Cytokines which are produced by host cells play an important role in pathogenesis both rheumatoid arthritis (RA) and chronic periodontitis (CP). In this study, we aim to investigate the levels of Interleukin (IL)-4 and IL-10 in gingival crevicular fluid (GCF). Seventeen patients with CP, 17 patients with RA and 17 healthy controls (HC) were included. The RA group was divided into two groups according to gingival sulcus depths (RA-a: PD 3 mm, (n = 12), RAb: PD > 3 mm, (n = 5)). For each patient, clinical parameters were recorded. The GCF samples were evaluated by enzymelinked immunosorbent assay (ELISA) for IL-4 and IL-10 levels. IL-4 levels in the RA-a, RA-b and CP subjects were significantly lower compared to the HC subjects (p < 0.05). The mean level of IL-4 in RA-b group was significantly higher than that in CP group (p < 0.05). IL-10 mean level in the HC group was higher than those in the other groups (p < 0.05). In the RA-a group, higher IL-10 level was found compared to the CP patients (p < 0.05). Within the limitations of this preliminary report, it can be concluded that the initiation and progression of periodontal inflammation may be due to a lack or inappropriate response of the anti-inflammatory cytokines in both CP and RA.

Bozkurt FY, Ay ZY, et al. Cytokine, Volume 35, Issues 3-4, August 2006, Pages 180-185.
http://www.sciencedirect.com/science? _ob=ArticleURL&_udi=B6WDF- 4KXF2VS- 1&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_ userid=10&md5=c2c0d4c5 2d4e9ae3f7e968023be1e09d

Background: A limited number of studies suggest a higher prevalence of periodontal disease among individuals with rheumatoid arthritis (RA); however, results have been inconsistent. Further, it is unclear to what extent poor oral hygiene among patients with RA may account for this association. Methods: The association between RA and periodontitis was examined in 57 subjects with RA and 52 healthy controls, matched by age and gender. Oral examination included plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment loss (CAL). Potential risk factors for periodontal disease, such as smoking, education, alcohol consumption, and body mass index (BMI), as well as chronic diseases associated with RA and periodontal disease were assessed through questionnaires. Results: In a stepwise logistic regression, including RA status, age, gender, education, smoking, alcohol consumption, and BMI, only RA status and age remained significant predictors of periodontal disease. Subjects with RA had a significant 8.05-fold increased odds (95% confidence interval: 2.93 to 22.09) of periodontitis compared to controls. The strength of the association was attenuated but remained statistically significant after further adjustment for PI, GI, or both. PI alone accounted for 12.4%, GI alone accounted for 11.1%, and PI and GI combined accounted for 13.4% of the association between RA and periodontitis. Conclusions: Subjects with RA have significantly increased periodontal attachment loss compared to controls. Oral hygiene may only partially account for this association.

Pischon N, Pischon T, et al. Journal of Periodontology, 2008, Vol. 79, No. 6, Pages 979-986. http://www.joponline.org/doi/abs/10.1902/jop.2008.070501

Cytokines are a complex family of small regulatory proteins able to mediate intercellular communication and play a crucial role in immunologic and inflammatory reactions. Many reports have demonstrated that some cytokines, in particular tumor necrosis factor a (TNFa) and interleukin (IL)-1ß 1ß, IL-6, and IL-8, so-called proinflammatory, may have a major role in the pathogenesis of joint diseases. Thus, high levels of these substances have been found in inflammatory arthropathies, in particular in those characterized by a more aggressive and destructive outcome, such as rheumatoid arthritis, gout, and infectious arthritis. In keeping with their role, the determination of cytokines in synovial fluid may be proposed for clinical purposes, including diagnostic and prognostic assessments. Furthermore, as some of these cytokines may reflect disease activity, their determination may also be useful in the evaluation of therapy.

