)

Department of Oral Biology, State University of New York at Buffalo, Buffalo, NY, USA
e-mail: fas1@buffalo.edu
K.W. Harris, DO
Pulmonology, John T. Mather Memorial Hospital, Port Jefferson, NY, USA
e-mail: kharris513@gmail.com

82 F.A. Scannapieco and K.W. Harris
medications, chronic medical diseases and recent infections which can diminish the
cough reflex, interrupt mucociliary clearance, and enhance pathogenic bacterial
adherence to respiratory mucosa to link the chain of events that may eventually lead
to CAP [1].
Viruses are common etiologic agents of CAP, for example, respiratory syncytial
virus or rhinovirus. The three most common bacterial causes of CAP in children over
the age of 5 include S. pneumoniae, M. pneumoniae, and C. pneumoniae. Other etio-
logic agents early in life include group B streptococci and gram-negative enteric
bacteria. S. pneumoniae and H. influenzae are often the cause of CAP in adults.
About four million CAP cases occur in the United States each year [2]. Most of
these patients are treated in the primary care setting. For example, a recent large,
population-based cohort study of 46,237 seniors aged ≥65 were observed over a
3-year period [3]. The overall rate of community-acquired pneumonia ranged from
18.2 cases per 1000 person-years among persons aged 65–69 years to 52.3 cases per
1000 person-years among those aged ≥85 years. In this population, 59.3 % of all
pneumonia episodes were treated on an outpatient basis. Overall, CAP annually
results in more than 600,000 hospitalizations, 64 million days of restricted activity,
and 45,000 deaths.
Risk factors for CAP include older age, male gender, chronic obstructive pulmo-
nary disease, asthma, diabetes mellitus, congestive heart failure, and smoking [3]. In
a study to identify risk factors for CAP, 1336 patients with CAP and 1326 controls
were recruited from a population of 859,033 inhabitants in eastern Spain [4].
Multivariate analysis found cigarette smoking, continual contact with children, sud-
den changes of temperature at work, inhalation therapy (particularly containing ste-
roids), oxygen therapy, asthma, and chronic bronchitis to be independent risk factors
for CAP. Interestingly, a visit to a dentist in the last month was an independent pro-
tective factor for CAP, presumably by encouraging improvements in oral hygiene,
which could limit colonization by respiratory pathogens.
Common clinical symptoms of CAP include cough, fever, chills, fatigue, dys-
pnea, rigors, and pleuritic chest pain [2]. Depending on the pathogen, a patient’s
cough may be persistent and dry, or it may produce sputum. Other symptoms
include headache and myalgia. Certain bacteria, such as legionella, may induce
gastrointestinal symptoms.
Chest radiography is a useful tool for the diagnosis of pneumonia. A positive
chest radiograph shows consolidation within a lobe, or a more diffuse infiltrate [2].
However, chest radiography performed early in the course of the disease often
proves negative for signs of pneumonia.
The usual treatment for CAP is a course of antibiotics. Typical antibiotic regimens
include the use of oral azithromycin, clarithromycin, erythromycin or doxycycline in
otherwise healthy patients, or oral moxifloxacin, gemifloxacin, or levofloxacin in
patients having other comorbidities. The emergence of community-acquired methi-
cillin-resistant Staphylococcus aureus (MRSA) as a cause of CAP emphasizes the
need to formulate novel strategies for prevention of pneumonia to reduce the need for
antibiotic use [5].
7 Oral Health and Pneumonia 83
As mentioned, there is a possibility that poor oral health may contribute to the
pathogenesis of CAP. A recent case–control study compared the periodontal status
of 100 individuals hospitalized for the treatment of an acute respiratory disease
(pneumonia, acute bronchitis, or a lung abscess) or an exacerbation of COPD to a
group of 100 controls without respiratory disease [6]. All periodontal parameters
(gingival index, plaque index, oral hygiene index, pocket depth, and clinical attach-
ment loss) for patients with respiratory disease were significantly worse than for
control subjects.
7.2.2 Hospital and Healthcare-Associated Pneumonias (HAP

and HCAP)
While hospital-acquired infections such as pneumonia, commonly referred to as

hospital-acquired pneumonia (HAP), remain a growing problem, the increasing
complexity and treatment strategies for chronic medical diseases have brought about
similar virulent infections outside of the hospital setting. Over the recent past, there
has been a shift in delivery of medical care from the hospital to the outpatient setting,
for delivery of services such as antibiotic therapy, chemotherapy, wound manage-
ment, outpatient dialysis centers, and short-term rehabilitation. As a result, the clas-
sification for pneumonia has broadened. While HAP is cited by some as the leading
cause of death among hospital-acquired infections partly due to the virulence of the
infection [7], the emergence of similarly resistant organisms within the healthcare
community has led to more complicated infections including pneumonia in some of
these outpatients. Patients who develop pneumonia within the above outpatient set-
tings are referred to as Health care-associated pneumonia (HCAP) [8].
HAP can be further divided into two subtypes: nonventilator-associated pneumonia
and ventilator-associated pneumonia (VAP). Most cases of HAP are due to the former
and occur outside of the intensive care unit (ICU). The trend in the incidence of non-
ventilator-associated hospital pneumonia is difficult to discern with different ranges
reported by several authorities. However, within the ICU, HAP is the most common
infection, accounting for 10 % of infections [9].
VAP is the second most common hospital-acquired infection [10, 11]. VAP is a
leading cause of death in critically ill patients in the ICU, with estimated prevalence
rates of 10–65 % and mortality rates of 25–60 % depending on the study, patient
populations, and medical/surgical conditions involved [9, 12–17]. VAP and other
forms of HAP are independent risk factors for mortality in hospitalized patients
irrespective of the severity and type of underlying illness [18]. An episode of HAP
adds approximately 5–6 days to the length of hospital stay and thousands of dollars
in cost to medical care [12–17]. The risk of developing VAP in the medical and
surgical ICU varies from 5 to 21 per 1000 ventilator days [19]. The onset of pneu-
monia easily can double the length of the patient’s hospital stay, and the cost of
VAP treatment has been estimated to average as high as $40,000 per case [20].
The mortality rate of HAP pneumonia can be as high as 25 %.
Nursing-home associated pneumonia (NHAP) is the most important common

infection affecting nursing home residents because of the high morbidity and mor-
tality associated with this infection [21], comprising 13–48 % of all infections [22].
Pneumonia is also a common reason for transfer of residents from the nursing home
to the hospital [23].
7.2.3 Aspiration Pneumonia
Aspiration pneumonia (AP) is an infectious process caused by the aspiration of

oropharyngeal secretions containing pathogenic bacteria [24]. AP is differentiated
from aspiration pneumonitis, which is typically caused by chemical injury follow-
ing inhalation of sterile gastric contents. AP is particularly prevalent in the elderly,
especially those in institutions such as nursing homes and those with several impor-
tant risk factors such as dysphagia or altered levels of consciousness [25, 26]. AP
can also be community acquired or associated with other healthcare delivery facili-
ties. AP is almost always caused by a mixed infection including anaerobic bacteria
derived from the oral cavity such as the gingival crevice and gastric contents. Indeed,
the important role of oral bacteria in this process has recently become better appre-
ciated. Patients diagnosed with AP typically are older (mean age of 77 years), with
a reported 30-day mortality of 21% [27]. Compared to CAP patients, AP patients
tended to have more frequent inpatient admissions, intensive care unit admissions,
comorbidities, and greater mortality.
Among risk factors, swallowing disorders (dysphagia) are most associated with
AP. Dysphagia is quite common in the elderly [28] as the result of a variety of condi-
tions including Parkinson’s disease, Alzheimer’s Disease, stroke, other neurodegen-
erative conditions, or advanced aging [29]. A recent systematic review demonstrated
dysphagia to have a positive correlation with AP (OR = 9.84; 95 % CI = 4.15–23.33)
[30]. Other risk factors include dependence for feeding, dependence for oral care,
tube feeding, smoking, multiple medical diagnoses, number of medications, number
of decayed teeth, chronic obstructive pulmonary disease (COPD), and diabetes [31,
32]. Dental risk factors for patients with natural teeth included the number of decayed
teeth, number of pairs of opposing teeth, and presence of decay and periodontal dis-
ease-causing organisms in saliva or dental plaque.
More recently, modifiable risk factors for pneumonia in elderly nursing home
residents were identified in a prospective study of 613 elderly residents of five nurs-
ing homes [33]. In this cohort, 18 % developed pneumonia. Statistical modeling sug-
gested that both inadequate oral care and difficulty with swallowing were associated
with pneumonia.
7.2.4 Pathogenesis
Under normal circumstances, the lower airway presents formidable defense against
aspirated bacteria [34]. A viscous mucous layer coating the epithelium, containing
host-derived mucins and antimicrobial components such as lactoperoxidase, lysozyme,
and other antimicrobial peptides [35], traps bacteria, which are then removed from the
lung by the mucocutaneous escalator which is a function of the unidirectional beating
of epithelial cilia. Complex bacterial surface components interact with pattern recogni-
tion receptors such as toll-like receptors to activate inflammation through the NF kappa
B signaling pathway. This in turn recruits activated macrophages and neutrophils that
engulf the invading bacteria.
Most events of pneumonia are the result of aspiration of infectious agents coloniz-
ing the oral cavity and/or upper respiratory tract [36, 37]. Approximately 45 % of
healthy subjects aspirate during sleep and a higher percentage occurs in severely ill
patients [38]. Any condition that compromises upper airway defenses will increase
the risk for pneumonia by allowing aspirated bacteria to attach to the respiratory epi-
thelium, which will then trigger the cascade of events that result in overt infection
(Fig. 7.1). Such conditions include those that reduce containment of the secretions to
the upper airway. For example, the placement of an endotracheal tube through the
larynx and trachea into the lung can provide a route for bacteria to bypass those struc-
tures that normally prevent aspirations, such as the glottis (Fig. 7.2). Another condi-
tion that will promote aspiration is dysphagia, already noted above as more common
in elderly individuals [40]. Dysphagia is also very common in nursing home residents
[41] and therefore represents an important risk factor for aspiration pneumonia.
Reduction in salivary flow, which occurs frequently in the elderly, most commonly as
a side effect of one or more medications, may also contribute to increased risk for
pneumonia by allowing enhanced microbial biofilm formation [42].
It is possible that dysphagia can occur in the absence of overt signs of swallow-
ing difficulty: so called “silent” aspiration [43]. Certain conditions, such as stroke
or impaired cough reflex may increase the frequency of such silent aspirations.
Cross-contamination from
environment, provider, Aerosols
equipment, invasive device, etc.
Oropharyngeal Gastric
colonization colonization
Aspiration Inhalation
Large bacterial
numbers or
Bacteremia virulence factors Translocation
overwhelm host
defense
Lung infection
Fig. 7.1 Factors influencing the risk of pneumonia

