Rheumatoid arthritis and periodontitis: Biological links and the emergence of dual purpose therapies
Depinder Kaur Modi, Vipinder Singh Chopra, Usha Bhau1
ABSTRACT ABSTRACT
Rheumatoid arthritis and periodontitis are widely prevalent diseases and are characterized by tissue destruction due to chronic inflammation. Recently, there is growing evidence that the two diseases share many pathological features. This article reviews their clinical and biological links. However, there are only a limited number of studies in this area, which prevent us from offering clear evidence.
Key words: Biological linkages, periodontitis, rheumatoid arthritis
Address for correspondence:
Dr. Depinder Kaur Modi,
E-mail: drdeepinder@rediffmail.com Department of Pharmacology, Government Medical College,
1Sarwal Hospital Jammu, J & K Health Services,
Jammu 180 001, India Received : 17-02-07 Review completed : 25-04-08 Accepted : 23-06-08 PubMed ID : 19336867 DOI: 10.4103/0970-9290.49070
Rheumatoid arthritis is a systemic autoimmune disease characterized by progressive joint destruction and a variety of systemic manifestations resulting from chronic inß ammation. It affects approximately 1% of the adult population.[1] Rheumatoid arthritis is characterized by the inß ammation of the synovial membrane, leading to an invasion of the synovial tissue into the adjacent cartilage matrix with degradation of the articular cartilage and bone.
Though the pathophysiological mechanism of cartilage and bone destruction in rheumatoid arthritis is not exactly understood, it is known that matrix metalloproteinases, cathepsins, and osteoclast activation signiÞ cantly contribute to bone erosion.[2,3] A number of cytokines like TNF-α, IL-1, and macrophage colony stimulating factor (MCSF) are also involved.[4]
Periodontal disease is one of the most common chronic disorders of infectious origin known in humans with a prevalence of 10–60% in adults depending on the diagnostic criteria.[5] It includes gingivitis (an inß ammatory condition of soft tissues surrounding the tooth) and periodontitis (a bacterial infection of the periodontium).
Periodontitis is the most common type of periodontal disease. Most patients of periodontitis respond to bacterial invaders by mobilizing their defensive cells and releasing cytokines like interleukin-1β, tumor necrosis factor-α, and interleukin-6, which ultimately causes tissue destruction by stimulating the production of collagenolytic enzymes like matrix metalloproteinases.[6] Recently, there has been growing evidence suggesting an association between periodontitis and the increased risk of systemic diseases such as atherosclerosis, diabetes mellitus, adverse pregnancy
outcome, and rheumatoid arthritis. Periodontitis and rheumatoid arthritis share many pathological aspects and immunological Þ ndings. This article reviews their clinical and biological interrelation and current therapeutic approaches emerging from these links [Table 1].
CLINICAL INTERELATION
Several prospective clinical trials have shown that individuals with rheumatoid arthritis are more likely to experience moderate to severe periodontal disease compared to their healthy counterparts.[7] On the other hand, some studies have reported a high incidence of rheumatoid arthritis in patients with periodontitis.[8] This clinical association between the two diseases might be due to a common underlying pathobiology of periodontitis and rheumatoid arthritis [Figure 1].
BIOLOGICAL LINKS
1. Periodontitis is caused by periodontopathic bacteria like actinobacillus actinomycetemcomitans, porphyromonas gingivalis, bacteroides forsythus, prevotella melaninogenica, prevotella intermedia, and eubacterium nodatum.[9] Pathogen-speciÞ c immunoglobin (IgG and IgA) levels against some of these bacteria have been found to be raised in the synovial ß uid of patients with rheumatoid arthritis, pointing towards the possibility that these antibodies directed against periodontopathic bacteria could be important in the etiopathogenesis of rheumatoid arthritis.[10]
2. Porphyromonas gingivalis is an important periodon- topathic bacteria that possesses a unique microbial enzyme, peptidyl arginine deaminase (PAD), which is the human equivalent of this enzyme and has been
3. Antibodies against heat shock proteins (hsp 70 Ab) of P-melaninogenica and P-intermedia have been found to be raised in the periodontal tissue as well as the synovial tissue of patients with rheumatoid arthritis. It has also been shown that when the hsp 70 expression is induced with certain stress-stimulating factors, pro- inß ammatory cytokines are induced in the synovium of these patients[12] further pointing towards the etiopathogenetic relation between rheumatoid arthritis and periodontitis.
