Volume 76 . Number | |

Periodontitis and Rheumatoid Arthritis:A ReviewP.M. Bartold,* R.l. Marshall , I and D.R. Haynesf

Periodontit is and rheumatoid arthrit is (RA) appear to sharemany pathologic features. In this review, the common patho-logic mechanisms of these two common chronic conditionsare explored. Emerging evidence now suggests a strong rela-tionship between the extent and severity of periodontal diseaseand RA. While this relationship is unlikely to be causal, it is clearthat individuals with advanced RA are more l ikely to experiencemore significant periodontal problems compared to their non-RA counterparts, and vice versa. A case is made that thesetwo diseases could be very closely related through common un-derlying dysfunction of fundamental inflammatory mecha-nisms. The nature of such dysfunction is sti l l unknown.Nonetheless, there is accruing evidence to support the notionthat both conditions manifest as a result of an imbalance be-tween proinflammatory and anti-inflammatory cytokines. Asa result, new treatment strategies are expected to emerge forboth diseases that may target the inhibit ion of proinflammatorycytokines and destructive proteases. The clinical implicationsof the current data dictate that patients with RA should be care-fully screened for their periodontal status. J Periodontol2005;76:2066-2074.

KEY WORDSArthritis, rheumatoid; periodontitis.

Department of Dentistry, University of Adelaide, Adelaide, South Australia, Australia.Department of Dent ist ry, Univers i ty of Queensland, Br isbane, Queensland, Austra l ia.Department of Pathology, University of Adelaide.

"ln fact, adult periodontitis andrheumatoid arthritis have much incommon, so much so that I haveargued that they are really the samedisease." 1

he above bold and challengingstatement may seem to bestretching the boundaries of con-

ventional thought too far. However,close inspection of two of the most com-mon chronic diseases affl icting humansreveals remarkable similarit ies that war-rant further investigation.

The relationship between rheumatoidarthrit is (RA) and the progression of in-flammatory conditions elsewhere in thebody, such as periodontit is, is controver-sial. While a number of studies havepresented conflicting results regardinga relationship between periodontit is andRA, there have been recent reports sug-gesting a significant association betweenthese two common chronic inflammatorvcondi t ions.2 6 In l ight of these repor ts ,there is a need for further investigationsto determine whether the severity of RAand the severity of periodontit is are inter-related. To do this, controlled, population-based, laboratory, and clinical (molecularepidemiology) studies are needed to ver-ify the immunological and biological as-sociations between RA and periodontaldisease.

PERIODONTAL D ISEASES

The periodontal diseases range from therelatively benign form of gingivit is to ag-gressive periodontit is. Many of theseconditions are not only a threat to thedentit ion, but may also be a threat to

Periodontol . November 2005

general health. There are reports suggesting in-creased prevalence of diabetes, atherosclerosis,myocardial infarction, and stroke in patients with peri-odontaldisease.T-e Thus, the likelihood of periodontaldisease being associated with systemic diseases is be-coming established fact. All forms of inflammatoryperiodontal disease are associated with chronic in-flammation (accumulation of B and T lymphocytesas well as monocytes and neutrophils) , resulting in de-struction of the periodontal ligament and bone' lf leftuntreated, significant tissue damage occurs, and theaffected teeth can become loose and may be lost ifthe disease continues to be active. What is particularlycurious about this disease is the great variability inpresentation. Because of its multifactorial nature,which is modified by systemic, environmental, andmicrobiological factors, not all individuals are af-fected to the same degree despite the ubiquitous pres-ence of dental plaque.

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is also a chronic destructive in-flammatory diseasel0 characterized by the accumula-tion and persistence of an inflammatory infiltrate inthe synovial membrane that leads to synovitis andthe destruction of the joint architecture resulting inimpaired function. As a systemic disease, RA hasextra-articular manifestations in systems such as thepulmonary, ocular, vascular, and other organs orstructures that may be affected by the inflammatoryprocess. The current paradigm for RA includes an ini-tiating event (possibly a microbial exposure or a puta-tive autoantigen) leading to significant synovialinflammation and tissue destruction. As for periodon-titis, there is an accumulation of inflammatory cells (Tand B lymphocytes, neutrophils, and monocytes), tis-sue edema, endothelial cell proliferation, and matrixdegradation. RA is also modified by systemic, genetic,and environmental variables.