Fig. 7.2 Route of infection in VAP. Bacteria that can cause pneumonia colonize the teeth within
the biofilm. The endotracheal tube, in close proximity to the teeth and oral biofilm, provides a route
to bypass defense mechanisms. The endotracheal tube can also become colonized by bacteria from
the teeth and oral secretions to form a biofilm. The bacteria then enter the lower airway to cause
infection (From Ref. [39])
Most cases of AP are the result of mixed infections that may be more virulent than
infections caused by a single species [44]. Bacteria normally indigenous to the oral
cavity can initiate disease, especially anaerobes associated with periodontal disease
[45]. It is also possible that oral species may potentiate the pathogenic potential of
other, more typically recognized respiratory pathogens, such as Streptococcus pneu-
monia, Staphylococcus aureus, or Pseudomonas aeruginosa. These species are nor-
mally found in low numbers in the mouth, but are found in large numbers in the oral
cavity of high-risk subjects such as those in nursing homes [46–49]. In some health-
care settings, over half the subjects assessed showed the presence of these bacteria in
the dental plaque, and the prevalence of colonization has been correlated with the
length of stay in the setting [25, 37].
7.2.5 Oral Health and Aspiration Pneumonia
Prior to the mid-1990s, the role of oral conditions in the pathogenesis of AP, particu-
larly poor oral hygiene and periodontal inflammation, was mostly ignored in the
medical and nursing care setting. This was in spite of the understanding that the
sources of the infectious agents causing the disease were often the oral microflora.
This situation began to change as knowledge of the specific role of the oral micro-
flora in the pathogenesis of pneumonia became known.
Much of the work at this time was performed in hospitalized patients, particu-
larly mechanically ventilated patients in intensive care units, who have substantially
elevated risk for pneumonia [26, 37]. It was shown that the teeth serve as a reservoir
for respiratory pathogen colonization [50–52], and thus serve as a source of bacteria
in aspirated secretions. Further studies also suggested that methods to improve oral
hygiene in these populations could reduce their risk of pneumonia [53–55]. Several
other studies suggested that the oral cavity might also serve as a reservoir for pul-
monary infection in nursing home residents [48, 49, 56]. Again, the oral cavities of
elderly residents of nursing homes were more frequently found to harbor respiratory
pathogens than those of ambulatory patients.
There is some evidence that periodontal disease may be associated with risk for
pneumonia in noninstitutionalized elderly patients. A study of an elderly Japanese
population found that the adjusted mortality due to pneumonia was 3.9 times higher
in persons with ten or more teeth with a probing depth exceeding 4 mm (i.e., with
periodontal pockets) than in those without periodontal pockets [57].
7.2.6 Oral Care to Prevent Ventilator and Aspiration Pneumonia
In light of these findings, it would seem intuitive that oral hygiene or periodontal
therapy would help prevent the onset or progression of AP in high-risk patients.
Indeed a number of studies, described below, have tested this hypothesis. Most of
the available literature addressing the role of oral care in the prevention of pneumo-
nia has been conducted in hospitalized and mechanically ventilated patients.
However, several studies have also been conducted in nursing home patients. These
studies have been critically reviewed by several recent systematic reviews of the
literature. Taken together, the evidence supports the link between poor oral health
and pneumonia [53, 58–60]. Oral interventions to reduce pulmonary infections have
been examined in both mechanically ventilated ICU patients and non-ventilated
elderly patients [53, 55, 58, 59]. A variety of oral interventions have been tested,
including topical antimicrobial agents such as chlorhexidine and Betadine. Fewer
studies have evaluated the effectiveness of traditional oral mechanical hygiene. The
use of oral topical chlorhexidine (CHX) reduces pneumonia in mechanically venti-
lated patients and may even decrease the need of systemic IV antibiotics or shorten
the duration of mechanical ventilation in the ICU [61–65]. Also, oral application of
CHX in the early post-intubation period lowers the numbers of cultivable oral bac-
teria and may delay the development of VAP [66]. Not all studies support the effec-
tiveness of oral CHX in reducing pneumonia, however [67–70]. The efficacy of oral
CHX decontamination to reduce pneumonia requires further investigation.
Several studies have demonstrated that mechanical oral care, in some cases in com-
bination with povidone-iodine, significantly decreases the risk of pneumonia in nurs-
ing home residents [71–73]. Once-a-week professional oral cleaning significantly
reduced influenza infections in an elderly population [74]. Implementation of profes-
sional oral care programs in nursing facilities, involving the deployment of dental
hygienists to provide direct oral care, including tooth, tongue, and denture brushing,
may help reduce the oropharyngeal microbial burden and therefore the number of
microbes that can be aspirated into the lower airway [75]. Such an approach may
also reduce the risk of other respiratory infections such as influenza [76].
Oral cleansing reduces pneumonia in both edentulous and dentate subjects, sug-
gesting that oral colonization of bacteria contributes to nosocomial pneumonia to
a greater extent than periodontitis per se. However, intervention studies on the
treatment of periodontitis on the incidence of pneumonia have not been performed
due to the complexities required in investigating ICU or bed-bound nursing home
patients. In edentulous patients, dentures could conceivably serve as a similar res-
ervoir as teeth for oral and respiratory bacterial colonization if not cleaned prop-
erly on a daily basis, although neither removable dentures nor the edentulous oral
cavity provide the anaerobic environments favored by periodontopathic
organisms.
7.2.7 Recommendations for Oral Care to Prevent Ventilator

and Aspiration Pneumonia
• Routine oral examination of the teeth, gums, tongue, mucous membranes, and lips
• The use of a soft bristled toothbrush, and dental floss if feasible, to remove debris
and dental plaque at least twice a day
• The use of mouth swabs (foam and cotton) only when there is a contraindication
to brushing (e.g., bleeding gums associated with thrombocytopenia)
• The use of oral rinse such as 0.12 chlorhexidine gluconate
• Minimize use of dental appliances – remove dentures during sleep
• Restoration of cavitations to minimize dental plaque retention
Conclusions
Understanding of the risk factors and preventive measures for pneumonia is
essential in the care of hospitalized and institutionalized patient. Control of oral
biofilm formation in these populations will reduce the numbers of potential
respiratory pathogens in the oral secretions, which in turn will reduce risk for
pneumonia. Together with other preventive measures (head of the bed position;
promotion of salivary flow; vaccination against pathogens such as Streptococcus
pneumoniae; management of swallowing disorders; etc.), improved oral hygiene
will help control lower respiratory infections in the hospital and nursing home
patients.
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Peripheral Inflammation and Alzheimer’s
Disease: Periodontal Disease 8
Angela R. Kamer, Ronald G. Craig, and Mony J. de Leon
8.1 Introduction
Alzheimer’s disease (AD) is one of the leading causes of dementia [1]. In the United
States alone, approximately 5.3 million patients have been diagnosed with AD [2]
and in view of the country’s aging demographics, its prevalence and incidence will
continue to increase as the population ages. One in 9 and one in 3 people older than
65 and 85, respectively, have AD, and approximately 61,000 and 240,000 new cases
of AD in the 65–75 and 85 and older age groups, respectively, were reported in 2015
[2]. Notably, AD in the United States is ranked the 9th leading cause of mortality
ahead of breast and colon cancer and is ranked 12th in contribution to years of dis-
ability [3]. It is estimated that delaying the onset of AD by 5 years could result in a
50 % decrease in prevalence 50 years later. Undoubtedly, as the population ages and
life span increases, the prevalence of AD will increase even further, and in 50 years,
AD is predicted to afflict approximately 16 million people [4]. Although the above
statistics underscore AD as a major public health concern, the prevalence of AD will
not significantly decrease unless novel approaches emerge to help prevent and slow
A.R. Kamer, DMD, MS, PhD (*)

Department of Periodontology and Implant Dentistry, New York University
College of Dentistry, New York, NY, USA
Department of Basic Sciences and Craniofacial Biology, New York University
M.J. de Leon, EdD, Professor
Department of Psychiatry, Director Center for Brain Health, New York University
Langone Medical Center, New York, NY, USA
e-mail: mony.deleon@med.nyu.edu

