V o l u m e7 6 .

N u m b e r | |

Periodontitisand RheumatoidArthritis:
A Review
P.M.Bartold,*R.l.Marshall,Iand D.R. Haynesf

Periodontitis and rheumatoid arthritis (RA) appear to share

many pathologic features. In this review, the common pathologic mechanisms of these two common chronic conditions
are explored. Emerging evidence now suggests a strong relationship between the extent and severity of periodontal disease
and RA. While this relationship is unlikely to be causal, it is clear
that individualswith advanced RA are more likely to experience
more significant periodontal problems compared to their nonRA counterparts, and vice versa. A case is made that these
two diseasescould be very closely related through common underlying dysfunction of fundamental inflammatory mechanisms. The nature of such dysfunction is still unknown.
Nonetheless,there is accruing evidence to support the notion
that both conditions manifest as a result of an imbalance between proinflammatory and anti-inflammatory cytokines. As
a result, new treatment strategies are expected to emerge for
both diseasesthat may target the inhibition of proinflammatory
cytokines and destructive proteases. The clinical implications
of the current data dictate that patients with RA should be carefully screened for their periodontal status. J Periodontol

2005;76:2066-2074.
KEY WORDS
Arthritis, rheumatoid;periodontitis.
Departmentof Dentistry,Universityof Adelaide,Adelaide,South Australia,Australia.
D e p a r t m e not f D e n t i s t r yU
, n i v e r s i t yo f Q u e e n s l a n dB, r i s b a n eQ
, u e e n s l a n dA, u s t r a l i a .
Departmentof Pathology,Universityof Adelaide.

"ln fact,
adult periodontitis and
rheumatoid arthritis have much in
common, so much so that I have
arguedthat they are reallythe same
1
disease."
he above bold and challenging
statement may seem to be
stretching the boundaries of conventional thought too far. However,
close inspection of two of the most common chronic diseases afflicting humans
reveals remarkable similarities that warrant further investigation.
The relationship between rheumatoid
arthritis (RA) and the progression of inflammatory conditions elsewhere in the
body, such as periodontitis, is controversial. While a number of studies have
presented conflicting results regarding
a relationship between periodontitis and
RA, there have been recent reports suggesting a significant association between
these two common chronic inflammatorv
c o n d i t i o n s . 26 I n l i g h t o f t h e s e r e p o r t s ,
there is a need for further investigations
to determine whether the severity of RA
and the severity of periodontitis are interrelated.To do this, controlled, populationbased, laboratory, and clinical (molecular
epidemiology) studies are needed to verify the immunological and biological associations between RA and periodontal
disease.
PERIODONTAL DISEASES
The periodontal diseases range from the
relatively benign form of gingivitis to aggressive periodontitis. Many of these
conditions are not only a threat to the
dentition, but may also be a threat to

Bartold, Marshall,

Periodontol . November 2005

generalhealth. There are reports suggesting increased prevalence of diabetes, atherosclerosis,

myocardialinfarction,and stroke in patientswith periThus,the likelihoodof periodontal
odontaldisease.T-e
diseasebeing associatedwith systemic diseasesis becoming established fact. All forms of inflammatory
periodontaldiseaseare associatedwith chronic inflammation(accumulationof B and T lymphocytes
aswellas monocytesand neutrophils), resultingin destructionof the periodontal ligament and bone' lf left
untreated,significant tissue damage occurs, and the
affectedteeth can become loose and may be lost if
thediseasecontinuesto be active. What is particularly
curious about this disease is the great variability in
presentation. Because of its multifactorial nature,
which is modified by systemic, environmental, and
microbiological factors, not all individuals are affectedto the same degreedespitethe ubiquitouspresenceof dental plaque.