SIMILARITIES BETWEEN RHEUMATOIDARTHRITIS AND PERIODONTITIS

Natural HistorgPeriodontal disease. Natural history studies of

periodontal disease in humans indicate the presenceof three distinct subpopulations: 11 1) no progressionof periodontal disease, in which around 10% of thepopulation manifest vdry little or no disease which isof no particular consequence to the dentition; 2) mod-erate progression, affecting around B0% of the popu-lation and representing a very slowly progressing formof disease that generally can be easily managed viaroutine therapies; and 3) rapid progression, affectingapproximately 8% of individuals whereby extensiveperiodontal destruction occurs which can be very dif-ficult to control.

Bartold, Marshall,

From the natural history studies of RA and peri-odontitis, it has been observed that certain RA andperiodontitis populations are characterized by aparticular type of patient who will experience dis-ease progression irrespective of any treatment pro-vided. Whether the RA grouP, in which diseaseprogression seems uncontrolled even after compre-hensive treatment, is the same group that is suscepti-ble to develop severe forms of periodontal diseaseremains to be established and is, indeed, a majorthesis of this review.

Rheumatoid arthritis. At least three types of dis-ease manifestation can also be observed in RA pop-ulations: 7) seltlimited: in these cases individualsoriginally presenting for RA have no evidence ofdisease 3 to 5 years later;12 2) eastlg controlled: Ihedisease is relatively easily controlled with only non-steroidal anti-inflammatory drugs (NSAIDs);13 3) pro'gressiue: these patients generally require second-linedrugs, which often still do not fully control the dis-e a s e . 1 4 , l 5

Etiologic FactorsPeriodontitis. The periodontal diseases are well

recognized as classic examples of chronic inflamma-tory diseases resulting from the induction of host in-flammatory responses to the subgingival biofilm'

Gingivitis is typically characterized as a robust in-flammatory response confined mainly to the superfi-cial gingival connective tissues and is a relativelynonspecific response to a nonspecific accumulationof dental plaque. How gingivitis progresses to peri-odontitis is stil l unclear.l6

Periodontitis, on the other hand, appears to bea more specific inflammatory response to specificperiodontal pathogens residing in the subgingival bio-film. Within the conditions known as periodontitis,there is considerable variability in terms of clinicalmanifestation and disease progression rates' This var-iability can be attributed to differences in compositionof the subgingival microbial flora, as well as factorsthat modify the host response to the microbial chal-lenge. Nonetheless, it must be noted that, althoughbacteria are necessary for disease initiation, theyare not sufficient to cause disease progression unlessthere is an associated inflammatory response withina suscept ible host. l6

Rheumatoid arthritis. Although the cause of RA isunknown, it has been recognized that many differentarthritogenic stimuli activate infl ammatory resPonsesin immunogenetically susceptible hosts. Thus, stud-ies have focused on exogenous infectious agents, en-dogenous substances, such as connective tissueproteins (e.g., collagens and proteoglycans), and al-tered immunoglobulins as the causative candidates.The concept that RA is an infectious disease has been

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considered for over 70 years. r / The idea that RA pa-tients acquire an infection that elicits an immune re-sponse in the synovial membrane would account forsome of the c l in ica l features and would a lso expla inthe accumulat ion of immunocompetent T and B cel lsin the Iesions. Data from different animal models dem-onstrate that arthrit is can develop secondarily to sev-eral different stimuli and through several differenteffector pathways. If such observations are also appli-cable to human RA, we might anticipate that differenttypes of infections as well as other environmentalexposures with capacity to induce excessive proin-flammatory cytokines in genetically susceptible indi-v iduals may a l l potent ia l ly contr ibute to d isease e i therin unison or iso lat ion.