4. Genes on the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in the patients of both rheumatoid arthritis and periodontitis.
HLA-DR4 antigens and their subtypes are directly associated with both these diseases.[13] This genetic association between the two diseases also indicates a potential connection between rheumatoid arthritis and periodontitis.
5. Studies of the cytokine profile of patients with rheumatoid arthritis and periodontitis has shown that patients of both these diseases have raised titters of IL- 10, IL-1α, tnf-α, LT-α, and low titters of auto antibodies to IL-1α and IL-6.[14] Similar patterns of blood cytokine proÞ le in both the diseases also point toward a common underlying disregulation of the inflammatory and immune response.
6. L-1 cytokines are key mediators of immune responses, inß ammation, and tissue destruction in both the diseases.
Increased levels of IL-1B are found in the synovial tissue nacrophages and in the periodontal crevicular ß uid in patients with rheumatoid arthritis and periodontitis, respectively. A recent study demonstrated that the polymorphism of the IL-1 gene affected the cytokine proÞ le in patients of both periodontitis and chronic arthritis like rheumatoid arthritis.[15]
7. Experimentally induced inß ammatory arthritis in rats was found to be associated with elevated levels of tissue matrix metalloproteinases, tumor necrosis factor –ά, and interleukin-1 beta in both the synovial tissue and the gingival tissue.[16] This study also shows that the two diseases could be closely related through a common dysfunction of fundamental inß ammatory mechanisms.
Figure 1: Possible mechanism of pathological and genetic association between rheumatoid arthritis and periodontitis
Table 1: A summary of the effects of drugs that target both rheumatoid arthritis and periodontitis
Drugs Cells affected Effect Clinical effect
Tetracyclins Oral microorganisms and ! endotoxins Inhibit lysosomal ! periodontal and joint tissue
macrophages, Þ broblasts enzymes, MMPs destruction
Bisphosphonates Osteoclasts Inhibit lysosomal enzymes ! bone destruction in alveoli and joints
NSAIDs Macrophages Prostaglandins(PGE2) ! alveolar bone destruction
Symptomatic relief in rheumatoid arthritis CMTs Macrophages, Þ broblasts, endothelial Inhibit lysosomal enzymes, MMPs, ! periodontal and joint tissue
cells NO synthesis destruction
Ornidazole Oral microorganisms - ! periodontal destruction and
! disease activity in rheumatoid arthritis.
Osteoprotegrin Osteoclasts Inhibit RANK-RANKL interaction ! bone destruction in alveoli and joints
CLA Osteoclasts Suppress RANKL signaling Reduce bone resorption
CMT - Chemically modiÞ ed tetracyclins, CLA – Conjugated linoleic Acid, MMP - Matrix Metalloproteinase, NSAID - Non-steroidal anti-inß ammatory drugs, NO - Nitric oxide, RANK - Receptor activation of nuclear factor kappa B, RANKL- Receptor activation of nuclear factor kappa B ligand
implicated as a susceptibility factor for rheumatoid arthritis. It has been proposed that individuals with periodontal infection with porphyromonas gingivalis are exposed to antigens generated by PAD such as de- aminated Þ brin/Þ brinogen, keratin, and vimentin. These antigens become systemic immunogens leading to the production of rheumatoid factor and local inß ammation of both gingiva and synovium.[11]
prostaglandin E2 synthesis with NSAIDs has been associated with unequivocal therapeutic efÞ cacy in patients with periodontitis.[26] Current protocols for the prevention of periodontal disease require long term use of NSAIDs.