From the natural history studies of RA and periodontitis, it has been observed that certain RA and
periodontitis populations are characterizedby a
particular type of patient who will experience disease progression irrespective of any treatment provided. Whether the RA grouP, in which disease
progressionseems uncontrolledeven after comprehensivetreatment,is the same group that is susceptible to develop severe forms of periodontal disease
remains to be establishedand is, indeed, a major
thesis of this review.
Rheumatoid arthritis. At least three types of disease manifestationcan also be observedin RA populations: 7) seltlimited: in these cases individuals
originally presenting for RA have no evidence of
disease 3 to 5 years later;122) eastlg controlled: Ihe
diseaseis relativelyeasily controlledwith only non3) pro'
steroidalanti-inflammatorydrugs (NSAIDs);13
gressiue:these patients generally require second-line
drugs, which often still do not fully control the dis-

RHEUMATOIDARTHRITIS
Rheumatoidarthritis is also a chronic destructive inby the accumulaflammatorydiseasel0characterized
infiltrate in
persistence
inflammatory
of
an
tion and
and
synovitis
leads
to
that
the synovial membrane
joint
in
resulting
architecture
the
the destruction of
has
RA
disease,
systemic
As
a
impairedfunction.
extra-articularmanifestationsin systems such as the
pulmonary, ocular, vascular, and other organs or
structuresthat may be affected by the inflammatory
process.The current paradigm for RA includesan initiatingevent(possiblya microbialexposureor a putative autoantigen) leading to significant synovial
inflammationand tissue destruction.As for periodontitis,there is an accumulation of inflammatory cells (T
andB lymphocytes,neutrophils,and monocytes),tissue edema, endothelialcell proliferation,and matrix
degradation.RA is also modified by systemic,genetic,
and environmentalvariables.

ease.14,l5

SIMILARITIESBETWEEN RHEUMATOID
ARTHRITISAND PERIODONTITIS
Natural Historg
Periodontal disease. Natural history studies of
periodontaldiseasein humans indicate the presence
11
of threedistinctsubpopulations: 1) no progression
of periodontaldisease,in which around 10% of the
population manifest vdry little or no diseasewhich is
of no particularconsequenceto the dentition;2) moderate progression,affecting around B0%of the population and representinga very slowly progressingform
of diseasethat generallycan be easily managed via
routinetherapies;and 3) rapid progression,affecting
approximately 8% of individuals whereby extensive
periodontaldestructionoccurs which can be very difficult to control.

Etiologic Factors
Periodontitis. The periodontal diseases are well
recognizedas classicexamplesof chronic inflammatory diseasesresultingfrom the induction of host inflammatory responsesto the subgingival biofilm'
Gingivitisis typically characterizedas a robustinflammatory responseconfined mainly to the superficial gingival connective tissues and is a relatively
nonspecific response to a nonspecific accumulation
of dental plaque. How gingivitis progressesto periodontitisis still unclear.l6
Periodontitis,on the other hand, appears to be
a more specific inflammatory response to specific
periodontalpathogensresidingin the subgingivalbiofilm. Within the conditions known as periodontitis,
there is considerablevariability in terms of clinical
manifestationand diseaseprogressionrates'Thisvariability can be attributedto differencesin composition
of the subgingival microbial flora, as well as factors
that modify the host responseto the microbial challenge. Nonetheless,it must be noted that, although
bacteria are necessary for disease initiation, they
are not sufficientto cause diseaseprogressionunless
there is an associated inflammatory responsewithin
host.l6
a susceptible
Rheumatoidarthritis. Although the causeof RA is
unknown, it has been recognizedthat many different
arthritogenicstimuli activate inflammatory resPonses
in immunogeneticallysusceptiblehosts.Thus, studies have focused on exogenousinfectiousagents,endogenous substances, such as connective tissue
proteins(e.g.,collagensand proteoglycans),and altered immunoglobulinsas the causativecandidates.
The concept that RA is an infectiousdiseasehas been
2067