Punzi L, Calo L, et.al. Critical Reviews in Clinical Laboratory Sciences Volume 39, Number 1/January-February 2002. P 63-88.
http://taylorandfrancis.metapress.com/content/xl7eupq0p2j9k8cq/

Objective: To conduct a robust, double-blind, placebo-controlled study examining the effects of tumor necrosis factor (TNF) modulation on concentrations of traditional and novel cardiovascular disease risk factors in patients with an inflammatory condition. This study is the first to demonstrate that targeting the TNF pathway can significantly decrease Lp(a) and homocysteine levels and elevate Apo A-I and SHBG concentrations. These data support an important precursor role for high-grade inflammation in modulating these putative risk parameters. However, TNF blockadeinduced increases in triglyceride and Apo B levels were unexpected and suggest that it is not possible, on the basis of biochemical changes in isolation, to suggest that cardioprotection would necessarily follow; rather, direct measures of atherosclerotic progression with TNF blockade (e.g., using carotid ultrasound) would be better.

Sattar N, Crompton P, et.al. Arthritis & Rheumatism, Vol 56, Issue 3, p 831-839.
http://www3.interscience.wiley.com/cgibin/ abstract/114130672/ABSTRACT

Inflammation is considered to be a leading cause of morbidity in systemic lupus erythematosus (SLE), yet inflammatory periodontal involvement is rarely encountered. A young lady suffering from active SLE accompanied by severe periodontal loss, manifested by gingival recession of all her teeth, was referred to our clinic for treatment. The association between periodontal involvement and connective tissue diseases is unclear, and the literature dealing with periodontal involvement in patients suffering from Sjogren's syndrome and rheumatoid arthritis is comprised of studies showing both normal and pathological periodontal status. We discuss the possible underlying mechanisms

Nagler RM, Lorber M, et al. Lupus, Vol. 8, No. 9, 770- 772 (1999)
http://lup.sagepub.com/cgi/content/abstract/8/9/770

Background: Lipopolysaccharide (LPS)-stimulated macrophages (M[Phi]) produce excess tumor necrosis factor (TNF), and the direct inhibition of I[kappa]B phosphorylation and its subsequent separation from the nuclear factor [kappa]B (NF[kappa]B)-I[kappa]B complex has been experimentally supported as a mechanism for [omega]-3 fatty acid (FA) inhibition of this TNF response. However, TNF production is a "late" event in the LPS-mduced M[Phi] inflammatory cascade, and in addition to NF[kappa]B-associated pathways, a separate transcription factor, activator protein-1 (AP-1) is an important pathway for M[Phi] proinflammatory cytokine production. The mitogenactivated protein kinase (MAPK) cascade regulates both NF[kappa]B-I[kappa]B-and AP-1-associated gene transcription through several cross-amplifying phosphorylation kinases, specifically p44/42 [ie, extracellular signal-regulated kinase (ERK) 1/2], p38, and c/jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK). The activation of these kinases occurs in the proximal MAPK cascade and activation modulates AP-1 activation. In this set of experiments, it was hypothesized that inhibition of MAPK signaling phosphorylation kinases by [omega]-3 fatty acids in a model of LPSstimulated M[Phi]s would alter the activation of the proinflammatory cytokine transcription factor AP-1. . Conclusions: [omega]-3 FA inhibited p44/42 and JNK/SAPK phosphorylation; however, p38 remained unchanged. Phosphorylation of p44/42 and JNK/SAPK are the immediate prior steps in AP-1 activation. Attenuated AP-1 activation and subsequent attenuated gene-level proinflammatory cytokine elaboration is anticipated after inhibition of these MAPK intermediates and is confirmed by the reduction in AP-1 activity. These results provide further evidence for the transcriptional level regulation in the elaboration of proinflammatory cytokines by [omega]-3 FA in this M[Phi] model.

Babcock TA, Kurland A, et.al. Journal of Parenteral and Enteral Nutrition 27:176-181, 2003. http://findarticles.com/p/articles/mi_qa3762/is_200305/ai_n9216984

Cytokines are important polypeptides mediators of acute and chronic inflammation. These molecules act as a complex immunological network, in which there are pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-a (TNF-a), and antiinflammatory mediators like IL-10 and transforming growth factor-b. In spite of some controversial findings, in general high levels of pro-inflammatory cytokines have been correlated with signs and symptoms of temporomandibular disorders (TMD) such as internal derangement and osteoarthritis. These mediators promote degradation of cartilage and bone joint by inducing release of proteinases and other inflammatory molecules. Indeed, pro-inflammatory cytokines have been associated with temporomandibular joint (TMJ) tissue destruction. However, its mechanisms and pathophysiology have not been clearly delineated. In attempt to summarize the role of cytokines in TMD pathophysiology and its potential for medical intervention, the purpose of the current study was to review the literature concerning the analysis.

