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Jo-Anne Jones, RDH
President of RDH
Connection Inc.;
International Lecturer
Lorne M. Golub,
DMD MSc, MD
(Honorary)
SUNY Distinguished
Professor; Department
of Oral Biology and
Pathology; Stony
Brook School of
Dental Medicine, SUNY
Ying Gu, DDS, PhD
Associate Professor;
Department of General
Dentistry; Stony Brook
School of Dental
Medicine
Maria Emanuel
Ryan, DDS, PhD
Professor and Chair;
Department of Oral
Biology and Pathology;
Stony Brook School of
Dental Medicine
Denis Masse, RDH
Program Director;
International
Dental Institute
Jacinthe
Simard, RDH
In-office Consultant;
International
Dental Institute
16 Is Periodontitis
an Infectious
or an Inflammatory
Disease?
T
he cornerstone of the dental hygiene profession is the application of critical thinking. Critical thinking has been defined as
“the use of self-correction and monitoring to
judge the rationality of thinking. It is the ability to challenge one’s own thinking.”1
Consider the following question: are we
treating periodontal disease as an infectious
disease or as an inflammatory disease? If
periodontitis is simply an infectious disease,
one would assume that through the employment of judicious therapeutic measures to reduce the microbial burden at regular intervals, great inroads would have been made in
the eradication of the disease. An infectious
disease is defined by the World Health Organization (WHO) as being ‘caused by pathogenic microorganisms, such as bacteria, viruses, parasites or fungi and may be spread,
directly or indirectly, from one person to another. 2 As dental professionals, we realize
this is simply not the case; a recent CDC report provides the following data related to
prevalence of periodontitis in the U.S.: 47.2
percent of adults aged 30 years and older
have some form of periodontal disease. Periodontal Disease increases with age, 70.1 percent of adults 65 years and older have periodontal disease. 3 We now know that
perio­dontal disease is one of the most prevalent non-communicable chronic diseases in
our population, similar to cardiovascular disease and diabetes.4
We have treated dental caries as a bacterial
infection and we are seeing a strong response
to our therapeutic interventions. Conversely,
are we achieving our therapeutic endpoints by
treating periodontal disease as an infection?
Mechanical debridement, employment of antimicrobials and short-term systemic antibiotic
regimens, have simply not sustained the desired therapeutic endpoints we had hoped for.
A meta-analysis to study the efficacy of systemic antibiotics was conducted by CunhaCruz et al. 5 and published in 2008. Historically,
systemic
antibiotics
have
been
recommended for the treatment of destructive
periodontal disease. However, Cunha-Cruz
found a lack of association between systemic
antibiotics and tooth loss in adults, coupled
with the growing concerns about antibiotic resistance, reinforcing the concern that prescription of antibiotics for chronic destructive periodontal diseases should only be made with
extreme caution. 5 (Note in the same statistical
study, sub-antimicrobial doxycycline, i.e.
Periostat, was found to be associated with decreased tooth loss.)
The late 80s began to delve into the aspect
of a destructive host response as a causative
etiologic factor in periodontal disease. A number of landmark studies began to draw the
conclusion that periodontal disease was an inflammatory disease.6 These papers, and literally hundreds of related papers, brought to the
forefront the realization that it was the inflammatory response, followed by the acquired immune response, that drove the pathogenesis of
periodontal tissue destruction.7
Emerging data suggests that periodontal
pathogens, that are more or less universally
present in low numbers, use inflammation to
provide an environment to foster their
growth. The implication is that the patholog-
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Research has shown that periodontal disease is
associated with several other diseases. For a long time
it was thought that bacteria was the factor that linked
periodontal disease to other diseases in the body;
however, more recent research demonstrates that
inflammation may be responsible for the association.
Therefore, treating inflammation may not only help
manage periodontal diseases but may also help with the
management of other chronic inflammatory conditions.
Source: www.perio.org/consumer/other-diseases
ic biofilm “emerges” as a result of inflammation.7 Traditional means of identifying active
disease have relied upon the measurement of
pocket depths, which are often indicators of
past disease, and not necessarily current active disease. Therefore, the focus should be
on inflammatory biomarkers in addition to
longitudinal measures of CAL.
