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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

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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

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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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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

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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

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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

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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

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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

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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 2071

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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. REFERENCES 1. GreenwaldRA, Kirkwood K. Adult periodontitis as a model for rheumatoid arthritis witir emphasis on treatment strategies. J Rheumatot 1999';26:1650_ I O?J.

2. Mercado FB, Marshall RI, Klestov AC, Bartold pM. Relationshipbetween rheumatoid arthritis and periodontitis.J periodontol2OO1 ;72:779_7g7. 3. KiisserUR, CleissnerC, Dehne n, tqicnaet A, Willershausen-Zonuchen B, BoltenWW.'Riskforperiodontal ai1.eqs5in patients with longstanding rheumatoid arthritis.Arth ritis Rheum I gg7:40:224A'_ZZS t. 4. C.leissner C, WillershausenB, Ku"rru. tt, notten WW. The role of risk factors for periodonial disease in patients with rheumatoid arthritis. Eur J Med Res 1998;3:387-392. 5. AlbandarJM. Some predictorsof radiographic alveo_ Ot *, t^n^eiOhtreduction over 6 y"uri."_, periodontal Res 1990;25:186-192. 6. Mercado F, Marshall Rl, Klestov AC, Bartold pM. Is there a relationshipbetween.f,eumuttia arthritis and periodontaldisease?J CIin periodontol2000;127:267_ 272. 7. DeStefanoF, Anda. RF, Kahn HS, Williamson DF, RussellCM. Dentaldiseaseand risk of coronary heart diseaseand mortality. Br Med J 1993;306:6gg:69 1. 8. Beck J, GarciaR, HeissG, VokonasFS,bffenuucne, S. Periodontaldisease and cardiovascular disease. J Periodontol1996;67:1 123_1137. 9. Yalda B, OffenbacherS, Collins JG. Diabetes as a 19^d]fi9^r_of p er iod on t a I d isease exp ressio n. p er iod on toI 2000 1994;6:37-49. 10. Weyand CM. New insights into the pathogenesis of rheumaroidarthritis. Rhiumatotogg ZObO;SSiSrppi.j, r 3-8. 11. HirschfeldL, Wasserma.nB. A long_term survey of tooth loss in 600 treated periodontal patients. peri_ J odo ntoI 1978 ;49:225-237'. 12. O'SullivanJB, Cathcart ES. The prevalence of rheu_ matoid arthritis.Follow-up evaluaiionof the effect of criteria on rates in Sudbury, Massachusetts. Ann InternMed 1972;76:573_577:' 13. PincusT, Marcum SB, CallahanLF. Long_term drug therapyfor rheumatoidarthritisin seuen,hLumatology private practices:Il:^S^9.glaline drugs and preaii_ sone.J Rheumatol1992;19:lgg5_lg9Z. 14. PincusT, Marcum SB, Callahanf_F,-"t-uf . Long-term drug .therapyfor rheumatoidarthriiis in seven rheu_ matology private practices.I. Non_steroidal anti_in_ rlammatory drugs. J Rheumatol 1992;19:1g74_ lQQA 15. Woife F, HawleyDJ, CatheyMA. Termination of slow actingantirheumatictherapy in rhematoidarthritis: A 74-year.prospective evaluaiionof 1017 consecutive starts.J Rheumatol1990;17 :994_1002.

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