94 A.R. Kamer et al.
the progression and manage AD. Therefore, efforts to “think out of the box” and iden-
tify novel, modifiable factors involved in the initiation and progression of AD are of
paramount importance.
Two types of AD are recognized. Early onset AD is present in less than 5 % of
the population and is genetically determined [5]. Late onset or sporadic AD
(LOAD) is the most prevalent type of AD and is believed to result from the interac-
tion of multiple genetic and environmental factors [6, 7]. As is true for atheroscle-
rosis and hypertension, AD is thought to be a continuous process developing over
many years and understanding the relative contributions of both genetic and envi-
ronmental factors to AD pathogenesis is essential to determine disease susceptibil-
ity and prevention. Although risk factors such as age, race, family history, and
disease-associated genes such as ApoE with an ε4 allele [5] are immutable, envi-
ronmental risk factors may be modifiable and serve as a target for therapy. Despite
the significant strives made in understanding the pathogenesis of AD, to date there
are no drugs that can modify the course of AD. Therefore, emphasis has been
placed on understanding the role of environmental risk factors. Among the risk
factors recognized by The Alzheimer’s Association are: cerebrovascular disease,
hypertension, diabetes, obesity, smoking, depression, psychological stress, and
history of head trauma [8]. In addition to these established risk factors, novel fac-
tors such as periodontal disease have also been implicated in the pathogenesis of
AD. Eradication of a single risk factor may not have a major effect but if several
risk factors are removed the combined effect may substantially reduce or delay the
onset of AD [9]. Delaying the onset of AD by only 1 year would constitute a major
effect [10]. With this goal in mind, the objective of this chapter is to briefly sum-
marize our current understanding of the pathogenesis of AD and the evidence
potentially linking periodontal disease with AD.
8.2 Clinical Diagnosis of AD
For almost 30 years the clinical diagnosis of probable AD was made using criteria
published by the National Institute of Neurological and Communicative Disorders
and Stroke (NINCDS) and the Alzheimer’s Disease and Related Disorders Association
(ADRDA) workgroup (NINCDS-ADRDA). By these criteria the diagnosis of AD was
based on the presence of a dementia syndrome encompassing an array of symptoms
and signs characterized by a decline in cognitive performance severe enough to inter-
fere with daily activities. Although the specific signs and symptoms depend on the
type of dementia, several symptoms are common to all types of dementia including
loss of memory, difficulty in planning and executing tasks, inability to recognize faces
and orient objects, difficulty in communicating, and behavior changes. A definite
diagnosis of AD, however, required a neuropathologic evaluation.
Recently, the National Institute on Aging (NIA) and the Alzheimer’s Association
(AA) workgroup updated the diagnostic criteria. The new diagnosis criteria acknowl-
edged that pathophysiologic processes in AD begin early in life and can be present in
cognitively normal (NL) individuals as well as individuals with mild cognitive
impairment (MCI). For the diagnosis of AD, NIA-AA proposed the utilization of the
8 Peripheral Inflammation and Alzheimer’s Disease: Periodontal Disease 95
following diagnostic classification groups: (1) probable AD dementia, (2) possible

AD dementia, and (3) probable or possible AD dementia with evidence of the AD
pathophysiological process [11]. The first two classifications are for clinical use. The
third classifying criteria include evidence of AD-specific biomarkers obtained by
techniques such as imaging or cerebrospinal fluid (CSF) analysis by lumbar puncture
and are intended to be used in research settings. Common diagnostic criteria for these
groups include:
• The presence of a dementia syndrome (defined above) encompassing impairments

affecting at least two of the following domains of cognition/behavior: memory,
executive function, visuospatial, language, and behavior/personality.
• The onset of the dementia is gradual and not acute. This feature differentiates a
dementia syndrome from other acute cognitive conditions (such as delirium).
• The course of dementia is progressive although not necessarily uniform.
• The dementia syndrome is not due to cardiovascular diseases, Lewy body forma-
tion, frontotemporal pathology, or conditions affecting the brain (i.e., tumors,
drugs). Therefore these conditions should be ruled out.
• The presence of objective signs of cognitive decline or the presence of a genetic
mutation known to be etiologic to AD (genes including APP, PSEN1, and PSEN2)
strengthens the diagnosis.
The classification of possible AD dementia is recommended when the dementia has

an atypical or mixed presentation. Probable or possible AD dementia with evidence of
the AD pathophysiological process is defined as the clinical entity with a clinical diag-
nosis of probable/possible AD that present with evidence of an AD-specific pathophysi-
ologic processes. This evidence encompasses the presence of AD-specific biomarkers
that are classified into (a) biomarkers related to Aβ deposition, (b) biomarkers related to
tau pathology, and (c) biomarkers related to neuronal damage. Markers of Aβ deposi-
tion are low levels of Aβ42 in subjects’ CSF and/or increased ligand retention by
PET imaging such as [C-11]-(2-[4-methyl-amino phenyl]-1,3-benzothiazol-6-ol), or
Pittsburgh Compound B (PiB), florbetapir F-18, flutemetamol F18, or florbetaben F18.
These ligands bind to fibrillar amyloid in the brain and correlate with brain amyloid
deposition. Tau pathology translates into increases in CSF P-tau (phosphorylated tau)
and increases in CSF T-tau (total tau). PET based measures of tau are currently in clini-
cal trials. Markers of increased neuronal degeneration include decreased [18F] FDG-
PET signal (brain glucose metabolism) and brain atrophy by MRI.
Mild cognitive impairment (MCI) is an intermediate state between NL and
dementia and has a high risk of progression to AD. MCI is also known as symptom-
atic pre-dementia. Patients with MCI present with impairment in memory, executive
function, attention, language, or visuospatial skills. However, they do not have
dementia and their cognitive impairments do not interfere with daily activities. MCI
due to AD assumes that this clinical syndrome is due to pathophysiology character-
istic of AD. In addition to clinical criteria, MCI includes AD-specific biomarkers
[12]. Preclinical AD also includes cognitively NL individuals expressing AD-specific
biomarkers [13, 14]. However the use of biomarkers is presently limited to research
and not clinical settings.
8.3 Management of AD
Present FDA approved treatments regimens focus on symptoms and not etiology.
Currently, two groups of drugs are used, acetylcholinesterase inhibitors and
N-methyl-D-aspartate (NMDA) receptor antagonists. Acetylcholinesterase inhibi-
tors act by preventing acetylcholine degradation, thus increasing the concentration of
acetylcholine in the synaptic cleft and prolonging cholinergic neurotransmission.
Acetylcholine inhibitors can be effective for 2–5 years and are usually indicated
in mild to moderate AD although donepezil can be administered in all stages.
N-methyl-D-aspartate (NMDA) receptor antagonists interfere with the sustained
activation of NMDA receptors thus facilitating neuronal function. The noncompeti-
tive NMDA-receptor antagonist memantine acts by regulating glutamate activity.
Memantine may be effective in moderate to severe disease but only over shorter time
periods. A combination therapy of donepezil and memantine has been approved
recently for moderate to severe AD. In addition to cognition, AD patients may exhibit
other symptoms such as depression, aggression, psychomotor agitation, and psycho-
sis. Oral complications are not commonly encountered for acetylcholinesterase
inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists; however, medi-
cations used to treat depressive and psychiatric symptoms have oral complications
including hyposalivation and xerostomia with associated sequelae.
8.4 Pathogenesis of AD
The pathologic hallmarks of AD are the presence of senile plaques, neurofibrillary

tangles, neuronal and synaptic dysfunction, and neuronal loss. The senile plaques
found in the brain parenchyma contain extracellular aggregates of amyloid β-peptide
(Aβ) [15]. Associated with senile plaques are activated glial cells, reactive astrocytes,
and inflammatory molecules [16]. Aggregates of Aβ also accumulate in brain vessel
walls forming cerebral amyloid angiopathy. Neurofibrillary tangles are neuronal intra-
cellular aggregates composed of phosphorylated tau proteins [17]. Macroscopically,
neuronal loss and brain atrophy occurs in several sites including the hippocampus and
temporal and parietal lobes resulting in the thinning of the cortex and enlargement of
the ventricles. first atrophy observed was in the hippocampal formation, a discov-
ery we published in the Lancet in 1989 and replicated in 1991. Afterwards the atrophy
spreads to the neocortex. AD is thought to be a continuous process starting as early as
30 years of age although the steps involved in AD pathogenesis are not well under-
stood. The amyloid and inflammatory hypotheses are the most prominent presently
hypotheses forwarded to explain the pathogenesis of AD
The amyloid hypothesis posits the initiating event in AD is the presence of amyloid
beta peptides (Aβ) that accumulate within the brain and initiate a cascade of events
leading to neurodegeneration and neuronal death. The accumulation of Aβ in the brain
in both parenchyma and blood vessels results from impairments in the Aβ hemostatic
mechanisms. Several mechanisms involving Aβ synthesis and clearance have been
proposed and include increased central (brain) synthesis, central degradation, decreased
amyloid clearance (efflux) from the brain [18], increased peripheral synthesis [19],
decreased peripheral degradation, and a combination of these mechanisms (Fig. 8.1)