Periodontitisand RheumatoidArthritis

c o n s i d e r e df o r o v e r 7 0 y e a r s . r / T h e i d e a t h a t R A p a tients acquire an infection that elicits an immune response in the synovial membrane would account for
some of the clinical featuresand would also explain
t h e a c c u m u l a t i o no f i m m u n o c o m p e t e n t T a n d B c e l l s
in the Iesions.Data from different animal models demonstrate that arthritis can develop secondarily to several different stimuli and through several different
effector pathways. If such observations are also applicable to human RA, we might anticipate that different
types of infections as well as other environmental
exposures with capacity to induce excessive proinflammatory cytokines in genetically susceptible indiv i d u a l sm a y a l l p o t e n t i a l l y c o n t r i b u t e t o d i s e a s ee i t h e r
in unisonor isolation.
Are Bacteria a Common Etiologic Link Between
Periodontitis and Rheumatoi"d A rthritis?
There are a number of shared features between
m i c r o o r g a n i s m st h a t c a n i n d u c e R A i n a g e n e t i c a l l y
susceptible host and the recognized periodontal
p a t h o g e n s .N o n e t h e l e s s ,R A i s s t i l l n o t l a r g e l y r e c o g nized as a disease resulting solely from bacterial
c h a l l e n g e .O n t h e o t h e r h a n d , t e c h n o l o g i c a l a n d c o n ceptual advances have permitted the identification of
bacteria or groups of bacteria associated with specific
p e r i o d o n t a ld i s e a s e s . l s C l o s e i n s p e c t i o n o f t h e v i r u lence factors of periodontal pathogens would suggest
t h a t s u c h a r e s p o n s e c o u l d b e f e a s i b l e .T h u s , t h e p o s s i b i l i t yt h a t o n g o i n g p e r i o d o n t i t i sc o u l d t r i g g e r R A i n
g e n e t i c a l l ys u s c e p t i b l ei n d i v i d u a l s i s p l a u s i b l e .
Notwithstanding the above, these concepts remain
speculative until the causative agent for RA can be definitively identified. To date, no infectious agents have
been identified as the cause of RA in humans. Indeed,
current information does not support the concept that
a single antigen is responsible for synovial inflammat i o n . I t i s p o s s i b l et h a t t h e r e i s n o s i n g l e p r i m a r y c a u s e
of RA and that different mechanisms may independently lead to synovial inflammation in susceptible individuals. It is important to recognize that, based on
current information, we do not propose that periodontal pathogens cause, or are associated with, RA. The
main focus of our attention is directed not towards
causality but rather associations between two chronic
inflammatory conditions that may have common und e r l y i n gp a t h o g e n i c m e c h a n i s m s .
Immunogenetics
Periodontitis. [t has been reported that more than
50% of the variance in several features of chronic periodontitis can be explained by genetic fss1..r. l9'20
Many of these interindividual variables relate ro severity of periodontal destruction, and other inflammatory
responsesare attributed partly to the amount and type
of cytokines that individuals produce.2l While the
HLA-DR phenotype is not particularly strong for peri-

odontitis, there is a report indicating that it is an

important component of the genetic susceptibility to
s o m e f o r m s o f t h i s d i s e a s e . 2 2I n a d d i t i o n , p o l y m o r p h i s m s i n t h e i n t e r l e u k i n -1 g ( l L - 1 B ) g e n e c l u s t e r h a v e
been shown to have a significant correlation with
some forms of periodontitis in certain populations.23
Rheumatoid Arthritis. Family studies and studies
on monozygotic and dizygotic twins have shown
that RA has several features indicative of a complex
genetic disease including genetic variance, incomplete penetrance, and multiple gene involvement.24
For RA, the strongest genetic associations are found
w i t h i n t h e H L A g e n e s . 2 3U s i n g D N A s e q u e n c i n g a n d
molecular-based typing, it has been demonstrated
that the disease-conferring portion of the D region is
confined to a short sequence within the third hypervariable region of HLA-DRB1 gene which includes
the amino acid positions 67 through 74.2s'2o 11-,t"
HLA genes and gender constitute about 30% ofthe genetic risk in RA, while other genetic factors such as
cytokine genes,germline genes,and T-cell receptors
also account for some of the genetic predisposition
to RA.1o
Effector Mechanisms of Tissue Destruction in
Rheumatoid Arthritis and Periodontitis
There is almost universal acceptance that a variety of
c y t o k i n e s a n d m a t r i x m e t a l l o p r o t e i n a s e s( M M P s ) a r e
u p r e g u l a t e da n d i n t i m a t e l y i n v o l v e d i n t h e p a t h o g e n esis of both periodontitis and RA; many of these effector moleculesappear to be common to both diseases.
The task now is to identify the specific cytokines, their
concentrations, the cells they affect in vivo, the stages
in which they are active, and the role and concentrations of their inhibitors. While the effects of cytokines
on normal cellular process are important, it is their
purported roles in pathophysiology that may result
from excessive production, dysregulation, or inadequate inhibition that have gained most attention.l
Very simply, cytokines can be classified into funct i o n a l g r o u p s b a s e do n t h e c e l l so f o r i g i n , a n d a l l m a j o r
types have been identified and located in inflamed
synovial and periodontaltissues.
Periodontitis has very similar cytokine profiles to
p4,27'28 consisting of persistent high levels of proinflammatory cytokines, including lL- 1B and tumor
n e c r o s i sf a c t o r - a l p h a ( T N F - c t ) ,a n d l o w l e v e l s o f c y t o kines which suppress the immunoinflammatory response such as IL-10 and transforming growth
factor-B (TGF B). These cytokines, together with
low levels of tissue inhibitors of metalloproteinases
(TIMPs) and high levels of MMPs and prostaglandin E2
(PGE2), are associated with the active stages of periodontitis.
The destruction of soft and hard tissues seen in RA is
also the result of not only a large number of cytokines

