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ID PMID Title PublicationDate abstract
21224040 A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence 2011 Jan Chikungunya virus (CHIKV), an emerging mosquito-borne Alphavirus, causes debilitating rheumatic disease in humans that can last for weeks to months. Starting in 2004, a CHIKV outbreak in the Indian Ocean region affected millions of people, and infected travelers introduced CHIKV to new regions. The pathogenesis of CHIKV is poorly understood, and no approved vaccines or specific therapies exist. A major challenge to the study of CHIKV disease is the lack of a small animal model that recapitulates the major outcomes of human infection. In this study, the pathogenesis of CHIKV in C57BL/6J mice was investigated using biological and molecular clones of CHIKV isolated from human serum (CHIKV SL15649). After 14-day-old mice were inoculated with CHIKV SL15649 in the footpad, they displayed reduced weight gain and swelling of the inoculated limb. Histologic analysis of hind limb sections revealed severe necrotizing myositis, mixed inflammatory cell arthritis, chronic active tenosynovitis, and multifocal vasculitis. Interestingly, these disease signs and viral RNA persisted in musculoskeletal tissues for at least 3 weeks after inoculation. This work demonstrates the development of a mouse model of CHIKV infection with clinical manifestations and histopathologic findings that are consistent with the disease signs of CHIKV-infected humans, providing a useful tool for studying viral and host factors that drive CHIKV pathogenesis and for evaluating potential therapeutics against this emerging viral disease.
23032798 Iguratimod: a new disease-modifying antirheumatic drug. 2012 Sep Iguratimod, a methanesulfonanilide, is a novel disease-modifying antirheumatic drug that has been developed exclusively in Japan and China. It inhibits the production of immunoglobulins and various inflammatory cytokines (interleukin-1, -6 and -8 and TNF), and exerts anabolic effects on bone metabolism by stimulating osteoblastic differentiation and inhibiting osteoclastogenesis. On the molecular level, it inhibits the nuclear transcription factor NF-κB but not its inhibitor, IκBα. In addition to these immunomodulatory and other long-lasting effects, iguratimod inhibits cyclooxygenase-2, which provides a synergistic short-term action against pain and inflammation. Efficacy and tolerability are comparable to salazosulfapyridine, and probably also to methotrexate. Combination with methotrexate is synergistic in patients with insufficient response to methotrexate and does not significantly increase adverse events. Liver enzyme elevations and thrombocytopenia are the most significant side effects to watch for. In summary, iguratimod is a welcome addition to the small-molecule drug therapy of rheumatoid arthritis.
21378403 Reporting of long-term extension studies: lack of consistency calls for consensus. 2011 Jun Double-blind, randomised controlled studies represent the gold-standard approach to determine the safety and efficacy of therapeutic interventions. In chronic conditions such as rheumatoid arthritis (RA), long-term data are vital to confirm maintenance of effect and identify potential safety signals. The recent introduction of numerous biological therapies for RA has been followed by various long-term extension (LTE) studies. Although useful, the design and method of analysis in such studies vary significantly, partly due to their complexity. This viewpoint highlights general considerations needed when undertaking a LTE study and illustrates the lack of consistency in studies of RA to date. It addresses issues of selection bias, patient discontinuation and missing data. Although used for safety reporting, the lack of adequate powering makes LTE studies of limited benefit. Ethical considerations and challenges are highlighted, including potential conflicts of interest. Finally, the authors suggest the need for consensus to ensure more reliable interpretation and application of data for clinical practice. Following the development of guidelines on reporting of clinical trials in RA and more recently, registry data, a similar approach for LTE studies would be a useful endeavour.
21728841 Copy number variation of the gene NCF1 is associated with rheumatoid arthritis. 2012 Jan 1 AIMS: The aim of this study was to investigate genetic variants in the gene neutrophil cytosolic factor 1 (NCF1) for association with rheumatoid arthritis (RA). In rodent models, a single-nucleotide polymorphism (SNP) in Ncf1 has been shown to be a major locus regulating severity of arthritis. Ncf1 encodes one of five subunits of the NADPH oxidase complex. In humans the genomic structure of NCF1 is complex, excluding it from genome-wide association screens and complicating genetic analysis. In addition to copy number variation of NCF1, there are also two nonfunctional pseudogenes, nearly identical in sequence to NCF1. We have characterized copy number variation and SNPs in NCF1, and investigated these variants for association with RA. RESULTS: We find that RA patients are less likely to have an increased copy number of NCF1, 7.6%, compared with 11.6% in controls; p=0.037. We also show that the T-allele of NCF1-339 (rs13447) is expressed in NCF1 and significantly reduces reactive oxygen species production. INNOVATION: This is the first finding of genetic association of NCF1 with RA. The detailed characterization of genetic variants in NCF1 also helps elucidate the complexity of the NCF1 gene. CONCLUSION: These data suggest that an increased copy number of NCF1 can be protective against developing RA and add support to previous findings of a role of NCF1 and the phagocyte NADPH oxidase complex in RA pathogenesis.