Are Bacteria a Common Etiologic Link BetweenPeriodontitis and Rheumatoi"d A rthritis?There are a number of shared features betweenmicroorganisms that can induce RA in a genet ica l lysusceptible host and the recognized periodontalpathogens. Nonetheless, RA is s t i l l not largely recog-nized as a d isease resul t ing sole ly f rom bacter ia lchal lenge. On the other hand, technological and con-ceptual advances have permitted the identif ication ofbacteria or groups of bacteria associated with specificper iodonta l d iseases. ls Close inspect ion of the v i ru-lence factors of periodontal pathogens would suggestthat such a response could be feasib le. Thus, the pos-s ib i l i ty that ongoing per iodont i t is could t r igger RA ingenet ica l ly suscept ib le indiv iduals is p lausib le.

Notwithstanding the above, these concepts remainspeculative unti l the causative agent for RA can be de-finit ively identif ied. To date, no infectious agents havebeen identif ied as the cause of RA in humans. Indeed,current information does not support the concept thata single antigen is responsible for synovial inflamma-t ion. I t is possib le that there is no s ingle pr imary causeof RA and that d i f ferent mechanisms may indepen-dently lead to synovial inflammation in susceptible in-dividuals. It is important to recognize that, based oncurrent information, we do not propose that periodon-tal pathogens cause, or are associated with, RA. Themain focus of our attention is directed not towardscausality but rather associations between two chronicinflammatory conditions that may have common un-der ly ing pathogenic mechanisms.

ImmunogeneticsPeriodontit is. [t has been reported that more than

50% of the variance in several features of chronic peri-odontit is can be explained by genetic fss1..r. l9'20

Many of these interindividual variables relate ro sever-ity of periodontal destruction, and other inflammatoryresponses are attributed partly to the amount and typeof cytok ines that ind iv iduals produce.2 l Whi le theHLA-DR phenotype is not particularly strong for peri-

odontit is, there is a report indicating that it is animportant component of the genetic susceptibil i ty tosome forms of th is d isease.22 In addi t ion, polymor-phisms in the in ter leukin- 1 g ( lL- 1 B) gene c luster havebeen shown to have a significant correlation withsome forms of periodontit is in certain populations.23

Rheumatoid Arthrit is. Family studies and studieson monozygotic and dizygotic twins have shownthat RA has several features indicative of a complexgenet ic d isease inc luding genet ic var iance, incom-plete penetrance, and multiple gene involvement.24For RA, the strongest genetic associations are foundwi th in the HLA genes.23 Using DNA sequencing andmolecular-based typ ing, i t has been demonstratedthat the disease-conferring portion of the D region isconfined to a short sequence within the third hyper-var iable region of HLA-DRB1 gene which inc ludesthe amino acid positions 67 through 74.2s'2o 11-,t"HLA genes and gender constitute about 30% ofthe ge-netic risk in RA, while other genetic factors such ascytok ine genes, germl ine genes, and T-cel l receptorsalso account for some of the genetic predispositiont o R A . 1 o

Effector Mechanisms of Tissue Destruction inRheumatoid Arthritis and PeriodontitisThere is almost universal acceptance that a variety ofcytok ines and matr ix metal loprote inases (MMPs) areupregulated and int imate ly involved in the pathogen-esis of both periodontit is and RA; many of these effec-tor molecules appear to be common to both d iseases.The task now is to identify the specific cytokines, theirconcentrations, the cells they affect in vivo, the stagesin which they are active, and the role and concentra-tions of their inhibitors. While the effects of cytokineson normal ce l lu lar process are important , i t is thei rpurported roles in pathophysiology that may resultfrom excessive production, dysregulation, or inade-quate inhib i t ion that have gained most at tent ion. lVery simply, cytokines can be classified into func-t ional groups based on the cel ls of or ig in, and a l l majortypes have been identif ied and located in inflamedsynovia l and per iodonta l t issues.