The transition from infectious disease to
inflammatory disease was redefined by the
American Academy of Periodontology
(AAP) in 2008. Today, the AAP refers to
periodontitis as an inflammatory disease
with far reaching destructive effects on systemic health. “For a long time, it was thought
that bacteria was the factor that linked perio­
dontal disease to other disease in the body;
however, more recent research demonstrates
that inflammation may be responsible for the
association. Therefore, treating inflammation (and the resultant increase in host-derived, tissue-destructive enzymes, e.g., collagenase plus other MMPs) may not only help
manage periodontal diseases, but may also
help with the management of other chronic
inflammatory conditions.”8
Tissue Destruction Mediated
by Inflammation
An article published in TIME magazine, titled ‘The Secret Killer’, positions the acute
inflammatory response as a lifesaver that initially enables our bodies to fend off bacterial, viral and parasitic invasions.9 The very
moment any one of these intruders enter, a
well-functioning immune system will react
and engulf foreign invaders, aiding in con-
trol of the inflammatory response. Under
normal conditions, the process subsequently
subsides and our bodies are then given the
chance to heal. However, when in the presence of a variety of inflammatory diseases
associated with periodontitis (e.g. Crohns
disease, rheumatoid arthritis, CVD), this
process is not “resolved”, then prolongation
of the inflammation leads to destruction of
the host tissues.
One of the most widely studied topics of
medical research today is the destruction
caused by the inflammatory pathway when a
transient infection becomes chronic. The
very thing that will perform well with a transient infection can literally turn the body
against itself when the inflammation becomes
chronic. Today’s population is subjected to
the attributes of a Western lifestyle, such as a
diet high in sugars and saturated fats, accompanied by little or no exercise, making it far
easier to sustain chronic inflammation.9
The role of chronic inflammation and its association with today’s most prevalent diseases, such as cardiovascular disease, Alzheimers, cancers, diabetes and autoimmune
disorders, are well documented.10 Coronary
Artery Disease (CAD) remains the number
one cause of death in the world. While traditional risk factors partially account for the
development of CAD, chronic inflammation
has been postulated to play a role in the development and propagation of this disease. A
systematic review was carried out by Roifman
et al. and published in the Canadian Journal
of Cardiology. The purpose of this systematic
review was to determine if patients with
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es and the increased risk of colon carcinoma.
The longer the inflammation persists, the
higher the risk of associated carcinogenesis.15 The chronic inflammatory states associated with infection and irritation may lead to
environments that foster genomic lesions and
tumor initiation.16
Figure 1. Chronic Inflammatory Process.
(Acknowledgment Dr. LM Golub)
Figure 2. Sub-antimicrobial Dose Doxycycline.
18 chronic inflammatory diseases have higher
rates of cardiovascular disease. The results
indicated that patients with chronic inflammatory conditions are at elevated risk for the
development of CAD.11 Chronic inflammation is now accepted as playing a potentially
important role in the promotion of atherosclerosis, a main cause of CAD.12 In this regard, chronic periodontitis is a very common
chronic inflammatory disease, which is increasingly being recognized as having an association with, and a potential causal relationship to, coronary artery disease.13,14
A substantial body of evidence supports
the conclusion that chronic inflammation can
predispose an individual to certain types of
cancer, as demonstrated by the association
between chronic inflammatory bowel diseas-
Treating Periodontal Disease
as an Inflammatory Disease
Do we really understand the far reaching destruction of inflammation on the entire body?
If so, are we treating periodontal disease as it
has been defined by leading authorities as an
inflammatory disease?
The foundational characteristics of all inflammatory diseases is the up-regulation of
cytokines, prostaglandins, MMPs (i.e. hostderived, tissue-destructive matrix metalloproteinases), reactive oxygen species, etc.
The only apparent difference between an inflammatory response in these diseases, such
as rheumatoid arthritis, atherosclerosis,
Crohn’s and periodontal disease, is the anatomical location.
Periodontal disease is a chronic inflammatory disease resulting in alveolar bone loss.