NSAIDs Þ nd their chief clinical application as anti- inß ammatory agents in the treatment of rheumatoid arthritis to reduce pain and inflammation. It has been documented that certain NSAIDs can directly inhibit the activation and function of neutrophils.[27]
They also inhibit TNF-α release from monocytes and non-killer (NK) cells.[28] These cycloxygenase independent effects may also contribute to the efÞ cacy of NSAIDs in the treatment of rheumatoid arthritis.
3. Bisphosphonates: Osteoclasts are responsible for the absorption and removal of bone. Agents that affect osteoclast function may be effective in the treatment of periodontitis and rheumatoid arthritis. A class of drugs known as bisphosphonates inhibits osteoclasts. They are incorporated into the bone and incapacitate osteoclasts thereby inhibiting lysosomal enzyme transport and secretion by osteoclasts.[29] Focal bone damage and generalized bone loss are features of rheumatoid arthritis. Studies have shown that new-generation bisphosphonates, like zoledronic acid, reduced the development of new bony erosions in patients with rheumatoid arthritis suggesting a structural beneÞ t with bisphosphonate therapy in these patients.[30]
Alveolar bone loss is an important complication of the inß ammatory process in periodontitis. Markers of inß ammation like TNF-α stimulate osteoclastic bone resorption in these patients. Bisphosphonate therapy is useful in them as they inhibit bone resorption and increase bone mass. Bisphosphonate treatment also improves the clinical outcome in patients with periodontitis and may be an important adjunctive treatment for periodontitis therapy for prevention of bone loss.[31]
EMERGING THERAPIES
1. Ornidazole: A synthetic, nitroimidazole with potent antiprotozoal and antibacterial activity. Ornidazole has good activity against most of the periodontopathic bacteria and is a commonly used drug for the treatment of periodontitis.[32] The usefulness of ornidazole has also been documented in patients with rheumatoid arthritis though its mechanism of action is not known. Ogrendik, et al.[33] showed that the administration of ornidazole in patients with active rheumatoid arthritis was associated with a signiÞ cant reduction in pain, duration of morning stiffness, erythrocyte sedimentation rate (ESR) and C-reaction protein levels. An overall reduction in disease activity was observed. Orinidazole was well tolerated in these patients at a dosage of 500–1000 mg/day with few adverse effects, such as headache, dry mouth, and nausea.
If there is validity to the biological base for linking aspects of rheumatoid arthritis and periodontitis then therapies that concordantly target these two diseases will be effective in reducing the levels of proinß ammatory cytokines and destructive proteases implicated in the pathogenesis of both diseases.
DUAL PURPOSE THERAPIES BASED ON BIOLOGICAL LINKS
1. Tetracyclines and its analogues: The tetracyclines are a group of broad-spectrum antimicrobial agents. They are active against a number of gram-positive and gram- negative bacteria. In the 1980s, periodontal research revealed that tetracyclines also inhibited collagenase activity.[17] Collagenases are a large family of enzymes that breakdown macromolecules in the connective tissue; they include matrix metalloproteinases (MMPs).
Tetracyclines reduce the activity of MMPs by depriving them of divalent cations, which are cofactors necessary for their activity. They chelate these ions thereby reducing their protein degrading activity.[18] This action of tetracyclines is observed at sub antimicrobial doses.[19]
Enhanced activity of the MMP has been demonstrated in synovial ß uid and synovial Þ broblasts of patients with rheumatoid arthritis and is partly responsible for joint destruction in these patients.[20] Tetracyclines by virtue of their anti-MMP activity are useful in patients with rheumatoid arthritis. Several clinical trials have shown that minocycline administration in patients with rheumatoid arthritis was associated with signiÞ cant reduction in disease activity.[21]
Soft and hard tissue destruction in periodontitis is partly due to bacterial virulence factors/enzymes and partly due to MMPs.[22] Tetracyclines and their analogues have been shown to be useful in the treatment of patients with rapidly progressive and refractory periodontitis.