Periodontit is has very similar cytokine profi les top4,27'28 consisting of persistent high levels of proin-f lammatory cytok ines, inc luding lL- 1B and tumornecrosis factor-a lpha (TNF-ct) , and low levels of cyto-kines which suppress the immunoinflammatory re-sponse such as IL- 10 and t ransforming growthfactor-B (TGF B). These cytokines, together withlow levels of t issue inhibitors of metalloproteinases(TIMPs) and high levels of MMPs and prostaglandin E2(PGE2), are associated with the active stages of peri-odontit is.

The destruction of soft and hard tissues seen in RA isalso the result of not only a large number of cytokines

d5 r

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Periodontol . November 2005 (Suppl.)

but also the sustained presence of other effector mol-ecules released by resident and migrating cells. To-gether, these soluble mediators of inflammation areable to induce degradation of collagen and proteogly-cans either through direct or indirect means. Produc-tionof the arachidonic acid metabolite PGE2 as well asthe release of neutrophil-associated enzymes, such asneutrophil elastase and B-glucuronidase, togetherwith the secretion of matrix metalloproteinases bymacrophages and synoviocytes, all contribute signif-icantly to the pathogenesis of RA.

Formulation of the HgpothesisOn the basis of the above considerable similarities be-tween the pathological and clinical features of RA andperiodontitis (especially in the advanced and aggres-sive forms of these diseases), we have proposed thatin some susceptible individuals, there are commonfeatures of an underlying and presently unknown dys-regulation of the inflammatory mechanism which pre-disposes these individuals to advanced, aggressive,and severe forms of either disease.

Studies on Relationships Between Periodontitisand Rheumatoid ArthritisTo date, very few studies have examined the associa-tion between RA and periodontal disease, and theresults have often been conflicting. For example,Finnish studies found no correlation between peri-odontal disease and arthritis,2e while others3,30 sug-gest a higher prevalence of periodontal bone loss inRA. A major reason for these discrepancies relatesto the lack of uniformity in classifying the variousforms of periodontal disease and RA. Indeed mostof the early studies,3'29-31 failed to take into accountthe various forms of RA and periodontal diseaseand, as a result, grouped all subjects as either havingRA or periodontal disease with little or no regard forsubclassification for more detailed analyses. In lightof these limitations, it is clear there is a need tore-examine the extent of the association betweenspecific types of RA and periodontal disease. In par-ticular, it is our thesis that the more aggressive orsevere forms of periodontal disease and RA will showa very close correlation in terms of coexistence.

ln our first pilot study,6 investigating self-reporteddisease experience, the prevalence of moderate tosevere periodontitis was significantly elevated in in-dividuals with RA (uhadjusted relative risk of 4.7).In addition, the converse was also true in that peri-odontitis patients had a higher prevalence of RA com-pared to the general population (unadjusted relativer isk of 1.5).

In a subsequent study, 65 patients attending arheumatology clinic were studied for their level of peri-odontitis and RA.2 A control group consisted of age-and gender-matched individuals who did not have

Bartold, Marshall,

RA. No differences were noted for the plaque andbleeding indices between the control and RA groups.The RA group did, however, have significantly moremissing teeth than the control group and a greater per-centage of these subjects had deeper pocketing com-pared to the controls. The percentage of alveolar boneloss correlated positively with the principal parame-ters of RA severity.

These two pilot studies have resulted in several sig-nificant findings. Contrary to current dogma, RA pa-tients do not have impaired oral hygiene (judged byplaque and bleeding scores). Perhaps more impor-tantly, it was noted that individuals with severe RAare more likely to have advanced periodontitis andvice versa. Although many RA patients take medica-tions that can reduce periodontal destruction (i.e.,NSAIDs and immunosuppressants), we have notedsignificant periodontal destruction in these patients.This indicates that prior to the development of RAsymptoms, the periodontitis was most likely develop-ing and not detected. Thus, disease duration may bea very important factor. Finally, in order to understandthe interrelationships between periodontitis and RA, itis necessary to categorize the disease on the basis ofseverity and duration (i.e., type of disease).

