ASSOCIATION OF PERIODONTITIS WITH RHEUMATOID ARTHRITIS: A PILOT STUDY

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Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease primarily of the joints that, if lelt untreated, results in functional disebility concordant with radiographic progression. It is well recognized that strking pathogenic similarities exist between periodontitis and RA. Proinflammatory cytokines such as tumor necrosis factoralpha (TNF a) and interleukin (IL) as well as microbial enzymes and host matrix metalloproteianses (MMP-8 and -9) appear to play important roles in both conditions....

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Nội dung Text: ASSOCIATION OF PERIODONTITIS WITH RHEUMATOID ARTHRITIS: A PILOT STUDY

ASSOCIATION OF PERIODONTITIS WITH RHEUMATOID ARTHRITIS: A PILOT STUDY Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease primarily of the joints that, if lelt untreated, results in functional disebility concordant with radiographic progression. It is well recognized that strking pathogenic similarities exist between periodontitis and RA. Proinflammatory cytokines such as tumor necrosis factoralpha (TNF a) and interleukin (IL) as well as microbial enzymes and host matrix metalloproteianses (MMP-8 and -9) appear to play important roles in both conditions. Bone metabolism is integral in both diseases, and the roles of the receptor activator of nuclear factorkappa B ligand (RANKL) and its in hibitor osteoprotegerin (OPG) in bone/jaw resorption and joint established. In addition, the two conditions share common genetic and environmental epidemiologic rick factors. Indeed, several observational studies demonstrated a high prevalence of periodontitis in patients with RA compared to the general population. Moreover, the presence of periodontitis in subjects with RA was associated with more active disease manifested by higher acutephase responses and a higher acutephare responses and a higher number of tender and/or swollen joints. Based on these studies, it was post ulated that periodontitis may be a rick factor for both RA onset and its progression. Periodontitis is a chronic inflammatory disease of the supporting structures of teeth that is present in as much as 15% to 20% of the general population, more prevalent than RA, which is thought to affect 1% of the population. The most important predisposing factor for periodontitis is poor oral hygiene resulting in the accumulation of plaque and calculus around gingival to active and more severe forms of periodontitis with the destruction of periodontal with a few, but mostly anaerobic , species of bacteria that form a bionfilm on the teeth are resistant to host defenses. Although mild disease is reversible destruction of the supporting bone and the eventual loss of involved teeth. Other contributors to periodontitis race, tobacco use, advancing age, comorbid diabetes mellitus (DM), and osteoporosis. The objective of this study is to evaluate the prevalence and severity of periodontitis in a population of United States (U.S) veterans with RA, making comparisons to a group of patients with noninflammatory arthritis. In this pilot study, we show that perodontitis was more common and more severe in patients with RA compared to patients with ostearthritis (OA).
Moreover, our results suggest that periodontitis is associated with autoantibody expression in RA, including seropositivity to cyclic citrullinated peptide (CCP) antibody, which is highly relevant given the diease specificity of this antibody and its pathogenic role in RA. MATERIALS AND METHODS Study population Study participants were enrolled over a 12-month perid from two Veteran Affairs (VA) rheumatlogy outpatient clinics (Dallas and Washington, DC, VA Medical Centers). All patients with RA satisfied Amerrican College of Rheumatology (ACR) classification criteria. A convenience sample of patient with rheumatologist-diagnosed OA (without concurrent active inflammatory arthritis: polymyalgia rheumatica, gout, pseudogout, and ankylosing spondylitis) served as controls. In addition to representing a convenience sample for comparison, this noninflammatory arthritis group was selected based on anticipated similarities with RA cases including age, gender, and racial distribution. Institutional review This study was conducted from August 2007 through January 2008 in conformity with the principles embodied in the Helsinki Declaration of 1975 as revised in2000. The protocol was approved by the Institutional Review Boards of all VA Medical Center sites in volved in this investigation and all study participants provided written informed consent to participate in the study. Oral Examination Twodentists (RR, MJ) at the Washington, DC, VA Medical Center and one dentist (GG) at the Dallas VA Medical Center, masked to the rheumatologic diagnoses, performed the examinations independently. Patient with