22113599 Interobserver reliability in ultrasound assessment of rheumatoid wrist joints. 2011 Jul OBJECTIVE: To evaluate interobserver reliability in the ultrasound assessment of synovitis in the radiocarpal (RC), midcarpal (MC) and ulnocarpal (UC) joints in RA. METHODS: Ultrasound examinations of 295 rheumatoid wrist joints were performed over a three month period. The RC, MC and UC joints were examined using dorsal longitudinal ultrasound scans. Synovial thickening was assessed by quantitative measurement and a previously established semi-quantitative scoring system (Grades 0 to 3). Interobserver reliability was determined by the comparing the findings of two radiologists who were unaware of each other findings. RESULTS: The intraclass correlation coefficient (ICC) between examiners for the quantitative measurement of synovitis in the RC, MC and UC recesses were 0.508, 0.346 and 0.240 (p<0.001), respectively. Weighted kappa values using the semi-quantitative scoring system were 0.308, 0.312 and 0.153 for the RC, MC and UC joints, respectively. CONCLUSION: Interobserver reliability of the ultrasound assessment in rheumatoid wrists proved good for the quantitative measurement of synovitis in the RC joint, but poor agreement was found for the MC and UC joints. Using the semi-quantitative scoring system, interobserver agreement was poor for all three joints (RC, MC and UC).
22731637 N-acetyltransferase-2 genotypes among patients with rheumatoid arthritis attending Jordan 2012 Sep AIM: To determine the frequency of major N-acetyltransferase (NAT2) alleles and genotypes among Jordanian patients with rheumatoid arthritis (RA). METHODS: The study was approved by the IRB of the Jordan University Hospital. An informed consent was signed by every patient. DNA samples from 150 healthy volunteers and 108 patients with RA were analyzed by polymerase chain reaction followed by a restriction fragment length polymorphism assay (PCR-RFLP) to determine the frequency of four major alleles: NAT2*4, NAT2*5, NAT2*6, and NAT2*7. RESULTS: The most prevalent genotypes are those that encode the slow acetylation phenotype. About 59.3% of the patients with RA carried the slow, 33.3% the intermediate, and 7.4% the fast-encoding genotypes. The frequency of NAT2 alleles was 0.241 (95% confidence interval [CI] 0.184-0.298) for NAT2*4, 0.449 (95% CI 0.383-0.515) for NAT2*5, 0.273 (95% CI 0.214-0.332) for NAT2*6, and 0.037 (95% CI 0.012-0.062) for NAT2*7 allele. The overall frequency of the slow acetylation genotype in patients with RA is similar to that in healthy Jordanian volunteers. However, the NAT2*5/7 genotype was found in seven patients (6.5%) with RA and was absent in Jordanian volunteers, and the z test revealed that the difference was statistically significant. This genotype constituted 10.9% of the genotypes encoding slow acetylation. CONCLUSION: The overall acetylator genotype in RA is similar to that in healthy volunteers. The overall slow acetylator genotypes do not seem to be a genetic risk factor for RA among Jordanians. However, the NAT2*5/7 genotype seems to be related to RA. The nature of this relationship needs further clarification.
23259652 Corticosteroids as disease modifying drugs in rheumatoid arthritis treatment. 2012 The current approach to treatment of RA includes early and aggressive treatment with routine monitoring of outcomes to give patients the best chance of decreasing disease activity as much as possible, with low disease activity and remission being a realistic goal for many patients. In this quest, DMARDs, especially MTX, are the anchor treatment, and low dose prednisone should also be considered in combination with MTX as the best initial choice for RA treatment. Current data suggest that corticosteroids are disease modifying agents that enhance the effects of DMARDs with no real impact on adverse events. We are much better positioned now then in earlier times to provide a good outcome for our patients, and every available tool needs to be considered and utilized for this purpose.