Recently, using an animal model, additional evi-dence has been presented to indicate a significant re-lationship between periodontitis and rheumatoidarthritis.32 From this study it was reported that induc-ing experimentalarthritis in the rat (adjuvant arthritis)resulted in periodontal breakdown characterizedby alveolar bone loss and increased matrix metallo-proteinase activity in adjacent gingival tissues. Inter-estingly, all of these reactions occurred withoutmanipulating the oral or subgingival microflora.

Osteoclast Actioation and Vascular Damage - ACommon Pathwag in Periodontitis andRheumatoid Arthritis?Most recently, studies from our laboratory (unpub-lished data) have begun to investigate the codistribu-tion of cytokines involved in vascular damage andbone resorption in biopsies from graded rheumatoidarthritis and periodontitis lesions. Since the tumor ne-crosis factor (TNF)-like molecules and their receptorshave been shown to be involved in both processes, wehave chosen to study the receptor activator of nF-kappa B ligand (RANKL), osteopretogerin (OPG),and TNF-related apoptosis inducing ligand (TRAIL)to determine at least one molecular mechanism com-mon to both conditions.

The cell surface TNF-like molecule, RANKL and itsreceptor, RANK have been shown to be key factorsregulating osteoclast formation and activation.33'34It has been shown that when RANKL binds to RANKon the surface of osteoclast precursors, these cells

Periodontitis and Rheumatoid Arthritis Volume 76 . Number | |

differentiate to form mature osteoclasts. It is now clearthat RANKL, together with macrophage-colony stim-ulating factor (M-CSF), is required for osteoclast for-mation. The soluble TNF "receptor-l ike" molecule,OPG, is a natural inhibitor of RANKL.35 OPG btndsto RANKL and prevents its l igation to RANK. The im-portance of these molecules in regulating bone me-tabolism has been demonstrated by transgenic andgene knock-out studies in mice.36 Since these factorscontrol physiologic osteoclast formation, it is reason-able to propose that they may also be key regulatorsof pathological bone resorption.3T'38 AlthoughRANKL is normally provided by osteoblast-l ike cellsin bone,38'3e there are reports suggesting that lym-phocytes present in rheumatoid tissues may be themain source of RANKL in inflammatory arthrit is.33'40Furthermore, CD3+ T cells from the human rheuma-toid joint express RANKL and can promote osteoclastformation from rodent spleen precursors.a0 In addi-tion to lymphocyte production of RANKL, inhibit ionof RANKL by OPG treatment in vivo reduces bothbone and carti lage destruction in a model of adjuvantarthrit is.a I

Under certain conditions, human osteoclasts arederived from osteoclast precursor cells present in ornear to the tissues of arthrit ic joints.a2,a3 More recentreports in humans44,45 un4 animals4l show thatRANK/RANKL interactions may be required for oste-oclast formation and bone resorption in the RA joint.Accordingly, we have recently demonstrated that OPCand RANKL are expressed in biopsies of inflamedrheumatoid synovium and periodontit is lesions.46 Inaddition, we have found (unpublished data) that an-other l igand for OPG, TRAIL, is expressed in the bothtypes of t issue (although not from the same patient).In these studies we have noted that OPC decreaseswith inflammation, RANKL increases with inflamma-tion, and TRAIL increases with inflammation. Thesefindings may be of considerable significance in l ightof OPG's abil ity to block the activity of TRAIL (andvice versa) and TRAIL's anti-inflammatory proper-ties.aT

The production of OPG by endothelial cells may besignificant for reasons other than its effects on bonemetabolism, and there is now evidence to suggest thatOPG might also regulate endothelial cell function.OPG has been reported to be required for endothelialcell survival and growth.as In addition, OPG knock-outmice have been shown to develop arterial calcif ica-6on49,50 as well as severe osteoporosis, suggestingthat vascular endothelial expression of OPC mayhave a role in vascular homeostasis.4l One of themost unexpected findings from our recent studies ofdiseased periodontal and synovial t issues was the ob-servation that endothelial cells produce large amountsof OPG (unpublished observations).