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p
ri

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Periodontol. November 2005 (Suppl.)

butalsothe sustainedpresenceof other effector moleculesreleasedby residentand migrating cells. Together,thesesolublemediatorsof inflammationare
ableto inducedegradationof collagenand proteoglycanseitherthroughdirect or indirectmeans.Productionofthearachidonicacid metabolitePGE2as well as
therelease
of neutrophil-associated
enzymes,such as
neutrophilelastase and B-glucuronidase,together
with the secretion of matrix metalloproteinases by
macrophages
and synoviocytes,all contributesignificantlyto the pathogenesisof RA.
Formulation of the Hgpothesis
Onthebasisof the aboveconsiderablesimilaritiesbetweenthepathologicaland clinicalfeaturesof RA and
periodontitis
(especiallyin the advancedand aggressiveformsof thesediseases),we have proposedthat
in somesusceptibleindividuals,there are common
features
of an underlyingand presentlyunknowndysregulation
of the inflammatorymechanismwhich predisposes
these individualsto advanced,aggressive,
andsevereforms of either disease.
Studieson Relationships Between Periodontitis
and Rheumatoid Arthritis
Todate,very few studieshave examinedthe association betweenRA and periodontal disease,and the
resultshave often been conflicting. For example,
Finnishstudiesfound no correlation between periodontaldiseaseand arthritis,2ewhile others3,30
suggesta higherprevalenceof periodontalbone loss in
RA.A major reason for these discrepanciesrelates
to the lack of uniformity in classifyingthe various
formsof periodontal disease and RA. Indeed most
oftheearlystudies,3'29-31
failed to take into account
the various forms of RA and periodontal disease
and,as a result,groupedall subjectsas eitherhaving
RAor periodontaldiseasewith little or no regard for
for more detailedanalyses.In light
subclassification
of these limitations, it is clear there is a need to
re-examinethe extent of the associationbetween
specific
types of RA and periodontaldisease.In particular,it is our thesis that the more aggressiveor
severeforms of periodontal diseaseand RA will show
a veryclosecorrelationin terms of coexistence.
ln our first pilot study,6investigatingself-reported
diseaseexperience,the prevalenceof moderate to
severeperiodontitis was significantly elevated in individualswith RA (uhadjustedrelative risk of 4.7).
In addition,the conversewas also true in that peripatientshad a higherprevalenceof RA comodontitis
paredto the generalpopulation (unadjustedrelative
riskof 1.5).
In a subsequentstudy, 65 patients attending a
rheumatology
clinicwerestudiedfor their levelof periodontitisand RA.2A control group consistedof ageand gender-matchedindividualswho did not have