[20]. Substantial evidence from genetic studies exists for the role of increased amyloid
brain synthesis. Several types of early-onset AD present genetic mutations that increase
the production of brain amyloid. In patients with late-onset AD, brain amyloid synthe-
sis accumulation appears to be mostly due to decreased clearance although increased
synthesis cannot be excluded [21, 22]. Peripheral Aβ contribution to the brain amyloid
accumulation is less certain; however current investigations are exploring these areas.
In addition to Aβ synthesis in the brain, Aβ can also be synthesized peripherally.
Although the production of Aβ in the peripheral tissue is ubiquitous, the major
peripheral producers of amyloid are platelets and perhaps endothelial cells, the liver
and muscle. Up to 90 % of peripheral amyloid is attributed to platelets. The cleavage
of APP into Aβ peptides occurs upon platelet activation. The released cleavage prod-
ucts are then stored in the alpha granules of platelets and released into the circulation
thus Aβ contribute to the Aβ systemic pool [23].
Amyloid clearance from the brain is a complex, multimodal process with several
pathways thought to contribute. In addition to enzymatic degradation and glial phago-
cytosis, these pathways include direct transport of the Aβ through the blood–brain bar-
rier, its transport to the cerebrospinal fluid with absorption in the venous compartment,
bulk flow of the interstitial fluid, and peripheral lymphatic system. Other transport
pathways such as via optic and olfactory nerves have also been described. The specific
contribution of these pathways to the Aβ clearance is not known and form active areas
of investigations. Animal models showed that most Aβ clearance takes place at the
blood–brain barrier by an active transport mechanism in which low-density lipoprotein
receptor-related protein 1 (LRP1) transport receptor plays a crucial role.
The inflammatory hypothesis is a second prominent hypothesis for the pathogenesis
of AD [24]. which believes inflammation can play an etiologic (primary) role or can be
Peripheral compartment
Clearance
Liver
Muscle Synthesis
Endoth
Platelets Inflammation
Inflammation infections
infections
RAGE
BBB
LRP
Bulk flow
Synthesis Clearance
Genetics
Brain compartment
Fig. 8.1 Model for peripheral inflammations/infections contribution to amyloid regulation. The accu-
mulation of Aβ in the brain is the result of several mechanisms involving Aβ synthesis and clearance
that can occur centrally and peripherally. BBB = blood brain barrier; RAGE = receptor for advanced
glycation endproducts (mediates Aβ transport into the brain); LRP = receptor-related protein
contributory (secondary) in AD pathogenesis. In an animal model acute as well as

chronic inflammation was able to induce AD-related pathology [25] and cognitive
decline. In contrast, other studies showed that AD associated molecules such as Aß,
p-tau, and degenerating neurons are themselves pro-inflammatory. Whether brain
inflammation is etiological or contributory, it is characterized by a self-reinforcing
cycle in which pro-inflammatory molecules including TNF-α, Il-1ß, Il-6, and C-reactive
protein (CRP) [26] act via paracrine and/or autocrine pathways to stimulate glial cells
pathways to stimulate glial cells to further produce more inflammatory and pathogenic
molecules such as Aß42, and P-Tau or impair their clearance [27, 28]. Multiple in vitro
and animal studies support the role of cytokines and LPS in Aβ production and tau
phosphorylation. In vitro, TNF-α, Il-1ß, and Il-6 have been shown to stimulate the
synthesis of Aß42 and the phosphorylation of tau protein, while Aß42 and P-Tau have
been shown to enhance the production of TNF-α, Il-1ß, and Il-6 by glial cells and the
activation of the complement pathway. In animal studies, inflammation associated
with LPS resulted in enhanced brain amyloid accumulation and tau phosphorylation
and Aß enhanced the glial production of cytokines and cognitive dysfunction.
More importantly, evidence for a role of inflammation in AD also comes from
clinical specimens and clinical studies. Senile plaques react with antibodies against
TNF-α, Il-1ß, Il-6, CRP, and complement proteins and reactive astrocytes and acti-
vated micro-glial cells associate with senile plaques. Elevated CRP increased the
risk of both developing AD and of cognitive decline in various populations. Pro-
inflammatory cytokines as predictors of AD have also been investigated [29] how-
ever some studies report conflicting results [30]. The variation in results among
studies is not unexpected for several reasons. Cytokines play important roles in
mediating cognition and this effect is concentration and time dependent [31]. They
also have beneficial effects on healing as well as amyloid phagocytosis. In addi-
tion, inflammation is the summation of multiple signaling and effecter pathways
that interact with each. Therefore, the increase or decrease in the individual pro-
inflammatory cytokine may not reflect the synergy or contribution from other
inflammatory cytokines. Most epidemiological studies investigated only selected
cytokines such as Il-6 IL-1ß and TNF-α, therefore reflecting only a limited aspect
of inflammation.
Sources of peripheral inflammation that produce significant systemic inflamma-
tory burden such as cardiovascular disease, diabetes, obesity, and the metabolic
syndrome also associate with cognitive dysfunction and AD and are now accepted
risk factors for AD. Infections with cytomegalovirus, Helicobacter pylori, spiro-
chetes, and herpes simplex virus have also been associated with AD and cognitive
dysfunction.
Genetic polymorphisms in the inflammatory/immune genes have also been asso-
ciated with AD. For example, the presence of a composite genotype characterized
by the presence of Il-1α-889 and Il-1β + 3953 polymorphisms conferred an almost
11-fold increased risk of developing AD [32] presumably due to increased Il-1 lev-
els [33]. In addition, findings from genome-wide association studies reported that
polymorphisms in immune and inflammatory genes PICALM, CLU, CR1, CR2,
TREM2, CD33 were associated with AD. Interestingly, our own study showed that
subjects with periodontal inflammation had lower cognition compared to those

without periodontal disease [34] and among the subjects with periodontal inflam-
mation, those having IL-1082 AA/AG genotype tested lower on the cognitive test
compared to periodontal subjects with IL-1082 GG genotype or subjects without
periodontal inflammation [35]. Since the IL-1082 AA/AG genotype has lower pro-
duction of the anti-inflammatory cytokine IL-10 compared to the IL-1082 GG geno-
type, this study showed that when a peripheral infection is associated with a
genotype predisposing to higher inflammatory response, it might have significantly
more effect on the brain.
8.5 Peripheral Inflammatory Mechanisms

in the Pathogenesis of AD
The brain is a privileged site whose homeostasis is maintained by the function of

a structurally sound blood–brain barrier. However, peripherally derived pro-
inflammatory molecules and bacteria or bacterial products can enter the brain by
two mechanisms: via systemic circulation and/or neural pathways [36]. Peripherally
produced pro-inflammatory molecules can enter the CNS in areas of the brain that
lack a blood–brain barrier such as the circumventricular organs, cross through
fenestrated capillaries of the brain blood barrier, use cytokine-specific transporters,
or activate brain endothelial cells to induce the production of cytokine, nitric oxide,
and prostanoids on the abluminal site of the brain (brain site). In addition the
blood–brain barrier also expresses toll-like receptors including TLRs1-4 and
LTR-6 [37] suggesting that pathogen-associated molecular patterns such a LPS-
endotoxin can influence the brain upon blood–brain barrier stimulation. Once in
the brain, pro-inflammatory molecules may directly increase the local pro-inflam-
matory cytokine pool, indirectly increase brain cytokine storage release and stimu-
late glial cells to synthesize additional pro-inflammatory cytokines [38].
Neurons may also provide an anatomic pathway through which peripherally
expressed cytokines or bacteria or bacterial products may access the brain [39]. For
example, the trigeminal neurons express TLR-4 and CD14 that could be bound by
LPS produced peripherally [40]. This mechanism has been demonstrated in the oral
cavity. Injection of interleukin IL-1β into the soft palate of rats induced a febrile
response that was significantly attenuated by bilateral glossopharyngeal nerve tran-
section [41].
Pro-inflammatory cytokines and bacteria or bacterial products can contribute to
AD by augmenting Aß synthesis [42], disrupting the brain blood barrier and/or amy-
loid beta trafficking [43], inducing phosphorylation of tau protein, decreasing synap-
tic strength and neuronal degeneration, and ultimately contributing to cognitive
decline [44]. Consistent with these mechanisms, we reported that periodontitis, a
chronic infection with significant inflammatory and infectious burden was associated
with amyloid accumulation in the brain as assayed by PIB uptake [45]. In addition,
subjects with periodontal disease had increased p-tau and t-tau in their CSF (unpub-
lished data) again suggesting that inflammation and inflammatory conditions can
contribute to AD-related pathology. If glial cells were already primed as occurs in

aging or genetic predisposition, stimulation by peripherally produced pro-inflamma-
tory cytokines would result in amplified effect.
8.6 Periodontitis and AD
Periodontitis is a chronic, polymicrobial, inflammatory disease. In the United States

alone, approximately 141 million adults ≥30 years old comprising 46 % of the den-
tate US adults have periodontitis, and among them 9–12 % have severe periodontitis
[46]. In addition to adults, 2–3 % of children have chronic periodontitis and another
0.2–2 % have a severe form called aggressive periodontitis [47].
Clinical data from our studies as well as others using a range of exposure indexes
and study designs have reported that measures of periodontal infection were associ-
ated with cognitive impairment, cognitive decline, dementia, and AD with odd and
hazard ratios of mild to moderate strength [34, 45, 48]. Using the NHANES III data
set, high titers of antibodies against P. gingivalis were associated with lower cognitive
function [49]. Furthermore, antibodies to A. actinomycetemcomitans, T. forsythus,
and T. denticola were predictive of the development of AD years before its clinical
diagnosis [50]. Taken together these studies strongly support an infection and/or
immune response role of periodontitis in AD pathogenesis. Since the end result of
periodontitis is tooth loss, this index has been used as a proxy of the presence of peri-
odontal disease as well as periodontal treatment outcome. Considering the high preva-
lence of periodontal disease in the general population, even if periodontal effect on
AD risk is modest, the numbers of people whose disease could be prevented are
staggering.
8.7 Proposed Model for the Effect of Periodontal

Disease on AD
Chapter 2 of this volume described the pathogenesis of periodontal diseases.