mobility (Miller mobitity index) and digital panoramic radiographs to evaluate the presence and severity of periodintitis. Alveolar boneloss percentages were mentally computed as either the overall average when there was widespread horizontal loss or a the average of the worst two teeth on each quadrant when bone loss was markedly uneven. In quentionablecases, linearmeasurement tools available in dental software were employed to determinne the bone loss. Panoramic radiograph equipment was set to provide a standard angle of incidence to the teeth and supporting bone with optimum resolution. Categories and critera for the application of diagnostic data were abbreviated from clinical guidelines published through the American Academy of Periodontology as follows: no periodontitis (essenntially a healthy periodontium); mild periodontitis =
Measures of RA disease activity included a multidimensional health assessment questionnaire (MD-HAQ), C-reactive protein (CRP) concebtration, and the four variable disease activity score- 28 [DAS28(4v)]. The MD-HAQ is a validated measure of physical function with a continuous score varying from 0 to 3, with higher scores reflecting greater disability. The DAS28(4v) is a mathematic calculation using compunent tender and swollen-joint counts (0to 28 joints), the score for patients’ global well being (0 to 100 mm, measured using a visual analog scale), and the erythrocyte sedimentetion rate (ERS;mm/hour), a laboratory measure of inflammation DAS28(v4) score were further categozized as follows: inactive (3.2 to 5.1) and severe (>5.1) disease activity. RA disease severity was assessed by the presence or absence of rheumatoid factor (RF) or anti-CCP antibody and the presence of radiographic erosions on hand or foot films documented through the process of routine rhoumatologic care. Statistical Analyses Univariate relationships with an RA diagnosis (RA versus OA) were examined using the chisquare x2 test for categoric variables and one-way analysis of variance for continuous variables. To investigate multivariate relationships of an RA diagnosis with periodontitis severity and other covariates, we used logistic regression with the folowing characteristics examined as predictors; periodontitis (none, mild, moderate/ severe), race, smoking (current, former, never),DM, age, BMI, and osteoporosis (none, osteopenia, or osteoporosis). Both BMI and osteoporosis had missing data (17% and 42% respectively), but because neither was significantly associated with RA or periodontitis in either univariate or multivariate analyses, both were excluded from RA versus OA comparisons to maintain the sample size. Models were testes using all predictors as well as in a back-ward-elimination model, in which a P value
(AIC) was used to evaluate the model fit, and this R2 were used to determine which models provided the best combination of a good fit and high explanatory power. Due to limited sample sizes (in particular, the number of seronegative patients), comparisons examining the associations of periodontitis with RA were unadjusted and done using the X2 test. Results Ninety-one patient with RA and 41 patient with OA were enrolled. The RA patients had an age range of 33 to 86 years (mean age =62 years), while the OA patients’ age range was 24 to 82 years (mean age =58 years). Twenty-eight edantulous patients, 22(245) with RA and six (15%) with OA (P=0.26), were excluded. Sixty-nine patients with RA (57 males and 12 females) and 35 with RA (57 males and 12 females) and 35 with OA (30 males and five female) remained for further study. There were diffirences between study cohorts (RA versus OA) in age, gender, race, smoking status, DM, osteoporosis, sicca sydrome, or use of a NSAID (table1). Among patients with RA, the majority were seropositive for both RF (81%) and anti-CCP antibodies (87%), and the majority were receiving concurrent prednisone, and a single patient was receiving doxycycline. Measures of disease activity, onle performed in patients with RA, indicated a moderately wellcontrolled disease with relatively low MD-HAQ scores (mean=1.25 mg/dl;SD=0.55 mg/dl; with normal values
adjustment, the odds of having RA increased 7.03 times for women (95% CI=1.37 to 36.14) versus men, and 2.87 times for current or former smokers (95% CI=0.96 to 8.53) versus those who never smoked. When we used backward elimination with the threshold for staying in the model set to a Wald X2 P valua of 0.05, we found that only one variable, periodontitis severity, remained in the model. The AIC was minimized (indicating best fit) for a model that included the predictors periodontitis severity, gender and current smoking (AIC=129.5), although the prediction accuracy was reduced (R2=0.10). in patients with RA, there was no sicca syndrome, osteoporosis, medication use (glucocorticoid, DMARD, or biologic) or disease duration. Moderate to severe periodontitis was more frequently odserved among RA patients who were seropositive for RF or the anti-CCP antibody. Speifically, among RA patients who were seropositive for RF,59% had