Bartold, Marshall,

RA. No differenceswere noted for the plaque and

bleedingindicesbetweenthe control and RA groups.
The RA group did, however,have significantlymore
missingteeththan the controlgroup and a greaterpercentageof thesesubjectshad deeperpocketingcomparedto the controls.The percentageof alveolarbone
loss correlatedpositivelywith the principal parameters of RA severity.
Thesetwo pilot studieshave resultedin severalsignificantfindings.Contraryto current dogma, RA patients do not have impaired oral hygiene (judged by
plaque and bleeding scores). Perhapsmore importantly, it was noted that individualswith severe RA
are more likely to have advanced periodontitisand
vice versa.Although many RA patientstake medications that can reduce periodontal destruction (i.e.,
NSAIDs and immunosuppressants),we have noted
significantperiodontaldestructionin these patients.
This indicatesthat prior to the development of RA
symptoms,the periodontitiswas most likely developing and not detected.Thus, diseaseduration may be
a very importantfactor.Finally,in orderto understand
the interrelationships
betweenperiodontitisand RA, it
is necessaryto categorizethe diseaseon the basisof
severityand duration (i.e.,type of disease).
Recently,using an animal model, additional evidencehas been presentedto indicatea significantrelationship between periodontitis and rheumatoid
From this study it was reportedthat inducarthritis.32
ing experimentalarthritis
in the rat (adjuvantarthritis)
resulted in periodontal breakdown characterized
by alveolarbone loss and increasedmatrix metalloproteinaseactivity in adjacentgingivaltissues.Interestingly, all of these reactions occurred without
manipulatingthe oral or subgingivalmicroflora.
Osteoclast Actioation and Vascular Damage - A
Common Pathwag in Periodontitis and
Rheumatoid Arthritis?
Most recently, studies from our laboratory (unpublisheddata) have begunto investigatethe codistribution of cytokines involved in vascular damage and
bone resorptionin biopsiesfrom graded rheumatoid
arthritisand periodontitislesions.Sincethe tumor necrosisfactor (TNF)-likemoleculesand their receptors
have beenshownto be involvedin both processes,we
have chosen to study the receptor activator of nFkappa B ligand (RANKL), osteopretogerin(OPG),
and TNF-relatedapoptosisinducing ligand (TRAIL)
to determineat leastone molecularmechanismcommon to both conditions.
The cell surfaceTNF-like molecule,RANKL and its
receptor,RANK have been shown to be key factors
regulatingosteoclastformation and activation.33'34
It has been shown that when RANKL binds to RANK
on the surface of osteoclastprecursors,these cells

Periodontitis
and Rheumatoid Arthritis

differentiateto form mature osteoclasts. It is now clear

that RANKL, together with macrophage-colony stimulating factor (M-CSF), is required for osteoclast formation. The soluble TNF "receptor-like" molecule,
OPG, is a natural inhibitor of RANKL.35 OPG btnds
to RANKL and prevents its ligation to RANK. The importance of these molecules in regulating bone metabolism has been demonstrated by transgenic and
gene knock-out studies in mice.36 Since these factors
control physiologic osteoclast formation, it is reasonable to propose that they may also be key regulators
of pathological bone resorption.3T'38 Although
RANKL is normally provided by osteoblast-like cells
in bone,38'3ethere are reports suggesting that lymphocytes present in rheumatoid tissues may be the
main source of RANKL in inflammatory arthritis.33'40
Furthermore, CD3+ T cells from the human rheumatoid joint express RANKL and can promote osteoclast
formation from rodent spleen precursors.a0 In addition to lymphocyte production of RANKL, inhibition
of RANKL by OPG treatment in vivo reduces both
bone and cartilage destruction in a model of adjuvant
arthritis.aI
Under certain conditions, human osteoclasts are
derived from osteoclast precursor cells present in or
near to the tissues of arthritic joints.a2,a3More recent
reports in humans44,45 un4 animals4l show that
RANK/RANKL interactions may be required for osteoclast formation and bone resorption in the RA joint.
Accordingly, we have recently demonstrated that OPC
and RANKL are expressed in biopsies of inflamed
rheumatoid synovium and periodontitis lesions.46 In
addition, we have found (unpublished data) that another ligand for OPG, TRAIL, is expressed in the both
types of tissue (although not from the same patient).
In these studies we have noted that OPC decreases
with inflammation, RANKL increases with inflammation, and TRAIL increases with inflammation. These
findings may be of considerable significance in light
of OPG's ability to block the activity of TRAIL (and
vice versa) and TRAIL's anti-inflammatory properties.aT
The production of OPG by endothelial cells may be
significant for reasons other than its effects on bone
metabolism, and there is now evidence to suggest that
OPG might also regulate endothelial cell function.
OPG has been reported to be required for endothelial
cell survival and growth.as In addition, OPG knock-out
mice have been shown to develop arterial calcifica6on49,50as well as severe osteoporosis, suggesting
that vascular endothelial expression of OPC may
have a role in vascular homeostasis.4l One of the
most unexpected findings from our recent studies of
diseasedperiodontal and synovial tissues was the observationthat endothelial cells produce large amounts
of OPG (unpublished observations).
2070