Campos MIG, Campos PSF, et.al. Braz J Oral Sci. July-September 2006 - Vol. 5 - Number 18 http://www.fop.unicamp.br/brjorals/temp2/ c18_Art1_inflammatory.pdf

This review considers the considerable similarities between periodontal disease and rheumatoid arthritis (RA). While the etiology of these two diseases may differ, the underlying pathogenic mechanisms are remarkably similar and it is possible that individuals manifesting both periodontitis and RA may suffer from a unifying underlying systemic dysregulation of the inflammatory response. In light of these findings, the implications for the use of disease-modifying medications in the management of these two chronic inflammatory conditions is apparent. Further longitudinal studies and medication-based intervention studies are required to determine just how closely these two conditions are allied. allied.] Mercado FB, marshall RI, et al.

Clinical Periodontology Periodontology, Vol 30, , Issue 9, pp 761-772. http://www3.interscience.wiley.com/journal/118839567/abstract

Aim: The aim of this study was to determine whether there is a relationship between disease experience of rheumatoid arthritis and periodontal disease. Conclusions: Based on data derived from self-reported health conditions, and not withstanding the limitations of such a study, we conclude that there is good evidence to suggest that individuals with moderate to severe periodontal disease are at higher risk of suffering from rheumatoid arthritis and vice versa.

Mercado F, Marshall RI, et.al. Journal of Clinical Periodontology Volume 27 Issue 4 Page 267 - April 2000.
http://www.blackwell-synergy.com/doi/ abs/10.1034/j.1600- 051x.2000.027004267.x?journalCode=cpe

The purpose of this clinical study was to investigate if periodontal disease and rheumatoid arthritis (RA) are associated. The study included 39 RA patients (test group) and 22 ageand gender-matched healthy individuals (control group). Questionnaires on general and oral health were applied and a complete periodontal exam, including visible plaque, marginal bleeding, attachment loss (AL) and number of teeth present, was also performed by a single calibrated examiner. Diabetes mellitus patients and smokers were excluded. RA patients had fewer teeth, higher prevalence of sites presenting dental plaque and a higher frequency of sites with advanced attachment loss. Although the prevalence of dental plaque was higher in the test group (Chi-square test, p = 0.0006), the percentage of sites showing gingival bleeding was not different (Fishers exact test, p > 0.05). Based on our results, we suggest that there is an association between periodontal disease and RA.

Ishi ED, Bertolo MB, et al. Braz. oral res. v.22 n.1 São Paulo ene./mar. 2008. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1806- 83242008000100013&lng=es&nrm=iso&tlng=es http://www.scielo.br/pdf/bor/v22n1/a13v22n1. pdf

Objective: Our aim was to compare the periodontal conditions in a group of juvenile idiopathic arthritis (JIA) patients with those in a control group of healthy subjects (CTR). Material and Methods: Thirty-two patients with JIA and 24 controls were selected. The measurements used to diagnose periodontal disease included plaque and bleeding scores, probing depths (PDs) and clinical attachment loss (CAL). Laboratory indicators of JIA activity included the erythrocyte sedimentation rate (ESR) and capsule-reactive protein (CRP). The Mann-Whitney test was used to evaluate the data (a a=0.05). Results: The mean ages were 15.9 =(±2.7) years and 14.7 (±2.3) years for groups JIA and CTR, respectively. The median ESR was 42 mm/h in the JIA group and 13 mm/h in the CTR group (p=0.032) and the median CRP was 1.9 and 0.4 mg/l, respectively (p p=0.001). The =prevalence of patients with a proximal attachment loss of 2 mm or more in the JIA group was 25% and in controls it was 4.2%. The mean percentages of visible plaque and marginal bleeding were similar in the JIA (54±22 and 30±16, respectively) and CTR groups (44±18 and 29±11, respectively). The mean percentages of sites with PD 4 mm were significantly higher in the JIA group (3±4.7) than in the CTR group (0.4±1.7) (p p=0.012). The mean percentages of sites with proximal CAL 2 mm =were 0.7 (±1.4) in the JIA group and 0.001 (±0.2) in the CTR group (p p=0.022). Conclusion: Adolescents with JIA present = more periodontal attachment loss than healthy controls, in spite of similar plaque and marginal bleeding levels.