Important to its role in the pathogenesis of AD are its infections and inflammatory
burden, both of which can contribute to AD pathogenesis by contributing to the brain
inflammation, neurodegeneration by increasing AD-specific pathology, and inducing
cognitive decline. The AD-specific pathology commences as early as 30 years of age,
and therefore periodontal disease-associated effects on AD pathology can occur
before or throughout its progression (Fig. 8.2).
Periodontal bacteria frequently gain access to the circulatory system. Bacteremia
can occur during manipulations of the oral tissues and daily procedures such as floss-
ing, brushing, and mastication particularly when periodontitis is present. Under nor-
mal physiologic conditions, bacteremia lasts approximately 30 min until cleared by
the immune system. However, if the immune response is weakened, keystone patho-
gens such as P. gingivalis, B. forsythus, and T. denticola can evade, subvert the
immune system, and metastasize at distant sites such as the brain and induce local
Cytokines/bacteria
Bacteria
LPS
TNF-α
IL-1β Environmental and genetic factors
IL-6
AB
IL-6 Activated
microglia TNF-α
Non-activated (ameboid form) IL-1β
TNF-α microglia IL-6
IL-1β
IL-6
CRP
Fig. 8.2 Model for periodontal disease contribution to AD progression. The central theme of AD
pathogenesis is the presence of brain inflammation characterized by increased proinflammatory cyto-
kines. The periodontal disease-derived pro-inflammatory molecules and bacterial products can contrib-
ute to the brain inflammatory pool via systemic circulation and/or neural pathways. In the brain, the
pro-inflammatory molecules may stimulate glial cells to synthesize additional pro-inflammatory cyto-
kines, and increase AD-specific pathology, induce neurodegeneration and subsequent cognitive decline
inflammation. They may also assist other bacteria in doing the same. Several peri-
odontal species can invade proximal tissue. By invading monocytes, bacteria can use
these cells as transport mechanisms to reach the brain [51]. At the local periodontal
tissue, the pathobionts assisted by the keystone bacteria maintain a continuous dys-
biotic, inflammatory milieu thus perpetuating this vicious circle.
Infection-induced effects on AD have been critically reviewed [52]. Miklossy pro-
posed that oral spirochetes could be possible candidates to invade the brain and cause
cognitive impairment in AD. Indeed, Riviere et al. detected six different periodontal
treponemes in the brains in more than 90 % of the 16 AD cases analyzed [53]. In addi-
tion, P. gingivalis-derived LPS was detected in the brains of AD patients [54].
Moderate to severe periodontitis is associated with increased systemic inflammation
characterized by elevated levels of IL-1β, IL-6, and TNF-α and CRP [55]. In fact the
elevation of the CRP in subjects with periodontitis can reach values that are considered
high risk for cardiovascular disease. When these intense host responses associated with
periodontal bacterial infections, the periodontal disease systemic effect was signifi-
cantly increased than when the indexes of periodontal infection and systemic inflam-
mation were absent [56], showing that the host response to the infectious challenge is
of significance [57–59].
Cytokines and LPS are found to consistently stimulate amyloid synthesis in the
brain and induce cognitive impairment [60]. Spirochetes were found to contribute to
amyloid deposition in the brain and cognitive decline [52] and possibly tau pathology
[45], findings consistent with our own studies [45].
In addition to central effects, periodontal-derived pro-inflammatory molecules
[61] and bacterial products may exert their effects by increasing the production of
amyloid peripherally and/or upregulating its transport into the brain. Although
direct evidence for this hypothesis does not exist, several possibilities exist that need
further investigations. Periodontal disease associates with platelet activation [62].
Since platelet activation increases APP proteolysis, periodontal disease-platelet
activation may lead to increased peripheral production of Aβ. Another possible
mechanism that could contribute to the brain amyloid accumulation is the upregula-
tion of the Aβ transport into the brain. Upregulating RAGE by periodontal-induced
inflammatory molecules or bacteria/bacterial products may enhance the Aβ influx
into the brain. It is known that bacterial products and inflammatory molecules can
increase RAGE production [63], and this has been also documented in periodontal
tissue of nondiabetic subjects [64]. In addition, animal models of nondiabetic-
related periodontitis showed increased production of RAGE. AGE is one of the
RAGE ligands, and a positive regulator of RAGE and AGE is increased in serum of
subjects with periodontitis.
In summary, we suggest that periodontal disease may constitute a risk for
AD. Assessing the role of risk factors and their preventive effect in AD pathogenesis
requires longitudinal cohort studies in which clinicians and researchers from medical
and dental fields collaborate. We recognize that these cohort studies are difficult and
expensive to implement. However, the benefits would outweigh the difficulties.
Acknowledgments This work was supported by NIH/NIA grants AG035137, AG032554,

AG022374, and AG13616, AG12101, AG08051, and NIH-HLB HL111724, NIH DE023139-02,
Alzheimer’s Association NIRG-12-173937.
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Periodontal Infections and Rheumatoid
Arthritis 9
Walter A. Bretz, Jose U. Scher, and Steven B. Abramson
9.1 Introduction
Rheumatoid arthritis (RA) is a chronic, destructive, autoimmune disorder character-

ized by autoantibody production and predilection for the joints that can lead to
accelerated morbidity, mortality, and disability [1]. Current understanding of RA
pathogenesis posits that a combination of host predisposition and risk factors is
most likely required for the initiation and sustainability of the inflammatory pro-
cess. However, the exact combination of factors and the precise timing for clinical
manifestations are still insufficiently understood [2]. Mounting evidence suggests
that environmental risk factors such as commensal and infectious microbiota may
contribute to RA in patients with genetic susceptibility [3]. New findings suggest
that germ-free mice, lacking all microbiota, are resistant to development of sponta-
neous autoimmune arthritis [4]. Intriguingly, recent evidence suggests that, in the
right genetic background [5], the presence of certain predisposing factors (i.e., peri-
odontitis (PD) and smoking) [6–9] along with serological markers (i.e., autoanti-
bodies and proinflammatory cytokines) may predict the emergence of RA [10].
Over the last two decades, there have been significant advances in the under-
standing of immunologic and molecular modulators of RA pathogenesis. Chief
among those is the discovery of tumor necrosis factor-α (TNF-α) and related cyto-
kines as main drivers of joint damage and destruction [11]. Furthermore, the use of
W.A. Bretz, DDS, PhD (*)

Department of Cariology and Comprehensive Care, New York University College of
e-mail: wb36@nyu.edu
J.U. Scher, MD
Division of Rheumatology, New York University School of Medicine, New York, NY, USA
New York University Langone Hospital for Joint Diseases, New York, NY, USA
S.B. Abramson, MD
Department of Medicine, New York University School of Medicine, New York, NY, USA

108 W.A. Bretz et al.
anti-TNF therapies has led to substantial improvements in RA outcomes and

improved the quality of life for many patients with the disease. However, up to one
half of subjects with moderate or severe RA still do not respond to these medica-
tions appropriately (or do not improve at all) [12]. The reasons for this discrepancy
remain largely elusive and result in increased patient frustration and unnecessary
exposure to potentially severe side effects (e.g., infections, cancer) and ultimately
lead to substantial health expenditures.
The microbiome represents the totality of microorganisms (and their genes) in a
given biological niche. Microorganisms sharing our body spaces total 100 trillion,
outnumbering human cells by a factor of 10, while the microbiome collective
genome (i.e., metagenome) is 100 times larger than that of the human host.
Microorganisms living in or on us have evolved to adapt to those favorable condi-
tions, extract the required energy, and survive. In exchange, our microbiomes sup-
port physiologic, metabolic, and immunological capacities that have contributed to
our evolutionary success. To better understand these complex biological interac-
tions, the National Institutes of Health have recently launched the Human
Microbiome Project (HMP) [13]. Utilizing revolutionary culture-independent tech-
niques, this project aims to characterize the microbial communities in the human
body and analyze their role in health and disease. Among diseases long considered
to be triggered by microorganisms, both PD and autoimmune processes occupy a
prominent position [14]. In particular, there is mounting evidence for a role of the
oral microbiome in the development and exacerbation of RA. In its long-range stra-
tegic plan for 2015–2019 [15], the National Institute for Arthritis and Musculoskeletal
and Skin Diseases (NIAMS) has established its future research priorities, notably
including the investigation of the human microbiome as a potential modulator for
rheumatic autoimmune diseases [16].
9.2 Role of Periodontitis and Subgingival Microbiome in RA