V o l u m e7 6 . N u m b e r | |

ln response to proinflammatory cytokines TNF-o

and lL- 1 P, OPG mRNA expression was dramatically
enhanced, resulting in secretion of newly synthesized
OPG and a reduction in cell-associated OPG. Such
findings are consistent with our observations in vivo
for active RA and periodontitis lesions. Vascular damage due to apoptosis is thought to precede vascular
calcification5l and contribute to atherosclerosis.52
I n a d d i t i o n ,d i a b e t i c e n d o t h e l i a l c e l l d y s f u n c t i o ni s a s sociated with DNA damage induced by poly (ADPribose) polymerase activation. The exact cause of
endothelial cell dysfunction is not known but it is possible that molecules such as TRAIL, expressed in
nearby cells and tissues, may be important.38,539u,
recent binding studies confirm that OPG binds to
TRAIL, although with less affinity than RANKL, in vitro, and blocks its activity (unpublished data). The final piece of compelling evidence for the role of OPG in
vascular damage comes from the fact that OPG
knock-out mice develop vascular calcification. It is
significant to note that calcification cannot be reversed by systemic treatment with recombinant OPG
postpartum.5o This supports our concept that OPG
must be expressed within the endothelial cells, either
in an appropriate form or associated with other molecules, and this only occurs following normal synthesis
within the healthy endothelial cells.
In light of the above, we propose that at least one
underlying common molecular pathway in common
between rheumatoid arthritis and periodontitis may
lie within the RANK/OPG/TRAIL axis whereby OPG
decreases leading to decreased vascular protection.
In addition, with an increase in RANKL and TRAIL
w i t h i n t h e t i s s u e s ,n o t o n l y i s v a s c u l a r d a m a g e p o s sible, but significant activation of osteoclasts may
result. This proposal still awaits verification.
C O M M O N P A T F I O G E N E S I S_ C O M M O N
TREATMENT?
Current and Emerging Therapies
Currently, the mainstream "first-line" modes of treatment for RA remain the NSAIDs such as aspirin, naproxen, diclofenac, and ibuprofen. Their mechanism of
action through the inhibition of cyclooxygenase
(COX) synthesis produces both analgesic and antipyretic properties. While these medications are effective
in reducing the pain symptoms in RA, they do not significantly alter its course.54
The use of NSAIDs for management of periodontal
disease has been studied over the past 20 years.s5-57
While the results appear promising, the widespread
clinical use of these medications to alter the course
of periodontitis has not been universal. One particular
problem with their use for the management of periodontitis appears to be a "rebound" effect to baseline
following cessation of the medication.5s

Periodontol . November 2005

With the discovery of two COX enzymes responsiblefor PGE2production, designatedCOX- 1 (constitutivelyexpressed)and COX-2 (inducible),a variety of
COX-2inhibitorshave been studied for their potential
to stopor slow down bone resorption.One of the first
COX-2inhibitorsdeveloped,tenidap,has beenshown
to inhibitnot only cyclooxygenaseand PGE2production but also IL-1, IL-6, and TNF-ct production.To
date, COX-2 inhibitors have not been thoroughly
studiedfor their potential to modify bone resorption
in periodontitis.
In contrast to the NSAIDS, which do not significantlyalter the course of RA, a newer family of medicationsdesignateddisease-modifyinganti-rheumatic
has been developed.To be classified
drugs(DtvtARDs)
as a D/vlARD.the medication must demonstrate an
abilityto change the course of RA for at least 1 year
as evidencedby sustained improvement in function,
decreasedsynovitis, and prevention of further joint
damage.5eExamples of these medications include
parenteral
gold salts, methotrexate,sulfasalazine,hydroxychloroquine(antimalarial drug), penicillamine,
azathioprine,
and leflunomide. A major drawback in
theuseof Dl4ARDsis their considerabletoxicity.60'61
The use of DMARDs for the management of periodontitishasbeen restrictedlargely due to the toxicity
issues.However,the use of gold salts in an animal
modelhas shown reduced periodontal destruction.62
To date,no human studies have been performed.
Anotheremerging area of potential for host modulationin periodontitisand rheumatoid arthritis is control of the lvlMPsthat are important mediators of
,tonnective
tissuebreakdown in both hard and soft tissues.In this regard,tetracyclinesand variouschemianalogueshave been found to inhibit MMP activity
a mechanismthat is independent of their antimiproperty.63,64
A number of clinicaltrialsusing
dose tetracycline to modify periodontitis have
carriedout, with the most recent data indicating
low-dosedoxycycline is safe and significantlyef65'665on"11'teless,
it is still recommended that
databe interpretedwith caution to differentiate
statisticallysignificant and clinicallyrelevant
67The role of MMP inhibitors in managing RA
beenless well studied but promising results are
In particular,a recentstudy has deming.68-zo
that low-dose and antimicrobial (higher)