The release of excessive MMP-8 or collagenase (as well as other less prominent MMPs,
i.e. MMP-13, MMP-12, plus other proteinases) is a key event in the pathogenesis of periodontal disease. Collagen forms 60 percent
of the gingival tissues and the periodontal
ligament. Moreover, 90 percent of the organic matrix (living part) of bone is collagen; calcium phosphate crystals are imbedded within
this collagenous matrix to provide the mineral (hard) part of this tissue. The destruction of collagen in all the periodontal tissues
is largely mediated by elevated MMP levels
attacking the living organic matrix.
A major event in the link between local
periodontitis and relevant systemic/medical
conditions is the release, from the inflamed
periodontal tissues of inflammatory mediators into the bloodstream, which subsequently travel to the liver. The following cascade of
events illustrates how chronic inflammation
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plays a strong etiologic role in the exacerbation of a stroke or a myocardial infarction.
Once inflammatory mediators are present in
the blood (i.e. derived from the inflamed gingiva), the liver is stimulated to produce acute
phase proteins, which are diagnostic markers
and mediators of inflammatory disease; one
being C-reactive protein or CRP (Figure 1).
To add insult to injury, LDL (low density lipoprotein) cholesterol, when oxidized by the
inflammatory response, then forms a chemical reaction with CRP. The end result is a
complex of oxidized LDL combined with
CRP, which is taken up by macrophages in
the atheroma. These macrophages differentiate into foam cells, which is characteristic of
this lipid-laden plaque in the arteries. They
are an indication of plaque build-up in atherosclerosis, which is commonly associated
with increased risk of heart attack and stroke.
The foam cells, in turn, release MMP’s, such
as MMP-8, also known as collagenase. Collagenase’s primary function is to break-down
collagen. The collagen rich protective cap,
which encapsulates the atherosclerotic
plaque, is now in great danger. The protective
cap destroyed by collagenase results in rupture, thrombosis, followed by stroke or a myocardial infarction (heart attack).
A Call to Action
We can no longer afford to ignore the impact
of the most common chronic inflammatory
disease known to mankind; periodontitis.
The consequence of relentless ongoing periodontal inflammation makes healing impossible and systemic disease more likely.
The human body is continually destroying
old collagen, followed by a renewal process of
normal turnover. In chronic inflammatory
disease, collagenases, particularly MMP-8,
become excessive. The repair process is halted. Until the cessation of inflammatory response, we are at a standstill in our treatment
progress, resulting in further destruction and
unpredictable outcomes.
What if we could slow down the breakdown
of collagen or somehow inhibit the production of collagenase to an acceptable level?
In research conducted at Stony Brook on
incidence (%) of adverse reactions
in periostat clinicals trials
Headache
Common Cold
Flu Symptoms
Tooth Ache
Periodontal Abscess
Tooth Disorder
Nausea
Sinusitis
Injury
Dyspepsia
Sore Throat
Joint Pain
Diarrhea
Sinus Congestion
Coughing
Sinus Headache
Rash
Back Pain
Back Ache
Menstrul Cramps
Acid Indigestion
Pain
Infection
Gingival Pain
Bronchitis
Muscle Pain
periostat
20 MG bid
(N=213)
Placebo
(N=215)
55 (26%)
47 (22%)
24 (11%)
14 (7%)
8 (4%)
13 (6%)
17 (8%)
7 (3%)
11 (5%)
13 (6%)
11 (5%)
12 (6%)
12 (6%)
11 (5%)
9 (4%)
8 (4%)
8 (4%)
7 (3%)
4 (2%)
9 (4%)
8 (4%)
8 (4%)
4 (2%)
1 (≤1%)
7 (3%)
2 (1%)
56 (26%)
46 (21%)
40 (19%)
28 (13%)
21 (10%)
19 (9%)
12 (6%)
18 (8%)
18 (8%)
5 (2%)
13 (6%)
8 (4%)
8 (4%)
11 (5%)
11 (5%)
8 (4%)
6 (3%)
8 (4%)
9 (4%)
5 (2%)
7 (3%)
5 (2%)
6 (3%)
6 (3%)
5 (2%)
6 (3%)
Table 1. Periostat Product Monograph Incidence
(%) of Adverse Reactions.