Pathogenesis
For decades, the presence of PD has been linked to RA pathogenesis [17–18]. There
are remarkable similarities in the histopathologies of PD and RA and strong epide-
miological evidence of co-association between the two [7, 17, 19]. The oral micro-
biome (totality of microorganisms residing in the oral cavity) is one of the most
dense and diverse. Multiple lines of investigation have implicated specific microor-
ganisms in the pathogenesis of PD, a chronic, polymicrobial disease affecting up to
47 % of the population [18], and highly associated with tobacco smoking. In semi-
nal work by Mikuls et al., the presence of PD in patients with RA was associated
with increased joint damage (i.e., higher radiographic scores) [20]. Moreover, exac-
erbation of bone erosion was a notable finding upon co-induction of both PD and
inflammatory arthritis in animal models [21].
An increasing amount of work has now focused on the link between smoking,
PD, oral microbes, and RA. One microbe of interest is the gram-negative anaerobe
Porphyromonas gingivalis. P. gingivalis is both a major cause of PD and unique in
9 Periodontal Infections and Rheumatoid Arthritis 109
its expression of the enzyme peptidylarginine deiminase (PAD). Although not iden-
tical to human PAD (limited to joints and several other tissues), P. gingivalis PAD
shares with the human enzyme the ability to modify arginine residues to citrulline,
catalyzing the formation of citrullinated neo-epitopes that have been directly impli-
cated in RA [22]. RA patients frequently express anti-citrullinated protein antibod-
ies (ACPAs); these are highly specific for RA, strongly associated with disease
severity, and postulated to be pathogenic [23]. The ability of P. gingivalis to express
PAD suggests that P. gingivalis infection could promote and/or exacerbate RA by
facilitating autoantigen presentation and the subsequent expression of disease-
specific autoantibodies, ultimately leading to overexpression of proinflammatory
and arthritogenic cytokines (e.g., TNF-α and interleukin-6 (IL-6)) in the synovium
[24]. Consistent with these speculations, elevated P. gingivalis titers in RA patients
are associated with increases in ACPA [25]. The specific role of oral microbiota-
derived TNF-α in PD pathogenesis has also been extensively documented. For
example, TNF-α augments invasion of P. gingivalis in human gingival epithelial
cells [26]. In alveolar bone resorption (an advanced manifestation of PD), P.
gingivalis-derived LPS is one of the major factors contributing to augmentation of
osteoclastogenesis via induction of TNF-α. Moreover, alveolar bone loss after local
periodontal infection with P. gingivalis is abrogated in TNF-α receptor-deficient
mice [27, 28], while the use of anti-TNF medications significantly decreases bone
loss in a model of PD [29]. We and others have shown increased production of
TNF-α in mice upon co-induction of experimental PD and RA [21, 30]. However,
the role of oral microbiota-induced TNF-α in arthritis pathogenesis remains elusive.
Noticeably, P. gingivalis may not be the only oral microbial pathogen contributing
to RA development. For example, oral bacterial DNA from P. gingivalis, but also
from other organisms, has been found in the synovium of RA patients [31]. For
example, Prevotella nigrescens [21] promotes concomitant dental attachment loss
and erosive arthritis in animal models. Importantly, these phenomena are accompa-
nied by marked production of several proinflammatory cytokines (most notably
TNF-α, IL-1, and IL-6).
Our group has analyzed the periodontal status and subgingival microbiota of new-
onset rheumatoid arthritis (NORA) patients, i.e., those at very early stages of the
onset of RA. We reported that advanced forms of PD are frequently present at the
onset of clinical RA [32]. Further, we utilized high-throughput, culture-independent
DNA sequencing technologies to compare the composition of microbial communi-
ties in subgingival oral biofilms and to establish correlations between levels of bac-
teria and disease phenotypes. The periodontal microbiota of NORA patients was
different from those of controls (Table 9.1). Interestingly, the relative abundance of
the bacterial species P. gingivalis – one of the best-studied periodontopathic bacteria
that have been associated with the autoimmune process in RA – was higher in chronic
RA (CRA) patients vs. controls, mostly due to elevated PD prevalence in this group.
Further, we have observed the presence of other known periodontopathic species
(i.e., Prevotella and Leptotrichia spp.) only in oral biofilms of NORA patients, inde-
pendently of PD severity. These findings suggest that both PD and the presence of
periodontopathic bacteria may promote autoimmunity in RA. These results were
Table 9.1 P. gingivalis, Prevotella, Leptotrichia, and Anaeroglobus species are characteristic of
the NORA subgingival microbiota
Arthritis phenotype Periodontitis
NORA vs. healthy CRA vs. healthy PD vs. no PD
↑Anaeroglobus* ↓Catonnella ↑Anaeroglobus****
↓Corynebacterium* ↓Corynebacterium* ↑Phocaeiola****
↓Streptococcus* ↑Prevotella*
↑Tannerella*
↑Treponema*
↑Porphyromonas*
↑Anaerog_OTU99*** ↑Anaerog_OTU99* ↑Anaerog_OTU99****
↑Leptotrich_OTU87*** ↑Tannerella_OTU13* ↑Prevotella_OTU62****
↑Prevotella_OTU60*** ↓Corynebact._OTU4*** ↑Prevotella_OTU20****
↑P. gingivalis* ↑Treponema_OTU139***
↓Corynebact._OTU4* ↑Tannerella_OTU13***
↑Treponema_OTU32***
↑P. gingivalis***
↓Corynebact._OTU4***
↑Significant increase in NORA or PD; ↓Significant decrease in NORA or PD
OTU operational taxonomic unit, NORA new-onset RA, CRA chronically treated RA
*P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.0005
recently validated in a large case–control study that included US veterans and non-
veterans, utilizing both PD clinical assessments and P. gingivalis-specific primers
[20]. A smaller study reported similar clinical associations in early RA patients, and
a trend toward P. gingivalis increases [33]. Interestingly, in a prospective cohort of
patients with recent-onset RA initiating disease-modifying antirheumatic drug
(DMARD) therapy, presence of self-reported PD correlated with a lower likelihood
of treatment response, while prior visits to a periodontist were associated with a
fourfold increased likelihood of achieving low disease activity [34].
9.3 Oral Microbiota-Induced TNF-α as a Barrier to TNF

Inhibitors (TNFis) Efficacy
TNFis (medications such as adalimumab, etanercept, and infliximab) represent one

of the most significant advances in RA therapy over the last two decades, and they
are widely prescribed to treat severe manifestations of RA. However, and for yet
unclear reasons, a large proportion of patients still do not respond adequately to
these medications [12], leading to advanced disease, disability, and, consequently, a
higher cost to the overall healthcare system. One possibility is that overproduction
of TNF-α in response to oral microorganisms in patients with concomitant RA and
PD may ultimately hamper the activity of TNFi. As a result, and because TNFi dos-
ing is fixed in nature, a substantial proportion of the molecule may actually be con-
sumed in the periodontal domain at the expense of anti-inflammatory responses in
synovial tissue. Our own recent studies, for example, demonstrated that subgingival
microbiota (bacteria residing deep in the periodontal pockets) of RA patients differs
from that of PD patients without RA or healthy controls with respect to the pre-
dominance of specific bacteria (i.e., P. gingivalis, Prevotella, Leptotrichia, and
Anaeroglobus spp.; Table 9.1). This microbiota is known to significantly increase
the periodontal levels of TNF-α [29] and might thereby mitigate the effects of TNFi
and ultimately prevent RA patients from achieving desired clinical outcomes. In
fact, this was recently demonstrated for early RA patients, in whom oral microbi-
ome was predictive of clinical response to methotrexate [35]. It is also conceivable
that what prevents the full effects of TNFi is actually the overall enzymatic activity
(metagenome) of a given oral microbiome (i.e., levels of PAD and/or related
enzymes), and not the relative abundance of a particular microorganism per se.
However, there is a need to better understand the actual pathogenicity of
RA-associated periodontopathic bacteria and the mechanisms underlying these
associations, taking advantage of models to determine the influence of PD on the
efficacy of TNFi treatment for inflammatory arthritis.
9.4 Could Antibiotics and DMARD Treatments for RA

Influence the Subgingival Oral Microbiome?
We conducted proof-of-concept studies looking at the effects of antibiotics and

DMARDs primarily on the gut microbiome and also on the subgingival oral micro-
biome. Patients were sampled for subgingival plaque samples at baseline and 2
months thereafter. Periodontal probing and bleeding scores were recorded for all
teeth and sites at both visits. All patients received a one-time subgingival scaling on
the dentition after baseline collection of subgingival samples in order to disturb the
subgingival microbiota. The effects of DMARDs (prednisone or equivalent) ≤5 mg
daily, methotrexate ≤15 mg/weekly (stable doses for at least 2 months), NSAIDs at
FDA-approved doses, and doxycyclines (100 mg twice a day for the duration of the
trial (2 months) in addition to their DMARD treatment for RA) on the subgingival
microbiota over- and underrepresented in NORA relative to CRA patients and
healthy controls (Table 9.1) were determined. Secondary outcomes included the
effects of these treatment modalities on periodontal parameters. Preliminary evalu-
ation revealed that the combination of doxycyclines and DMARDs (baseline to
2-month results, n = 4) suppressed the genera, and most phylum and overrepresented
species associated with NORA relative to CRA and healthy controls present in sub-
gingival plaque samples, albeit these results, did not achieve statistical significance
probably as result of the low number of participants. These same trends observed
for the microbial flora in the doxycycline plus DMARDs group could not be
observed for the group that used DMARDs only (n = 10). Notably, periodontal prob-
ing depth and bleeding scores were significantly improved at the 2-month visit for
the doxycycline plus DMARD group. These preliminary observations indicate that
in-depth periodontal manipulation via comprehensive scaling and root planing (as it
will be further discussed) plus antibiotics aimed at the periodontal microbiome of
RA patients (in combination with DMARDs) should be further considered in ran-
domized clinical trials (RCTs) of large cohorts of RA patients.
9.5 Background on PD Treatment as Adjuvant for RA

Clinical Outcomes
The combination of scaling and root planing (SRP) remains the mainstay of PD
treatment. If in fact PD is at least partially responsible for the systemic inflamma-
tory process found in RA, then it follows that scaling and root planing should help
ameliorate synovitis and disease outcomes. A systematic review and meta-analysis
conducted in 2014 revealed that based on clinical and biochemical markers, scaling
and root planing in patients with periodontal diseases and RA showed improve-
ments in markers of disease activity in RA [36].
Studies have consistently reported RA clinical improvement after nonsurgical
PD treatment. One of the first such trials evaluated disease outcomes in two RA
groups: a cohort already receiving DMARDs as part of their care and the other
group receiving combination of DMARDs plus TNFi [37]. Each group was ran-
domized to either SRP or no PD treatment. Patients who received SRP showed a
significant decrease in both RA disease activity and serum TNF-α levels at week 6
compared to those without PD therapy. Curiously, TNFi therapy also resulted in a
significant improvement in clinical PD parameters. These findings have been inde-
pendently validated in populations from different geographic regions [38–41]. In a
more recent prospective study on RA patients initiating anti-TNF treatment, it was
shown that the presence of persistent PD hampered the clinical response to TNFi,
since only those patients without established PD achieved good RA outcomes [42].
Despite these studies, the use of concomitant TNFi and nonsurgical PD treat-
ment in RA clinical outcomes, and possibly periodontal microbiota further modula-
tion via the use of antibiotics, are yet to be investigated. This should be emphasized
in studies utilizing high-throughput DNA sequencing in an attempt to improve tar-
geted therapies for RA.
Conclusions
Periodontal diseases are highly prevalent in patients with RA. Mounting evi-
dence suggests that, in the right genetic background, the presence of periodontal
diseases and additional predisposing factors (e.g., smoking, one of the best char-
acterized risk factors for PD) along with serological markers may predict the
emergence of RA. In-depth knowledge of the subgingival microbiome associated
with NORA may allow for the study of targeted therapies to curtail periodontal
infections that could ameliorate symptoms of RA. The use of anti-TNF and other
biologic therapies (i.e., anti-IL-6, CTLA4-Ig, etc.) has led to substantial improve-
ments in RA outcomes and improved the quality of life for a large fraction of
patients with the disease. However, the role of oral microbiota-induced TNF-α
(and related cytokines) in arthritis pathogenesis remains elusive. The use of anti-
biotics and antirheumatic therapies may have some effect on the subgingival
microbiome. Treatment of periodontal infections with nonsurgical approaches
and antibiotics may be a readily modifiable strategy for the treatment of RA
patients. A large RCT will be therefore required to address this highly relevant
question by incorporating periodontal microbiota analyses/manipulation and
RA/PD outcomes in order to better understand the biologic implications between