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ln response to proinflammatory cytokines TNF-oand lL- 1 P, OPG mRNA expression was dramaticallyenhanced, resulting in secretion of newly synthesizedOPG and a reduction in cell-associated OPG. Suchfindings are consistent with our observations in vivofor active RA and periodontit is lesions. Vascular dam-age due to apoptosis is thought to precede vascularcalcif ication5l and contribute to atherosclerosis.52In addi t ion, d iabet ic endothel ia lce l ldysfunct ion is as-sociated with DNA damage induced by poly (ADP-ribose) polymerase activation. The exact cause ofendothelial cell dysfunction is not known but it is pos-sible that molecules such as TRAIL, expressed innearby cells and tissues, may be important.38,53 9u,recent binding studies confirm that OPG binds toTRAIL, although with less affinity than RANKL, in vi-tro, and blocks its activity (unpublished data). The fi-nal piece of compelling evidence for the role of OPG invascular damage comes from the fact that OPGknock-out mice develop vascular calcif ication. It issignificant to note that calcif ication cannot be re-versed by systemic treatment with recombinant OPGpostpartum.5o This supports our concept that OPGmust be expressed within the endothelial cells, eitherin an appropriate form or associated with other mole-cules, and this only occurs following normal synthesiswithin the healthy endothelial cells.

In l ight of the above, we propose that at least oneunderlying common molecular pathway in commonbetween rheumatoid arthrit is and periodontit is maylie within the RANK/OPG/TRAIL axis whereby OPGdecreases leading to decreased vascular protection.In addition, with an increase in RANKL and TRAILwi th in the t issues, not only is vascular damage pos-sible, but significant activation of osteoclasts mayresult. This proposal sti l l awaits verif ication.

COMMON PATFIOGENESIS _ COMMONTREATMENT?

Current and Emerging TherapiesCurrently, the mainstream "first-l ine" modes of treat-ment for RA remain the NSAIDs such as aspirin, nap-roxen, diclofenac, and ibuprofen. Their mechanism ofaction through the inhibit ion of cyclooxygenase(COX) synthesis produces both analgesic and antipy-retic properties. While these medications are effectivein reducing the pain symptoms in RA, they do not sig-nificantly alter its course.54

The use of NSAIDs for management of periodontaldisease has been studied over the past 20 years.s5-57While the results appear promising, the widespreadclinical use of these medications to alter the courseof periodontit is has not been universal. One particularproblem with their use for the management of peri-odontit is appears to be a "rebound" effect to baselinefollowing cessation of the medication.5s

Periodontol . November 2005 Bartold, Marshall,

With the discovery of two COX enzymes responsi-ble for PGE2 production, designated COX- 1 (constitu-tively expressed) and COX-2 (inducible), a variety ofCOX-2 inhibitors have been studied for their potentialto stop or slow down bone resorption. One of the firstCOX-2 inhibitors developed, tenidap, has been shownto inhibit not only cyclooxygenase and PGE2 produc-tion but also IL-1, IL-6, and TNF-ct production. Todate, COX-2 inhibitors have not been thoroughlystudied for their potential to modify bone resorptionin periodontitis.

In contrast to the NSAIDS, which do not signifi-cantly alter the course of RA, a newer family of med-ications designated disease-modifying anti-rheumaticdrugs (DtvtARDs) has been developed. To be classifiedas a D/vlARD. the medication must demonstrate anability to change the course of RA for at least 1 yearas evidenced by sustained improvement in function,decreased synovitis, and prevention of further jointdamage.5e Examples of these medications includeparenteral gold salts, methotrexate, sulfasalazine, hy-droxychloroquine (antimalarial drug), penicillamine,azathioprine, and leflunomide. A major drawback inthe use of Dl4ARDs is their considerable toxicity.60'61

The use of DMARDs for the management of peri-odontitis has been restricted largely due to the toxicity

of elevated IL-1 in inflamed tissues.T2-74 Similarly,other studies have shown that blocking the activityof another important inflammatory cytokine, TNF-a,has therapeutic efficacy in RA patients.T5-78 The rolesof IL-1 and TNF antagonists in a primate model ofperiodontitis have demonstrated a reduction in theinflammatory infiltrate in close proximity to bone aswell as reduction in the formation of osteoclasts andreduced bone loss.79