[23] They act both by suppressing the growth of putative microorganisms implicated in periodontitisand by decreasing the destruction of collagen in gingival, periodontal ligament and alveolar bone by inhibiting MMPs in these patients.[22]
2. Nonsteroidal anti-inflammatory drugs (NSAIDs):
The principal mechanism by which NSAIDs act is by inhibition of cycloxygenase—the enzyme responsible for the biosynthesis of prostaglandins. Studies have shown that periodontally diseased tissues have higher prostaglandin levels, especially prostaglandin E2, than in healthy tissue.[24] In vivo studies have also shown that bone resorption in periodontitis is mediated in part by prostaglandins, showing that these may be important mediators of periodontal disease.[25] If prostaglandins are important mediators of bone resorption in periodontitis, the use of NSAIDs should be effective in preventing inflammation-induced bone loss. Both animal and human studies have demonstrated that inhibiting
2. Chemically modiÞ ed tetracyclines (CMTs): These are the drugs that were developed to eliminate the antimicrobial properties of tetracyclines while retaining their non antimicrobial properties by modifying the tetracyclic naphthacene carboxamide ring of tetracyclins.[34]
CMTs inhibit the synthesis of MMPs.[35] Non antibiotic analogues of doxycyclin (CMT-3) and minocyclin (CMT-8) have been shown to be potent inhibitors of osteoclastogenesis in vitro.[36] CMT-8 has also been shown to exert anti-inß ammatory effects by inhibiting nitric oxide (NO) synthesis, and it can also modify cell viability by exerting a strong apoptotic activity.[37] Such CMTs may reduce tissue breakdown and bone resorption in rheumatoid arthritis and periodontitis and might emerge as future disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis.
3. Osteoprotegrin (OPG): Recent evidence shows that the interaction between the receptor activation of nuclear factor kappa B ligand (RANKL) and its receptor activator (RANK) has an essential role in the activation of osteoclast and bone resorption.[38] OPG is a naturally occurring high afÞ nity soluble decoy receptor for RANKL. It inhibits RANKL interaction with RANK thereby inhibiting osteoclast activation as a result of this interaction.[39] RANKL appears to be the important pathogenetic principle that is responsible for the destruction of bone matrix in patients with both rheumatoid arthritis and periodontitis.[3,39] It has also been documented that OPG expression on synovial lining cells is deÞ cient in patients with rheumatoid arthritis with active synovitis and in gingival cervical ß uid in patients with periodontitis.[38,40] In view of the ability of OPG to block RANK-RANKL interaction and osteoclast activation, it may have a therapeutic role in conditions where bone destruction is a major sequel of chronic inß ammation such as rheumatoid arthritis and periodontitis.
4. Conjugated linoleic acid (CLA):[41] It has been found to be an important inhibitor of osteoclastogenesis. It acts by modulating the RANKL signaling pathway. CLA has also been shown to positively inß uence calcium and bone metabolism. Thus, it may have important therapeutic implications in the treatment of inß ammatory diseases associated with bone destruction.
CONCLUSION
The past few years have witnessed an increase in research evidence suggesting an association between periodontitis and an increased risk of rheumatoid arthritis. How are the two diseases linked? Probably the inß ammatory mediators and microbial products (endotoxins) are the likely conduits.
Inhibition of common mediators and effector molecules such as MMPs can reduce the severity of both of these diseases.
However, there is still a clear need for methodologically rigorous observational studies and therapeutic trials in this area.
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How to cite this article: Modi DK, Chopra VS, Bhau U. Rheumatoid arthritis and periodontitis: Biological links and the emergence of dual purpose therapies.
Indian J Dent Res 2009;20:86-90.
Source of Support: Nil, Confl ict of Interest: None declared.
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