moderate to severe periodontitis, 25% had mild periodontitis, and 16% had no periodontitis. In contrast, among patients who were RF negative, corresponding rates were 15% (moderate to severe), 54% (mild), and 31% (none) (P=0.02 for the diffirence). Similarly, among patients who were RA seropositive for the anti-CCP negative, corresponding rates were 22% (moderate to severe), 22% (mild), and 56% (none) (p=0.01 for the difference) (table 2). The presence of radiographic erosions was not associted with periodontitis status (P=0.18), and there were no associations of periodontitis and measures of RA disease activity as measured by DAS28(4v), CRP, or MD-HAQ (data not shown). DISCUSSION In this cohort, periodontitis was more common and more severe in patients with RA compared to controls with OA. The association remained after adjusting for potential confounders such as age, gender, race, smoking status, prednisone and other medication use, and DM. RF and anti-CCP antibodies were both associated with more severe periodontitis in patients with RA. To
out knowledge, this is the first report to show an association between the anti-CCP antibody and periodontitis in patients with RA. To our knowledge, this is highly relevant given the numerous studies that linked the anti-CCP antibody to a poor prognosis in patients with RA in addition to the potential pathogenic role of this autoantibody in the disease. Indeed, this is consistent with a recent study that showed associations of anti-CCP antibody concentrations in patients with RA antibodies targeting porphyromonas gingivalis, a major pathogenic organism in periodontitis. Periodontal studies in the U.S. veteran population indicate that periodontitis is common. In the Miami, lowa, and North Carolina VA conhorts, periodontitis was reported in as many as 40% of patients, with up to 50% of their geriatric population of the combined cohorts being edentulous. In our RA cohort of patients who had longstanding disease, 81% had some degree of periodontitis , which was moderate to severe in approximately one-half of the patients. Up to a quarter of patients with RA were edentulous copared to 15% of controls (patients without inflammatory rheumatic disease). Several studies documented an increased prevalence and severity of periodontitis in patients with RA. Among ~1,400 students enrolled in a dental study, 4% who were diagnosis of RA, >60% of whom had severe periodontitis. In another study of almost 2,000 patients who underwent tooth extraction secondary to periodontitis, patients with RA had the highest odds ratio for increased periodontitis among all encountered diseases after adjusting for age, gender , oral hygiene, smoking status, DM, and hypertension. These reports of the association of periodontitis with RA appear to apply to those with recent disease onset in addition to those with more established RA. Among 15 subjects with RA, those with early disease (mean of 8 month) were more likely to have periodontitis and higher tender and swoolen joint counts. In contrast, in 50 patients with longstanding disease, severe
periodontitis was more frequent compared to 101 matched controls. The assiation between periodontitis and seropositivy in RA was evaluated in only a limited number of report, none of which examined the association of periodontitis with the anti-CCP antibody. In a previous study of 103 older patients with RA, there was no diffirence in the rate of RF-seroposivity based on the presence/absence of periodontitis. This may be due to the use of modified “dianostic criteria” for RA used in this study with investigators requiring the presence of only three of six ACR critera, which usually require satisflying four of seven criteria. The possibility require satisfying four of seven criteria. The possibility of case misclassification in this study is undrscored by the very low overall prevalence of RF positivity observed (30%) compared to a prevalence of 60% to 80% in most epidemiologic studies in RA. Studies of genetic susceptibility to periodontitis indicated a linkage to human leukocyte antigen (HLA) DR4 subtypes 0401, 0404, 0405, and 0408, subtypes that were strongly associated with rick of RA. It is hypothesized that the association of these select HLA DRB1 subtypes with RA rick was due to a shared sequence coding for the binding groove in the third hypervariable region of DR4,referred to as the shared epitope. In addition to its associations with RA, these shared epitope alleles appeared to be associated with rapidly progressive periodonal inflammation. This was shown in a recent French study of 150 patients with RA, with a prevalence of periodontitis >50%. In this study, a shared epitope status was found to be assciated with periodontitis, conferring a more than two-ford rick for wrist or periodontal radiographic destruction. Conversely, the presence of erosions and periodonal destruction conferred a four-ford rick in having the shared epitope. Men with the shared epitope were at a greater rick for periodontitis than females. However, despite the repored correlation of the anti-CCP antibody with the HLA-DRB1 shared epitope, to our knowledge, ours is the first and only study to date