PD and RA. Taken together, these studies may support the notion that PD may
affect treatment efficacy in patients with RA and that a dual, combination
approach may be warranted to potentially increase the clinical response of vari-
ous immunosuppressive drugs.
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Summary and Possible Future Directions
10
Angela R. Kamer and Ronald G. Craig
As detailed in the preceding chapters, independent of known confounders including

age, gender, and smoking, periodontitis has been significantly associated with type
2 diabetes mellitus, atherosclerosis and atherosclerotic complications, renal disease
and adverse outcomes of renal hemodialysis maintenance therapy, preterm labor,
some forms of pneumonia, Alzheimer’s disease, and rheumatoid arthritis. The
strength of the association varies with the disease but appears to be strongest with
increasing periodontitis severity. Periodontitis has also been forwarded as a cause or
as a risk factor for atherosclerosis and atherosclerotic complications such as myo-
cardial infarction, chronic renal disease, preterm labor, some forms of pneumonia,
Alzheimer’s disease, and rheumatoid arthritis. In addition, the association in some
cases may be bidirectional since some systemic diseases have also been reported to
promote periodontal disease prevalence and severity such as diabetes mellitus and
ESRD patients on hemodialysis maintenance therapy.
The question therefore arises, what biologic mechanism(s) underlie the associa-
tion between periodontitis and this array of seeming non-related systemic diseases
and conditions? Central to all of the diseases discussed in this volume is the role
of systemic inflammation. Moderate to severe periodontitis is associated with the
appearance of Gram-negative assacharolytic anaerobic bacteria within the periodon-
tal microbial biofilm. The loss of periodontal connective tissue attachment and the
A.R. Kamer, DMD, MS, PhD (*)

Department of Basic Sciences and Craniofacial Biology, New York University

118 A.R. Kamer and R.G. Craig
formation of the periodontal pocket further increase the periodontopathic bacterial

load and the epithelial surface area in contact with the biofilm. In response, an intense
innate and adaptive immune response is generated that increases local and systemic
levels of proinflammatory cytokines such as TNF-α, IL-1, and Il-6. Increased systemic
levels of proinflammatory cytokines in turn generate an acute phase response that
includes increased serum glucose, dyslipidemia, and elevation in systemic markers of
inflammation such as CRP. The contribution of periodontitis to systemic inflammation
and the central role that inflammation plays in each of the systemic diseases discussed
in this volume make this mechanism particularly attractive.
However, evidence has also been presented in this volume for other biologic
mechanisms in addition to increased systemic inflammation. Direct seeding of peri-
odontopathic bacteria into non-oral sites has been reported for atherosclerosis, pre-
term labor, Alzheimer’s disease, pneumonia, and rheumatoid arthritis. Molecular
mimicry of bacterial GroEL and human heat shock protein 60 expressed on arterial
endothelial cells during endothelial dysfunction have been forwarded as a cause of
cross-reactive antibody production in atherosclerosis. The expression of peptidylar-
ginine deiminase by P. gingivalis permits the conversion of arginine to citrulline and
the generation of citrullinated epitopes. The expression of anti-citrullinated protein
antibodies is highly specific for rheumatoid arthritis, is associated with disease
severity, and has been forwarded as pathogenic for rheumatoid arthritis. Advanced
glycation end products in poorly controlled diabetes have been forwarded as a
mechanism for the increased prevalence and severity of periodontitis observed in
diabetic patients, while depressed immune responsiveness in hemodialysis patients
has been suggested to underlie the increased prevalence and severity of periodontitis
observed in ESRD patients. In view of the above mechanisms, it is entirely possible
that some mechanisms proposed for the association of moderate to severe periodon-
titis with systemic disease in this volume need not be mutually exclusive.
Of greater importance to the practicing clinician is whether effective periodontal
therapy can alter the course of systemic disease. As discussed in this volume, peri-
odontal therapy for patients with moderate to severe periodontitis has been shown
to decrease markers of systemic inflammation including CRP, decrease measures of
endothelial dysfunction and carotid intima–medial thickness, aspiration pneumo-
nia, and possibly blood glucose levels. However, to date, no large randomized con-
trolled clinical trials have been able to demonstrate an effect of periodontal therapy
on hard end points such as preterm low-birth-weight infants, myocardial infarction,
glycemic control, or mortality.
As discussed in Chap. 6, many possible reasons can be forwarded for the inability
of periodontal intervention trials to show an effect on hard end points. The contribu-
tion of periodontitis to various systemic diseases may not be of sufficient magnitude
or may be swamped by the contribution of confounding risk factors such as obesity
or smoking. The timing of the intervention may be critical and may need to begin
prior to the appearance of clinical symptoms. This is methodologically difficult
to achieve with progressive complex diseases that evolve over prolonged time spans.
The effectiveness of the periodontal intervention is also critical. As described in Chap. 2,
effective periodontal therapy is presently based upon meticulous debridement of the
10 Summary and Possible Future Directions 119
pathogenic biofilm by the patient and health care professional and in practice requires
periodontal recall and maintenance. Providing a single or limited periodontal inter-
vention may not be effective. Therefore, additional well-designed randomized clinical
trials that build upon the lessons learned from earlier intervention trials need to be
conducted to resolve whether effective periodontal therapy can alter clinically impor-
tant hard end points in systemic diseases.
Based on these considerations, it may be entirely possible that periodontal inter-
ventions may never show a definitive effect on hard end points of systemic disease.
However, periodontal diseases are treatable and therefore present a reversible source
of systemic inflammation. In addition, the treatment of periodontal diseases offers
health benefits of their own. Therefore, consideration of the potential contribution
of periodontal diseases to systemic disease risk appears appropriate.
Acknowledgments This work was supported by NIH DE023139-02, Alzheimer’s Association

NIRG-12-173937.
Index
A Atherosclerotic vascular diseases (ASVD)

Advanced glycation end products (AGEs), 30 ASVD and periodontitis, 43–44
Alzheimer’s disease (AD), 2, 117, 118 biologic mechanisms, 44
clinical diagnosis, 94–95 Framingham risk, 40
incidence, 93 healthy diet and exercise plan, 40
late onset/sporadic AD (LOAD), 93 hypercholesterolemia, 40
management, 95 infection, 45–46
pathogenesis inflammation, 46–47
amyloid β-peptide, 96 atheroma enlargement, 42
brain amyloid accumulation, 97 cholesterol, 41, 42
cytokines, 98 C-reactive protein (CRP), 43
genetic polymorphisms, 98 endothelial cells, 41
inflammatory hypothesis, 97 endothelial dysfunction, 41
low-density lipoprotein receptor-related extracellular matrix deposition, 42–43
protein 1 (LRP1), 97 foam cell formation, 42
peripheral inflammation, 98 high-density lipoproteins (HDL), 42
peripheral inflammatory mechanisms, hyperlipidemia, 41
99–100 intracellular non-degraded
senile plaques, 98 cholesterol, 42
and periodontitis lipid accumulation, 41
bacteremia, 100 low-density lipoprotein (LDL), 42
cytokines and LPS, 101 matrix metalloproteinases (MMPs), 43
infection-induced effects, 101 pro-inflammatory mediators, 41
monocytes, 101 smooth muscle cell proliferation, 41, 42
RAGE production, 102 thrombosis and/or intraplaque
prevalence, 93 hemorrhage, 42
American Academy of Periodontology thrombus formation (embolism), 43
(AAP), 6 molecular mimicry, 46
American Association of Clinical mortality, 39
Endocrinologists (AACE), 27 periodontal therapy, 47–48
Aspiration pneumonia prevention, 39
oral care risk factor, 47
chlorhexidine (CHX), 87 vascular occlusion, 39
edentulous patients, 88
oral interventions, 87
oral health C
nursing home residents, 87 Carotid intima-media thickness (CIMT), 48
oral microflora, 86 Centers for Disease Control (CDC), 6
Atherosclerosis, 2, 117, 118 Chlorhexidine (CHX), 87