22611947 [An investigation on vitamin D levels in peripheral blood in rheumatoid arthritis]. 2012 Mar OBJECTIVE: To study the association between vitamin D levels and RA. METHODS: Seventy-two postmenopausal female patients with RA (group RA) and fifty-eight healthy volunteers (group control) were included in this study. 25-hydroxyvitamin D3 (25-(OH) D3) levels were determined by ELISA method and disease activity of RA was assessed according to the Disease Activity Score in 28 joints (DAS28). The difference of 25-(OH) D3 levels between two groups and the relationship between 25-(OH) D3 levels and DAS28 were assessed. RESULTS: 25-(OH) D3 levels in peripheral blood in group RA were significantly lower than that in group control (P < 0.05), and 25-(OH)D3 levels were negatively correlated with DAS28. CONCLUSION: Vitamin D may have double actions of prevention, treatment and evaluation during the diagnosis and treatment process with RA disease.
22087444 Effectiveness of radiosynoviorthesis in the treatment of chronic synovitis of small and mi 2011 Sep Our aim was to describe and evaluate our experience in the treatment of radiosynoviorthesis (RSO) of small and middle-sized joints in patients with rheumatoid arthritis (RA). Eighty six patients with RA enrolled in the study. The criterion for enrolment was destructive process of the joint detected by X-rays and classified as a stage II-III according to Larsen. Seventy-six middle-sized joints were treated each with 74MBq or rhenium-186 sulphate and other 80 small joints with 10-40MBq of erbium-169 citrate each. The effect of treatment was evaluated at 6 and 12 months following the RSO treatment. The obtained values were compared with those of the initial state. The inflammatory and structural changes in activity were assessed according to the results of ultrasound examination, regression of pain, swelling of the joint and the improvement in mobility. The data obtained were statistically processed with the Chi-square test. Our results showed that RSO significantly decreased pain of the affected joints, however the influence upon joint motion was minimal. The best treatment results were observed in shoulders and elbows, while the ankles were the worst to respond to the RSO treatment. The significant (P<0.05) beneficial effect of the RSO treatment on pain and swelling reduction were only transient started on 1 week to 1 month and declined over 12 months. In conclusion, our study showed that RSO is a suitable alternative in the treatment of chronic synovitis, with a low potential of adverse effects. However the beneficial effect on pain and swelling reduction was only transient and declined over 12 months.
21946941 Expression levels of matrix metalloproteinase (MMP)-9 and its specific inhibitor TIMP-1, i 2012 Jun PURPOSE: In cases of septic knee arthritis, there is excess of matrix metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs), due to enhanced expression and activation that are induced by bacteria in comparison with rheumatic or degenerative arthritis. The aim of this study was to explore the expression levels of synovial gelatinase MMP-9 and its specific inhibitor TIMP-1 in septic and aseptic arthritis and their potential use as additional aids to clinical investigation. METHODS: Gelatin zymography and western blot analysis were applied in effusions from knees of the patients with septic (SA-10 patients), rheumatic (RA-10 patients) and osteoarthritis (OA-10 patients). RESULTS: Zymographic analysis revealed that all samples contained latent MMP-2 activity, albeit activated MMP-2 appeared in more of the septic than aseptic effusions. MMP-9 was not detected in osteoarthritic synovial fluid samples. Only trace amounts of MMP-9 activity were detected in 4 of 10 patients with RA, whereas higher MMP-9 levels were evident in all samples from SA (P = 0.0241). In immunoblotting assays, samples from SA showed significantly higher levels of MMP-9 compared with samples from RA (P = 0.0052), confirming zymographic results. Although no significant difference in TIMP-1 levels was observed, the estimated MMP-9/TIMP-1 ratio of septic effusions was significantly higher compared with aseptic ones (P = 0.0029). CONCLUSIONS: The data presented suggest enhanced expression and activation of MMP-9 in septic native knee arthritis compared with aseptic. The presence of high levels of MMP-9 with concomitantly increased MMP-9/TIMP-1 ratio and activated gelatinases in effusions, independent of neutrophilic counts, may be indicative for infection.
22366145 Citrullination under physiological and pathological conditions. 2012 Oct Citrullination, one of the enzymatic posttranslational modifications has become a hot topic of recent research as it is involved in various physiological and pathological processes. Antibodies against citrullinated proteins called anti-citrullinated protein antibodies, are the hallmark (diagnostic and prognostic factors) of rheumatoid arthritis, and are specific for the disease. Citrullination has an important role in the normal function of the immune system, skin keratinization, the insulation of neurons and the plasticity of the central nervous system including its essential role in gene regulation. Abnormal citrullination has been proposed to play a role in multiple sclerosis and Alzheimer's disease, and recent research has drawn attention to its implication in tumorigenesis. Still, it is unclear whether citrullination is the cause or the consequence of these pathological alterations. Here, we discuss crucial aspects of citrullination during both physiological and pathological conditions.