Miranda LA, Fischer RG, et al. Journal of Clinical Periodontology, Volume 30 Issue 11, Pages 969 - 974. http://www3.interscience.wiley.com/journal/118839441/abstract

Background: Because of several similar features in the pathobiology of periodontitis and rheumatoid arthritis, in a previous study we proposed a possible relationship between the two diseases. Therefore, the aims of this study were to study a population of rheumatoid arthritis patients and determine the extent of their periodontal disease and correlate this with various indicators of rheumatoid arthritis. Methods: Sixty-five consecutive patients attending a rheumatology clinic were examined for their levels of periodontitis and rheumatoid arthritis. A control group consisted of age- and gender- matched individuals without rheumatoid arthritis. Specific measures for periodontitis included probing depths, attachment loss, bleeding scores, plaque scores, and radiographic bone loss scores. Measures of rheumatoid arthritis included tender joint analysis, swollen joint analysis, pain index, physician's global assessment on a visual analogue scale, health assessment questionnaire, levels of C-reactive protein, and erythrocyte sedimentation rate. The relationship between periodontal bone loss and rheumatological findings as well as the relationship between bone loss in the rheumatoid arthritis and control groups were analyzed. Results: No differences were noted for the plaque and bleeding indices between the control and rheumatoid arthritis groups. The rheumatoid arthritis group did, however, have more missing teeth than the control group and a higher percentage of these subjects had deeper pocketing. When the percentage of bone loss was compared with various indicators of rheumatoid arthritis disease activity, it was found that swollen joints, health assessment questionnaire scores, levels of C-reactive protein, and erythrocyte sedimentation rate were the principal parameters which could be associated with periodontal bone loss. Conclusions: The results of this study provide further evidence of a significant association between periodontitis and rheumatoid arthritis. This association may be a reflection of a common underlying disregulation of the inflammatory response in these individuals.

Mercado B, Marshall RI, et al. J Periodontol 2001;72:779-787.
http://www.joponline.org/doi/abs/10.1902/ jop.2001.72.6.779

Objective. To quantify periodontal disease in rheumatoid arthritis (RA) patients and controls, and to correlate the degree of destruction from periodontal disease and from RA. Methods. Fifty RA patients were matched for age, sex, smoking status, and oral hygiene with 101 controls. Correlations between indices of chronic destruction in periodontal disease (gingival attachment loss) and in RA (Larsen radiographic score) were determined. Results. Patients with longstanding active RA (mean ± SD 13 ± 8 years) who were receiving treatment with disease-modifying antirheumatic drugs (n = 46), corticosteroids (n = 38), or nonsteroidal antiinflammatory drugs (n = 43) had a higher rate of gingival bleeding (increased by 50%), greater probing depth (increased by 26%), greater attachment loss (increased by 173%), and higher number of missing teeth (increased by 29%) compared with controls. No correlation was found between the Larsen radiographic score and gingival attachment. Conclusion. Patients with longstanding active RA have a substantially increased frequency of periodontal disease, including loss of teeth, compared with controls. Antiinflammatory treatment interferes with periodontal disease and might have masked a possible correlation between the indices of chronic destruction in RA and periodontal disease.