collagen-destruction mechanisms and perio­
dontal disease, Golub and his colleagues
made an unexpected discovery; namely, that
tetracyclines, a class of drugs that had been
recognized only as antibiotics, were unexpectedly found to block collagenase in mammals.6 This exciting discovery led to further
research to develop a formulation of doxycycline that would inhibit collagenase (MMP-8)
and other MMPs at a blood level so low that it
would NOT perform as an antibiotic (Figure
2). The sub-antimicrobial level would eliminate the typical antibiotic side effects (Table
1). The drug today is known as, and prescribed under the trade name, of Periostat®
(Figure 3). Over 10 million prescriptions have
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Figure 3.
been written in the U.S. alone,
and it is the most widely prescribed drug for treating periodontal disease in the world.
The American Dental Association (ADA) Council on
Scientific Affairs published
the
following
statement;
“Periostat® has been shown
to help stop the progression of
periodontitis when used as directed as an adjunct to scaling
and root planing, in a conscientiously applied program of
oral hygiene and regular professional care.”
[Note: scientifically, Periostat®
is described as SDD or sub-antimicrobial-dose doxycycline.]
The science found in the following doubleblind clinical studies on patients with periodontitis, and published in leading journals,
is both extensive and compelling comparing
SRP + SDD versus SRP + placebo;
• Significantly more effective than SRP +
placebo with no antibiotic side-effects.17-20
• 75 percent fewer teeth lost than patients
treated with SRP + placebo. 21
• 8 0-90 percent reduction of “active” pockets21–27; “active” pockets are defined as
those which get deeper with time.
• No “rebound” effect.17,28
• 50-60 percent reduction of biologic mediators of tissue breakdown and bone resorption (i.e., MMP-8/collagenase, MMP-9, IL1ß).17,29
• In rapidly progressing periodontitis, adjunctive SDD (versus adjunctive placebo) produced a 73 percent reduction in “active”
pockets; combined with two to three times
greater mean attachment gain (i.e. 2.2 mm. vs.
0.8 mm); and significant reduction of
BOP.18,24,25
Who Would Benefit from SDD?
22 With the large baby-boomer cohort aging,
our dental hygiene client population is expe-
riencing a rapid increase in diabetes, cardiovascular disease and other prevalent diseases, all with a common denominator; the
inflammatory pathway. The success of low
dose or subantimicrobial dose doxycycline
(SDD), as the first-ever systemically administered collagenase inhibitor drug approved by
the U.S. FDA and by Health Canada for periodontal disease, has also made a resounding
impact on other inflammatory mediated diseases. As expected, this has gained significant attention from the medical community.
Diabetes
Consider the diabetic patient; more than one
in four Canadians lives with diabetes or prediabetes. This will rise to more than one in
three by 2020. 30 Chronic periodontitis is
prevalent and more severe in the diabetic patient. A six-month, multicenter, randomized
clinical trial was conducted on participants
who had type two diabetes. All were taking
stable doses of medications, HbA1c levels between seven percent and nine percent (i.e.
poorly controlled hyperglycemia) and untreated chronic periodontitis. Five hundred
and fourteen participants were enrolled with
the treatment group (n=257) receiving SRP
plus chlorhexidine oral rinse at baseline and
supportive periodontal therapy at three and
six months. The control group (n=257) received no treatment for six months. Enrollment was stopped early because of futility.
At six months, mean HbA1c levels in the
periodontal therapy group increased 0.17
percent compared with 0.11 percent in the
control group, with no significant difference
between groups. The study concluded that
nonsurgical periodontal therapy did not improve glycemic control in patients with type
two diabetes and moderate to advanced
chronic periodontitis. These findings do not
support the use of nonsurgical periodontal
treatment in patients with diabetes for the
purpose of lowering levels of HbA1c. 31
However, drastically different results were
seen in a separate three-month, randomized
placebo-controlled pilot clinical trial, which
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included 45 patients with long-standing type
two diabetes and untreated chronic periodontitis. These subjects received conventional nonsurgical periodontal therapy combined with either:
(a) a three-month regimen of sub-antimicrobial-dose doxycycline (SDD), or
(b) a two week regimen of antibiotic therapy, or
(c) placebo.