Periodontal Diseases, DOI 10.1007/978-3-662-49699-2
122 Index
Chronic kidney diseases (CKD) HbA1c, 23, 26

end-stage renal disease (ESRD) high-sensitivity C-reactive protein (hsCRP)
causes, 55 levels, 27
incident counts and adjusted rates, 56 hyperglycemia, 25
incident rate, 55 insulin resistance, 28
medical complexity, 54 insulin therapy, 22
mortality, 54 ketoacidosis, 21
periodontitis ketones, 21
management, for CKD patient, 61–62 kidney dysfunction, 31
prevalence and severity, 59–60 long-term complications, 20
risk factor, 60–61 matrix metalloproteinases (MMPs), 30
renal hemodialysis, 54 metabolic syndrome, 24
and renal replacement therapies microvascular and macrovascular
donor kidneys, 58 complications, 26
glomerular filtration rate (GFR), 54 monocytic hypersecretory phenotype, 30
heparin, 55 motor and sensory nerve conduction
histocompatibility leukocyte antigen velocity, 26
(HLA) complexes, 57 multivariate risk analysis, 29
immune suppression, 58 neuropathy, 26
incident and prevalent patient counts, 56 NHANES III database, 27
patient’s circulatory system, 55 NHANES III study, 29
peritoneal dialysis, 55 ominous octet, 22
renal hemodialysis, 55, 56 oral changes, 27
transplant survival rates, 58 oral inflammation, 30
systemic inflammation, 58–59 osmotic and oxidative stress, 25
pancreatic autoimmune β-cell
destruction, 21
D pathophysiological abnormalities, 23
Diabetes mellitus periodontal wound healing, 29
advanced glycation end products (AGEs), 30 physical activity and dietary changes, 20
AGE-RAGE interactions, 28 prevelance, 20
bacterial burden, 30 proteinuria, 31
bacterial infections, 31 retinopathy, 29
CARE study, 27 screening, 22–24
categories, 24 self-monitoring of blood glucose
chronic periodontal inflammation, 30 (SMBG), 26
classic signs and symptoms, 22 serum CRP levels, 28
classification, 21 therapeutic strategies, 31–32
clinical management TNF-α, 31
dental considerations, 33
medical considerations, 33–34
complication, 25 E
criteria, 23, 24 Endothelial dysfunction, 48
cytokine activation, 25 End-stage renal disease (ESRD), 31
degenerative vascular changes, 30 causes, 55
Diabetes Control and Complications Trials incident counts and adjusted rates, 56
(DCCT), 26 incident rate, 55
disability and death, 27
DNA analysis, 28
epidemiologic studies, 29 F
FPG, 23 Fasting plasma glucose (FPG), 23
gestational diabetes mellitus (GDM), 21 Flurbiprofen, 16
Index 123
G nursing-home associated pneumonia

Genome-wide studies, 9–10 (NHAP), 84
Glucosyltransferase-6 gene, 10 pathogenesis, 84–86
Gram-negative anaerobic species, 2, 117
Gram-negative assacharolytic anaerobic
bacteria, 13 P
Gram-negative cocci and rods, 11 Periodontal diseases, 1–3
classification and prevalence, 6–7
dental biofilm
H arachidonic acid cascade, 12
High-density lipoproteins (HDL), 42 asaccharolytic bacteria, 11
Hypercholesterolemia, 40 bone resorption pathways, 13
exopolysaccharide matrix, 10
F. nucleatum species, 11
I gingival epithelial cells, 12
Insulin Resistance Atherosclerosis Study gingival epithelium, 13
(IRAS), 28 Gram-negative cocci and rods, 11
Gram-positive aerobic cocci, 11
Gram-positive aerobic saccharolytic
L bacteria, 11
Low-density lipoprotein (LDL), 42 growth factors and metabolites, 10
host matrix metalloproteinase, 13
metabolic and nutrient
M requirements, 11
Matrix metalloproteinases Nod receptors, 12
(MMPs), 16, 43 Peyer’s patches, 12
Metabolic syndrome, 24 salivary and bacterial proteins, 11
scaffold, 10
toll-like receptors (TLRs), 12
N host subversion
Neutrophils, 14 bystander bacteria, 14
Nod receptors, 12 Gram-negative assacharolytic anaerobic
Non-steroidal anti-inflammatory bacteria, 13
medications, 16 matrix metallo-proteinases, 14
Nursing-home associated pneumonia neutrophils, role of, 14
(NHAP), 84 peptides and amino acid, 13
P. gingivalis, 14
management, 15–17
O pathogenesis, 2
Oral health and pneumonia susceptibility
community-acquired pneumonia chronic adult periodontitis, 8
antibiotics, 82 clinical significance, 10
bacterial pneumonia, 81 DNA sequence, 9
chest radiography, 82 gene polymorphisms, 9
clinical symptoms, 82 genetic component, 8
etiologic agents, 82 genome-wide studies, 9–10
immunosuppression, 81 gingival inflammation, 9
morbidity and mortality, 81 gingival vasoconstriction, 8
risk factor, 82 glucosyltransferase-6 gene, 10
treatment, 82 risk factors, 7
HAP and HCAP single nucleotide polymorphisms, 9
aspiration pneumonia, 84, 86–88 smoking, 7–8
124 Index
Periostat®, 16 environmental risk factors, 107

Peyer’s patches, 12 host predisposition and risk factors, 107
Pneumonia, 117, 118 microbiome, 107
Preterm labor (PTL), 118 periodontitis and subgingival microbiome
alcohol consumption, 70 antibiotics and DMARD
clinical trials, 70 treatments, 111
concomitant medication, 75 anti-TNF medications, 109
dental plaque, 71 bone erosion, 108
drug use, 70 new-onset rheumatoid arthritis (NORA)
genetic abnormalities, 76 patients, 109
gestational age, 72 peptidylarginine deiminase
gum inflammation, 75 (PAD), 109
inflammation and gum swelling, 71 scaling and root planing (SRP), 112
inflammatory gum disease, 68 TNF-α, 107, 110
inflammatory marker C-reactive TNFis, 110–111
protein, 75
inflammatory markers, 68
low birth weight incidence, 71 S
meta-analysis, 69–70, 73–74 Scaling and root planing (SRP), 112
microbial infections, 68 Self-monitoring of blood glucose
nonalcoholic antiseptic mouthwash, 72 (SMBG), 26
observational studies, 69 Single nucleotide polymorphisms, 9
oral hygiene, 72
outcome measures, 72
progesterone treatment, 75 T
smoking, 70 Toll-like receptors (TLRs), 12
subject selection criteria, 75 Type 2 diabetes mellitus, 2, 117
treatment, 72, 75
US study, 71
U
United Kingdom Prospective Diabetes Study
R (UKPDS), 26
Retinopathy, 29 United States National Health and Nutrition
Rheumatoid arthritis (RA), 2, 117, 118 Examination Survey (NHANES), 6

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A Clinician’s Guide to

ISBN 978-3-662-49697-8 ISBN 978-3-662-49699-2 (eBook)

Library of Congress Control Number: 2016940199

© Springer-Verlag Berlin Heidelberg 2016

Printed on acid-free paper

This Springer imprint is published by Springer Nature

1 Introduction and Overview of the Systemic Effects of Periodontal

Steven B. Abramson, MD Department of Medicine, New York University School

Frank A. Scannapieco, DMD, PhD Department of Oral Biology, State University

Ronald G. Craig and Angela R. Kamer

R.G. Craig, DMD, PhD (*)

© Springer-Verlag Berlin Heidelberg 2016 1

To meet this need, A Clinician’s Guide to Systemic Effects of Periodontal

1. Summarize the current research on the effects of periodontal diseases on

The volume is not meant to be an exhaustive discussion on the systemic effects of

The following Chaps. 3, 4, 5, 6, 7, 8, and 9 discuss the association of periodontal

Acknowledgments This work was supported by NIH DE023139-02, Alzheimer’s Association

Our understanding of the pathogenesis of periodontal diseases has greatly pro-

R.G. Craig, DMD, PhD

© Springer-Verlag Berlin Heidelberg 2016 5

2.2 Classification and Prevalence of Periodontal Diseases

Periodontal diseases present a continuum of inflammatory conditions that afflict the

non-Hispanic blacks which were followed by Asian-Americans. Non-Hispanic

2.3 Susceptibility to Periodontal Diseases

The question therefore arises, what determines susceptibility to periodontal dis-

periodontitis as well as other chronic diseases including atherosclerosis. The num-

in the glucosyltransferase-6 gene as being associated with aggressive periodontitis

2.4 A Microbial Profile Shift Occurs with the Transition

Regardless of an individual’s disease susceptibility, a dental biofilm is required for

other Gram-negative anaerobic asaccharolytic species is associated with periodon-

2.5 Host Response to Dental Biofilm Development

Within the gastrointestinal tract, the presence of teeth presents an anatomically

In disease-susceptible individuals, the emergence within the biofilm of Gram-

2.6 Subversion of the Host Response in Periodontitis

The Gram-negative assacharolytic anaerobic bacteria residing within the periodon-

2.7 Management of Periodontal Diseases

health intervention. The high prevalence of periodontitis within the population

Periodontitis is currently viewed as a polymicrobial complex disease possibly

M.E. Ryan, DDS, PhD (*)

© Springer-Verlag Berlin Heidelberg 2016 19

3.2 Diabetes: Presentation, Prevalence, Diagnosis,

Diabetes mellitus is a systemic endocrine disorder driven primarily by a dysregula-

Table 3.1 Diabetes mellitus Type 1 diabetes

Table 3.2 Classic signs and Polydipsia, polyuria, nocturia, polyphagia

African Americans, Latinos, Asian Americans, Pacific Islanders, and Native

Fig. 3.2 Pathophysiological abnormalities targeted by currently available antidiabetic medica-

Table 3.3 Criteria for the diagnosis of diabetes [9]

Early diagnosis facilitates optimal management and a significant reduction in long-

Table 3.6 Testing for type 2 diabetes in asymptomatic children [9]

Table 3.7 Classic complica- Macrovascular disease (accelerated atherosclerosis)

Table 3.8 Factors Duration of diabetes

hyperglycemia. Reduced motor and sensory nerve conduction velocity associated

3.3 Common Ground Between Periodontal Diseases

3.4 The Impact of Diabetes on Periodontal Tissues

Fig. 3.3 Poor glycemic Hyperglycemia

Clinical attachment loss

Periodontitis initiated by infection and driven by inflammation is a known compli-

3.5 The Impact of Periodontitis on Diabetes

3.6 Therapeutic Strategies

Periodontitis is often referred to as the world’s most common chronic inflamma-

maintenance regimen. As oral healthcare providers will see increasing numbers of

3.7 Clinical Management of the Diabetic Patient

3.7.1 Dental Considerations