that measured anti-CCP antibody positivity in patients with RA with periodontitis definrd using systematic periodonal examinations. Prior studies also suggested that specific species of bacteria implicated as pathogens in periodontitis may be involved in the pathogenesis of RA. DNA-hybridization assays and immunoglobulin levels to Gram-negative anbic bacteria (particularly P. gingivalis) responsible for periodontitis were detected more frequently in patients with RA than in health controls. P. gingivalis trigger the release of inflammatory cytokines such as IL-12 and TNF-a, key mediators in the pathogenesis of RA, and the microbial enzyme peptidylarginine deiminase (PAP). PAP is an important virulence factor for P. gingivalis, an enzyme that mediates post-translational conversion of arginine into citrulline, a process that leads to the formation of unfolded, cyclic, citrullinated peptides. This is important because citrullinated is known to enhance the binding affinity of shared epitope alleles to candidate au toantigens and, thus, may be an important trigger in the early inflammation that characterzes RA. Although lacking periodonal examinations, a recent study found that immunity to P. gingivalis (measured with serum immunoglobulin G antibody) was more commomly seen in patients with RA than in health controls. Moreover, these investigators found significant correlations of the P. gingivalis antibody concentration with anti-CCP antibody values. Recent studies examined the effect of periodontitis therapy in patients with RA. However, these data are equivocal and potentially confounded by competing compliance between the required regular follow-up for patients with RA and dental care. Two studies have reported the relative lack of dental care and resulting poor oral hygiene as explanations for the higher frequency of periodontitis occurring in patientswith RA compared to controls. In a small cohort of patients with RA periodontitis, fullmouth scaling and root planting resulted insignificantly reduced periodontitis severity in addition to significant reductions
in ESR and DAS28 scores compared to those receiving only oral hygiene instruction. Therefore, it is possible that the prevention and appropriate treatment of periodontitis could improve RA disease activity. Patients included in the present study, although capable of performing routine daily oral hygiene, were not assessed for actual hygiene frequency and adequacy using standard plaque indices. The significance of oral hygiene and/or stendard dental care in preventing periodontitis in our RA cohort remains to be determined. One of the strengths of our study was the inclusion of a control group of patients with OA in whom there was no other inflammatory arthritis and who were demographically similar to the patients with RA. We were also able to control for many of the potential confounder of the relationship between RA and periodontitis inflammation. Such as smoking, DM, gender, race, medication use, and age. Limitations of our study include the ralatively low number of patients, particularly in the comparator group with OA. Also, the exact effect of the medications used to treat both RA and OA on periodontitis requires a larger cohort that also includes normal controls. In addition, one-third of the patients with RA had inactive disease as measureed by DAS28(4v), which, albeit an important clinical goal, may have limited our ability to dectect significant correlations with periodontitis severity. In addition, this piot study does not include relevant genotyping and serologic analyses, efforts that will be critical in future studies examining these clinical association. Also, given the unique attibutes of this U.S veteran cohort (predonminantly older men), it is possible that our findings are not applicable to other RA populations, specifically, younger women. CONCLUSIONS As RA patients with RF and anti-CCP antibody positivity are more likely to have a poor prognosis, including a more frequent development of erosive disease and increased rates of physical disbility, futher srudies assessing the precise etiopathogenic role
of periodontitis (and related pathogenic bacteria) are needed. It will be essntial to study larger numbers of patients in a prospective fashion to more precisely understand the temporal relationship of periodontitis with desease activity in RA. Likewise, large the role of periodontitis in RA desease susceptibility. However, our finding argue for greater attention to dental care in U.S veterans with RA, and the prevention and treatment of periodontitis needs to be advocated by dentists, rheumatologists, and policy makers charged with the care of this population. ACKNOWLEDGMENT The authors report no conflicts of interest related to this study