Note that all subjects were taking stable doses of oral hypoglycemic medications and/or
insulin.
Treatment response was assessed by measuring hemoglobin A1c (HbA1c), plasma
glucose, and clinical periodontal disease
measures. At one-month and three-month
follow-ups, clinical measures of periodontitis were decreased in all groups. At threemonths, mean HbA1c levels in the SDD
group were reduced from 7.2 percent
units±2.2 (±SD), to 6.3 percent units±1.1,
which represents a 12.5 percent improvement. In contrast, there was no significant
improvement in HbA1c in the antibiotic
(7.5%±2.0 to 7.8%±2.1) or placebo (8.5%±2.0
to 8.5%±2.6) groups. The results of this pilot
study suggest that the treatment of periodontitis with sub-gingival debridement and
three-months of daily sub-antimicrobialdose doxycycline may decrease HbA1c in
patients with type two diabetes taking normally prescribed hypo­g lycemic agents. 32
Cardiovascular Disease
The effect of subantimicrobial-dose-doxycycline (SDD) has been widely studied for its
potential to reduce serum biomarkers of systemic inflammation. CRP (C-reactive protein, an acute-phase protein produced by the
liver and an important biomarker in the circulation of systemic inflammation) along
with several other serum biomarkers, are
widely studied risk factors for coronary artery disease (CAD). These patients show elevated CRP in their blood samples, indicating patients at elevated risk for future cardiac
events, such as a heart attack. One of the
groups who are particularly at risk for CAD
are post-menopausal women. 33,34 A randomized, double-masked, placebo-controlled
clinical trial, conducted by Payne et al. and
published in the JADA in March 2011, randomly assigned 128 eligible post-menopausal
women with chronic periodontitis to a twicedaily regimen of subantimicrobial-dose-doxycycline (SDD), or placebo tablets, for two
years as an adjunct to periodontal maintenance therapy. Following the two-year regimen, SDD significantly reduced the serum
inflammatory biomarkers (CRP and MMP’s)
and among women, more than five years
post-menopausal, increased the HDL (high
density lipoprotein) “good” cholesterol,
which is correlated with reduced risk of atherosclerosis). 35
As discussed earlier, chronic inflammation,
whereby macrophages secrete excessive
MMPs, eventually degrade the collagen rich,
fibrous protective cap. This destabilizes the
atherosclerotic plaques, leading to plaque
rupture, thrombosis, and heart attack (MI).
It was hypothesized that if MMP activity
could be inhibited or suppressed, there may
be less risk of rupture of the protective cap.
A randomized, double-blind, placebo-controlled pilot study of six months of SDD, or
placebo treatment, to reduce inflammation
and prevent rupture events was conducted. A
total of 50 patients all diagnosed with severe
CAD (i.e. acute coronary syndromes or ACS)
were enrolled; 24 randomized to placebo and
26 to SDD (30 patients completed the six
month study; 17 SDD and 13 placebo). In the
SDD-treated patients, C-reactive protein
(CRP) in the circulation was reduced by 46
percent, whereas CRP was not significantly
reduced in placebo patients. Interleukin
(IL)-6 was decreased in SDD-treated patients but did not decrease significantly in
placebo-treated patients. MMP-9 (also
known as type IV collagenase) was also reduced 50 percent by SDD therapy, whereas it
was unchanged by placebo treatment. [It
should be recognized that these reductions in
CAD biomarkers in the patient’s blood sam-
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ples are recognized as indicators of reduced
risk for cardiac events, including reduced risk
for heart attack]. The study concluded that
SDD appears to exert potentially beneficial
effects on inflammation that could promote
plaque stability, preventing plaque rupture
events. 36
Osteopenia/Osteoporosis
26 The medical condition of osteoporosis, a
disease characterized by low bone mass and
deterioration of bone tissue, leads to increased bone fragility and risk of fracture,
and in many cases, fatality. Twenty-eight
percent of women and 37 percent of men
who suffer a hip fracture will die within the
following year. 37 A preliminary study by
Payne et al. had previously demonstrated
that
subantimicrobial-dose-doxycycline
(SDD) treatment of post-menopausal women with periodontitis and osteopenia (reduced bone mass of lesser severity than osteoporosis) reduced periodontal disease