22889643 CD40L demethylation in CD4(+) T cells from women with rheumatoid arthritis. 2012 Oct We have previously demonstrated that DNA demethylation of CD40L on the X chromosome is responsible for female susceptibility to systemic lupus erythematosus (SLE). It is unknown whether aberrant methylation of the CD40L gene also contributes to the higher incidence of rheumatoid arthritis (RA) in females. In this study, we used real-time RT-PCR and flow cytometry to compare CD40L expression levels, and bisulfite sequencing to assess the methylation status of the CD40L promoter region. The results show that CD40L is upregrulated in CD4(+) T cells of female patients with RA. In addition, the CD40L promoter region in CD4(+) T cells from female RA patients was found to be demethylated, which corresponded with increased CD40L mRNA expression. These findings suggest that DNA demethylation contributes to CD40L expression in RA CD4(+) T cells and may in part explain the female preponderance of this disease.
21384280 Increased incidence of pre-diabetes mellitus at a department of rheumatology: a retrospect 2011 Oct We aimed to retrospectively review the incidence of pre-diabetes mellitus (preDM), one of the factors in metabolic syndrome screening, in patients with rheumatic diseases. We examined the levels of hemoglobin A1c (HbA1c) in a total of 498 patients with rheumatic diseases between April 2007 and March 2008 at the Department of Rheumatology in Nagasaki University Hospital. Of the 498 patients, 409 (82.1%) had HbA1c levels higher than 5.6% (National Glycohemoglobin Standardization Program; NGSP) and were recommended for health guidance with a focus on metabolic syndrome. Serum HbA1c levels higher than 6.0%, a possible indicator of DM, were seen in 227 patients (45.6%). Serum HbA1c levels higher than 6.5%, which constitute a high risk for DM, were found in 115 patients (23.1%). PreDM increased gradually with age. Our results suggest that the incidence of preDM may be higher in patients with rheumatic diseases than in patients with other diseases and that these patients should receive healthcare guidance to prevent metabolic syndrome.
23115849 [Rhupus: when rheumatoid arthritis meets lupus]. 2012 Sep There exists diseases in rheumatology fulfilling classification criteria for either rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). They are called "rhupus". We retrospectively analyzed the data base "GLIMS" of the CHU de Liège from the starting date of november 2005 until april 2011 to identified those patients that were positive for the anti-sDNA antibody marker of SLE and for the anti-CCP antibody, marker of RA. Fourteen patients were identified and two other patients were added, one suffering from SLE, and the other from RA, and likely to be rhupus. Of the 16 patients analyzed, 9 were real RA with anti-dsDNA antibodies induced by anti-TNF-alpha therapies. Seven were candidates to be rhupus and 6 were retained. They were all women, with a median age of 51 years and in addition were all anti-SS-A antibody positive.
22246418 Managing cardiovascular risk in patients with chronic inflammatory diseases. 2012 Apr The role of traditional risk factors in the development of cardiovascular disease has been well studied. However, the relationship between chronic inflammatory conditions and cardiovascular risk has only recently been appreciated. Expression of numerous pro-inflammatory cytokines is common to the pathogenesis of both atherosclerosis and other chronic inflammatory diseases and may suggest that systemic inflammation independently contributes to elevated risk. This article examines the magnitude of cardiovascular risk in several of the most common chronic inflammatory diseases and summarizes currently available data to discern whether this risk is largely due to the presence of co-existing traditional risk factors for cardiovascular disease or the effect of increased systemic inflammation. Evidence is summarized to show which therapies may positively or negatively impact cardiovascular risk. Evidence is discussed in context of practical patient management tools, appropriate treatment based on risk, and treatment targets for high-risk patients. Overall, patients with chronic inflammatory diseases are at an often underestimated increase in cardiovascular risk and require individualized therapy and specific patient management strategies to address the disease process, cardiovascular risk factors, and comorbidities.
22205118 Whole-body fluorodeoxyglucose positron emission tomography/computed tomography in patients 2012 Sep OBJECTIVES: To investigate fluorodeoxyglucose (FDG) accumulation in large joints, bursas, and large vessels in patients with polymyalgia rheumatica (PMR) using 18-FDG positron emission tomography/computed tomography (PET/CT) and to differentiate PMR from similar diseases. METHODS: Fourteen untreated patients with active PMR and 17 control patients with rheumatoid arthritis (n = 11) or other active rheumatic diseases (n = 6) underwent 18-FDG PET/CT. FDG uptake in large joints, bursas and vertebral spinous processes was evaluated by calculating maximum standardised uptake values and by visual scoring (scale 0-4). PET scan images were scored in seven vascular regions, and total vascular scores (range 0-21) were calculated. RESULTS: Polymyalgia rheumatica patients showed increased FDG uptake in ischial tuberosities, greater trochanters, and lumbar spinous processes. Positive results at two or more of these sites showed high sensitivity (85.7%) and specificity (88.2%) for the diagnosis of PMR, and shoulder or hip-joint involvement showed low disease specificity. High FDG accumulations were found in the aortas and subclavian arteries of two PMR patients who were asymptomatic for temporal arteritis and scanty synovium and perisynovium, based on FDG uptake. PET/CT images of the 12 PMR patients without apparent vascular involvement showed synovitis and/or perisynovitis. CONCLUSIONS: Fluorodeoxyglucose-PET/CT may be useful for the detection of PMR lesions, which are difficult to identify using other methods.