doxycycline,when used adjunctivelywith meth, producesenhancedimprovementsin global

of RA severitv in humans than methotrexate
with placebo.Tl

Controlof cytokines and their receptors is also

as a field of considerablepromise.For exblocking
the lL- 1 receptor and using gene
,
to deliver IL-1 receptor antagonistare two
under investigationto modulate the effect

Bartold, Marshall,

Similarly,
of elevated IL-1 in inflamed tissues.T2-74
other studies have shown that blocking the activity
of anotherimportant inflammatorycytokine, TNF-a,
The roles
has therapeuticefficacy in RA patients.T5-78
of IL-1 and TNF antagonistsin a primate model of
periodontitis have demonstrated a reduction in the
inflammatory infiltrate in close proximity to bone as
well as reduction in the formation of osteoclastsand
reducedbone loss.79
Clearly,many of these biologic agents,which target specific molecular events associatedwith acute
and chronic inflammation,have significantpotential
to alter clinical outcomes for both RA and periodontal
disease. With the emerging understanding that RA
and periodontitisare multifactorialdiseases,combination therapies that target multiple disease outcomes are also emerging. For example, in an
animal study, it was reported that the administration
of a combinationof a chemicallymodifiedtetracycline
(CMT-1) plus an NSAID,such as flurbiprofenor tenidap, synergisticallyinhibitedseverebone destruction
in arthritic rats, with the suppressionof MMPactivity in
Similarencouragingresultshave been
the joints.80'81
reportedfor periodontitisin humans.82
Notwithstandingthe above, it must be recognized
that periodontitis differs in one significant way from
RA through our understanding that the subgingival
biofilm is a key etiologic factor. Unlike periodontal
disease,no specificbacterialetiologyhas been identified for RA. Thus, while host modification of disease
processes are possible for periodontitis, controlling
the bacteriathat causeperiodontalinfectionsremains
a significant focus for periodontal treatment and prevention.At best,host modificationcan be only an adjunct treatment for periodontitis. However, until an
etiologic factor can be found for RA, host modification
remainsthe mainstayof treatment.
CONCLUSIONS
There is no question that periodontitis and RA have
many pathologicfeaturesin common. Emergingevidence suggestsa strongrelationshipbetweenthe extent and severityof periodontaldiseaseand RA.While
this relationshipis unlikelyto be causal,it is clearthat
individualswith advancedRA are more likely to experience more significantperiodontalproblems compared to their non-RA counterparts,and vice versa.
Hence, the possibility exists that both conditions result from a common underlying dysregulation of the
host inflammatory response. The precise nature of
this dysregulationremainsto be established.
There is accruing evidence to support the notion
that both conditionsmanifestas a resultof an imbalance betweenproinflammatoryand anti-inflammatory
cytokines. As a result, new treatment strategieswill
emergefor both diseasesthat may target the inhibition
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Periodontitisand RheumatoidArthritis

of proinflammatory cytokines and destructive pro_

teases.
Through a better understanding of these rwo
com_
mon chronic inflammatory conditions, it is hoped
that
areas of similarity can be exploited to determine
the
true relationship between these diseases
and com_
mon areas of treatment. Already, it can be predicted
that the periodontal status of paiients with
RA should
be carefully screened.
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Correspondence:
Dr. P.M. Bartold,Universityof Adelaide,
Department of Dentistry, Frome Road, Adelaide, South
A u s t r a l i a5 0 0 5 , A u s t r a l i a .F a x : 6 1 - 8 - 8 3 0 3 - 3 4 3 5 ;e - m a i l :
mark.bartold@adelaide.edu.au.
Acceptedfor publicationMarch 7,2005.