progression, including decreased alveolar
bone loss, biomarkers of collagen destruction, and bone resorption locally in periodontal pockets, in a double-blind placebocontrolled clinical trial. 38
An earlier study by Golub et al. (1999), using a rat model of post-menopausal osteoporosis, clearly demonstrated that oral administration of a NON-antimicrobial doxycycline
not only reduced the severity of systemic
bone loss in skeletal tissue (femur), but also
reduced local bone loss in the periodontium,
which was associated with reduced collagenase in adjacent gingival tissues. 39
The National Institutes of Health (NIH)
funded study screened 600 women of which
128 were selected. Participants had to be
post-menopausal, have osteopenia, radiographic evidence of alveolar bone loss and
not be taking bisphosphonates or other medications that would impact osteoporosis. The
128 post-menopausal women with chronic
periodontitis and osteopenia randomly received SDD or placebo tablets daily for two
years, adjunctive to periodontal maintenance
therapy every three to four months. Blood
was collected at baseline and at one and twoyear appointments, and sera were analyzed
for bone resorption and bone formation/
turnover biomarkers. In conclusion, the twoyear regimen of SDD therapy not only reduced the clinical, radiologic and biochemical markers of periodontal disease in
post-menopausal women, but also reduced
the risk of conversion of mild systemic bone
loss (osteopenia) into a severe form of bone
disease (osteoporosis).40
Rheumatoid Arthritis (RA)
Historically rheumatoid arthritis and periodontitis have been linked. Is it the lack of
manual dexterity and ineffective biofilm removal that was the accepted explanation several decades ago? We now understand that
the link exists through vascular transport
into the circulation. The inflammatory mediators (cytokines, prostaglandin, MMPs) present with oral inflammation, flow into the
blood bi-directionally from the gingiva into
the circulation, resulting in systemic inflammation. The profiling of elevated inflammatory markers is similar for both periodontitis
and rheumatoid arthritis.
A clinical study was conducted to compare
the efficacy of doxycycline plus methotrexate
(MTX) versus MTX alone in the treatment of
early seropositive rheumatoid arthritis (RA),
and to attempt to differentiate the antibacterial
and anti-metalloproteinase (SDD) effects of
doxycycline. Sixty-six patients with seropositive RA of <one year’s duration who had not
been previously treated with disease-modifying anti-rheumatic drugs, were randomized to
receive 100 mg of doxycycline twice daily with
MTX (high, antibiotic-dose doxycycline
group), 20 mg (low, NON-antibiotic-dose, i.e.
SDD) doxycycline twice daily with MTX
(SDD), or placebo with MTX (placebo group),
in a two-year double-blind study. The study
concluded that in patients with early seropositive RA, initial therapy with MTX plus doxycycline was superior to treatment with MTX plus
placebo. The therapeutic responses to low-dose
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and high-dose doxycycline were essentially the
same, except that the high-dose doxycycline
group exhibited greater side effects, while SDD
was similar to the placebo group. This study
demonstrated that the SDD effects on host response were responsible for the beneficial effects on RA, rather than the antibacterial effect of the high-dose doxycycline.41
Conclusion
The overwhelming amount of science speaks
for itself.
Robert Burton, an english scholar at Oxford University in the 17th century, made the
following profound statement regarding
health: “Restore a man to his health, his
purse lies open to thee.” There is no greater
wealth or richness in life than good health.
Our CDHA professional statement represents our professional mandate very clearly.
“I am a dental hygienist. I educate and empower Canadians to embrace their oral
health for better overall health and well-being.” It’s time to put our words into action
and recognize our role in reducing inflammation, and sustaining overall health for our
dental hygiene clients. n
Acknowledgements:
The first author would like to acknowledge
Dr. Lorne Golub, Dr. Ying Gu, and Dr. Maria Ryan for their assistance in preparing this
manuscript.
Disclaimer:
The authors received no compensation for
the writing of this article.
References:
All sites accessed March 2015.
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