21885518 The OMERACT ultrasound task force--status and perspectives. 2011 Sep This article reports the most recent work of the Outcome Measures in Rheumatology (OMERACT) Ultrasound Task Force, and highlights the future research priorities discussed at the OMERACT 10 meeting. Results of the following studies were presented: (1) intra- and interobserver reliability of ultrasound detecting and scoring synovitis in different joints of patients with rheumatoid arthritis (RA); (2) systematic review of previous ultrasound scoring systems of synovitis in RA; (3) enthesitis systematic review and Delphi definition exercise in spondyloarthritis enthesitis; (4) enthesitis intra- and interobserver reliability exercise; and (5) Delphi definition exercise in hand osteoarthritis, and reliability exercises. Study conclusions were discussed, and a future research agenda was approved, notably further validation of an OMERACT ultrasound global synovitis score (GLOSS) in RA, emphasizing the importance of testing feasibility, predictive value, and added value over standard clinical variables. Future research areas will include validating scoring systems for enthesitis and osteoarthritis, and testing the metric qualities of ultrasound for evaluating tenosynovitis and structural damage in RA.
22225620 Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibo 2012 Jan 8 INTRODUCTION: Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients. METHODS: The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6). RESULTS: We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo. CONCLUSIONS: Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.
21346230 N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase in 2011 Apr 1 Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a recently described pan-PAD inhibitor, could affect the development of arthritis and autoimmunity by treating mice in the CIA model with Cl-amidine on days 0-35. Cl-amidine treatment reduced total synovial and serum citrullination, decreased clinical disease activity by ∼50%, and significantly decreased IgG2a anti-mouse type II collagen Abs. Additionally, histopathology scores and total complement C3 deposition were significantly lower in Cl-amidine-treated mice compared with vehicle controls. Synovial microarray analyses demonstrated decreased IgG reactivity to several native and citrullinated epitopes compared with vehicle controls. Cl-amidine treatment had no ameliorative effect on collagen Ab-induced arthritis, suggesting its primary protective mechanism was not mediated through effector pathways. Reduced levels of citrullinated synovial proteins observed in mice treated with Cl-amidine are consistent with the notion that Cl-amidine derives its efficacy from its ability to inhibit the deiminating activity of PADs. In total, these results suggested that PADs are necessary participants in the autoimmune and subsequent inflammatory processes in CIA. Cl-amidine may represent a novel class of disease-modifying agents that modulate aberrant citrullination, and perhaps other immune processes, necessary for the development of inflammatory arthritis.
22941768 Association between a history of periodontitis and the risk of rheumatoid arthritis: a nat 2013 Jul OBJECTIVE: To investigate the association between the risk of rheumatoid arthritis (RA) and a history of periodontitis. METHODS: This nationwide, population-based, case-control study used administrative data to identify 13 779 newly diagnosed patients with RA (age ≥16 years) as the study group and 137 790 non-patients with RA matched for age, sex, and initial diagnosis date (index date) as controls. Using conditional logistic regression analysis after adjustment for potential confounders, including geographical region and a history of diabetes and Sjögren's syndrome, ORs with 95% CI were calculated to quantify the association between RA and periodontitis. To evaluate the effects of periodontitis severity and the lag time since the last periodontitis visit on RA development, ORs were calculated for subgroups of patients with periodontitis according to the number of visits, cumulative cost, periodontal surgery and time interval between the last periodontitis-related visit and the index date. RESULTS: An association was found between a history of periodontitis and newly diagnosed RA (OR=1.16; 95% CI 1.13 to 1.21). The strength of this association remained statistically significant after adjustment for potential confounders (OR=1.16; 95% CI 1.12 to 1.20), and after variation of periodontitis definitions. The association was dose- and time-dependent and was strongest when the interval between the last periodontitis-related visit and the index date was <3 months (OR=1.64; 95% CI 1.49 to 1.79). CONCLUSIONS: This study demonstrates an association between periodontitis and incident RA. This association is weak and limited to lack of individual smoking status.