Kasser UR, Gleissner C, et al. Arthritis and Rheumatism, 1997, vol. 40, no12, pp. 2248-2251.
http://cat.inist.fr/? aModele=afficheN&cpsidt=2089082 http://www3.interscience.wiley.com/journal/112212854/abstract

The objective of this study was to detect soluble-form tumour necrosis factor receptors (sTNFRs) in temporomandibular joint (TMJ) synovial fluid aspirates, and to compare the sTNFR concentrations between painful anterior disc displacement without reduction and osteoarthritis (ADDwoR/OA) and asymptomatic TMJs. Synovial fluid was sampled from the superior TMJ cavity of 11 painful ADDwoR/OA cases (mean age: 36.9 years) and 10 asymptomatic females (mean age: 24.7 years) by diluted aspiration. The concentrations of sTNFR-I and -II in the synovial fluid were measured using human sTNFR-I and -II enzyme-linked immunosorbent assays. The total protein concentrations in synovial fluids were measured using a bicinchoninic acid protein assay kit. All data were normalised to the total protein concentration of each sample. Two-way factorial analysis of variance and post hoc multiple comparison revealed that: (1) mean normalised sTNFR-I and -II concentrations were higher in TMJ synovial aspirates from ADDwoR/OA patients than from healthy controls; (2) in the ADDwoR/OA patients and the healthy controls, the sTNFR-I concentration in TMJ synovial aspirates was higher than the sTNFR-II concentration; and (3) high TMJ synovial aspirate sTNFR-II seemed to be associated with less TMJ pain and a less restricted range of mouth opening in the ADDwoR/OA patients. The concentrations of sTNFRs in TMJ synovial fluid are higher in the presence of painful ADDwoR/OA, which could modulate intracapsular inflammation.

Uehara J, Kuboki T, et.al. Arch of Oral biology vol 49, Issue 2, P 133-142.http://www.aobjournal.com/article/PIIS0003996903002036/abstract

There are conflicting reports whether patients with rheumatoid arthritis (RA) are at a higher risk for periodontal disease (PD). Analogous mechanisms of tissue destruction have been reported for both diseases. This cross-sectional study should quantify PD in patients with longstanding RA and examine a possible association between the two diseases. It should also be investigated whether PD in RA patients could be the result of reduced functional capacity or be amplified by concomitant medical treatment. 50 RA patients were matched for age, sex, smoking and oral hygiene with 101 healthy controls. Data on the medication over the last three years was obtained by questionnaire. Among the rheumatological parameters recorded were a 28-joint-count, C-reactive protein (CRP), grip strength testing, upper extremity function (Keitel Index) and the Larsen-score of radiological joint destruction. The oral examination included the recording of individual oral hygiene measures and sicca symptoms, a modified Approximal Plaque- and Sulcus-Bleeding-Index (SBI), probing depths and clinical attachment loss and the Community Periodontal Index of Treatment Needs. The mean duration of RA was 13 (+/- 7.9) years. RA patients under treatment with disease modifying antirheumatic drugs (DMARDs, n = 46; 92%), corticosteroids (n = 38; 76%) and non steroidal antirheumatic drugs (NSAIDs, n = 43; 86%) had a higher rate of gingival bleeding (+ 50%), probing depth (+ 26%), clinical attachment loss (+ 173%) and number of missing teeth (+ 29%) compared with controls. While no correlation between the rheumatological variables (radiological destruction, functional capacity, grip strength) and the periodontal measurements (SBI, probing depth, clinical attachment loss) could be demonstrated, a positive correlation was observed between the CRP and the periodontal attachment loss (r = 0.32; p <0.05). In spite of a strong correlation between the duration of DMARD- and cortisone-medication and the Larsen-score (r = 0.48 and 0.64; p = 0.0005 and 0.0001, rsp.), no correlation between the duration of pharmacotherapy and the periodontal parameters could be established. Patients with long-term active RA present a substantially higher degree of PD including loss of teeth compared with controls. Functional impairment of the upper extremity might amplify present PD. The longterm use of NSAIDs, corticosteroids and DMARDs shows no connection with the severe PD observed in these patients. Oral hygiene amplifies PD severity and treatment need. Intensive prophylactic measures are required to prevent or reduce the damage of the periodontal tissues in RA patients.

Gleissner C, Willershausen B, et al. Eur J Med Res. 1998 Aug 18;3(8):387-92.
http://www.ncbi.nlm.nih.gov/pubmed/9707521