Clearly, many of these biologic agents, which tar-get specific molecular events associated with acuteand chronic inflammation, have significant potentialto alter clinical outcomes for both RA and periodontaldisease. With the emerging understanding that RAand periodontitis are multifactorial diseases, combi-nation therapies that target multiple disease out-comes are also emerging. For example, in ananimal study, it was reported that the administrationof a combination of a chemically modifiedtetracycline(CMT- 1) plus an NSAID, such as flurbiprofen or teni-dap, synergistically inhibited severe bone destructionin arthritic rats, with the suppression of MMP activity inthe joints.80'81 Similar encouraging results have beenreported for periodontitis in humans.82

Notwithstanding the above, it must be recognizedthat periodontitis differs in one significant way fromRA through our understanding that the subgingivalbiofilm is a key etiologic factor. Unlike periodontaldisease, no specific bacterial etiology has been iden-tified for RA. Thus, while host modification of diseaseprocesses are possible for periodontitis, controllingthe bacteria that cause periodontal infections remainsa significant focus for periodontal treatment and pre-vention. At best, host modification can be only an ad-junct treatment for periodontitis. However, until anetiologic factor can be found for RA, host modificationremains the mainstay of treatment.

CONCLUSIONSThere is no question that periodontitis and RA havemany pathologic features in common. Emerging evi-dence suggests a strong relationship between the ex-tent and severity of periodontal disease and RA. Whilethis relationship is unlikely to be causal, it is clear thatindividuals with advanced RA are more likely to expe-rience more significant periodontal problems com-pared to their non-RA counterparts, and vice versa.Hence, the possibility exists that both conditions re-sult from a common underlying dysregulation of thehost inflammatory response. The precise nature ofthis dysregulation remains to be established.

There is accruing evidence to support the notionthat both conditions manifest as a result of an imbal-ance between proinflammatory and anti-inflammatorycytokines. As a result, new treatment strategies willemerge for both diseases that may target the inhibition

issues. However, the use of gold salts in an animalmodel has shown reduced periodontal destruction.62To date, no human studies have been performed.

Another emerging area of potential for host modu-lation in periodontitis and rheumatoid arthritis is con-trol of the lvlMPs that are important mediators of,tonnective tissue breakdown in both hard and soft tis-sues. In this regard, tetracyclines and various chemi-

analogues have been found to inhibit MMP activitya mechanism that is independent of their antimi-

property.63,64 A number of clinical trials usingdose tetracycline to modify periodontitis havecarried out, with the most recent data indicating

low-dose doxycycline is safe and significantly ef-65'66 5on"11'teless, it is still recommended that

data be interpreted with caution to differentiatestatistically signifi cant and clinically relevant67 The role of MMP inhibitors in managing RA

been less well studied but promising results areing.68-zo In particular, a recent study has dem-

that low-dose and antimicrobial (higher)doxycycline, when used adjunctively with meth-

, produces enhanced improvements in globalof RA severitv in humans than methotrexate

with placebo.TlControl of cytokines and their receptors is also

as a field of considerable promise. For ex-, blocking the lL- 1 receptor and using gene

to deliver IL-1 receptor antagonist are twounder investigation to modulate the effect

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Periodontitis and Rheumatoid Arthritis

of proinflammatory cytokines and destructive pro_teases.

Through a better understanding of these rwo com_mon chronic inflammatory conditions, it is hoped thatareas of similarity can be exploited to determine thetrue relationship between these diseases and com_mon areas of treatment. Already, it can be predictedthat the periodontal status of paiients with RA shouldbe carefully screened.

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Correspondence: Dr. P.M. Bartold, University of Adelaide,Department of Dentistry, Frome Road, Adelaide, SouthAustra l ia 5005, Austra l ia . Fax: 61-8-8303-3435; e-mai l :mark.bartold@adelaide.edu.au.

Accepted for publication March 7,2005.

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