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ID PMID Title PublicationDate abstract
20491791 Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression 2010 Jul 1 Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177-mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
19669172 Symptom profile of persons self-reporting whiplash: a Norwegian population-based study (HU 2009 Sep The aetiology of chronic whiplash associated disorder (WAD) is unclear and the condition has been perceived both as a chronic pain disorder, based on the injury to the neck, and as a functional somatic disorder. Based on the hypothesis that chronic WAD should be perceived as a functional somatic syndrome, we compared the symptom profile of persons with chronic WAD with the profile of persons with a functional somatic disorder, and with the profile of persons with an organic pain disorder. A sample of 55,046 persons participating in a Norwegian population-based health study (HUNT 2) was divided into four study groups: chronic WAD, fibromyalgia, rheumatoid arthritis, and controls (none of these disorders). Symptoms were categorized as pain and stiffness, cardiopulmonary and gastrointestinal symptoms, and mental disorders. Odds ratios (ORs) with 95% confidence intervals (CIs) from logistic regression were used to compare the prevalence of symptoms among the groups. The chronic WAD group had a significantly higher prevalence of symptoms from all body parts, across organ systems and also mental symptoms, compared to the control group. The fibromyalgia group had an even higher prevalence of all symptoms, while the rheumatoid arthritis group showed an increase in the prevalence of particularly pain and stiffness symptoms and also a minor increase in the prevalence of other symptoms compared to the control group. We conclude that this study provide evidence in favour of the hypothesis that chronic WAD should be perceived as a functional somatic syndrome. Persons with chronic WAD had a symptom profile more similar to people with a functional somatic disorder than an organic pain disorder, consisting of a wide array of symptoms, not only predominantly pain symptoms.
19217445 Plasma asymmetric dimethylarginine is related to anticitrullinated protein antibodies in r 2009 Mar We have recently demonstrated elevated plasma levels of an endogenous nitric oxide synthase inhibitor, asymmetric dimethyl-L-arginine (ADMA), and its association with carotid atherosclerosis in rheumatoid arthritis (RA). Both an elevated risk of myocardial infarction and increased levels of anticitrullinated protein antibodies (ACPAs), specific for RA, had been shown to precede the onset of clinical RA symptoms. Therefore, our aim was to verify the hypothesis that ADMA accumulation might accompany raised ACPAs titers in RA of short duration (< or = 3 years). Twenty patients (16 women, 4 men; mean age, 45 +/- 12 years; mean disease duration, 2.3 +/- 0.5 years) with active RA despite chronic disease-modifying antirheumatic medication, free of cardiovascular disease or atherosclerotic risk factors, were studied. Plasma levels of ADMA and its stereoisomer, symmetric dimethyl-L-arginine (SDMA), were assayed by liquid chromatography/tandem mass spectrometry. The ACPAs were measured by a second-generation enzyme-linked immunosorbent assay. In addition to routine biochemical assays, plasma concentrations of tumor necrosis factor alpha, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1 soluble form were analyzed with respective enzyme-linked immunosorbent assays. A significant positive correlation between levels of ACPAs and ADMA (r = .60, P = .005), but not SDMA (r = -.02, P = .9), was found. Neither ADMA nor SDMA was correlated to any of the clinical or biochemical parameters reflecting disease activity and inflammatory activation. Thus, excessive ADMA accumulation accompanies elevated ACPAs levels in patients with RA of short duration free of cardiovascular disease or risk factors.
20398018 Effect of novel therapeutic glucocorticoids on circadian rhythms of hormones and cytokines 2010 Apr The morning stiffness and pain of rheumatoid arthritis (RA) is accompanied by a rise in serum interleukin-6 (IL-6) from 2 am to 7 am. Using a formulation that releases prednisone at 2 am (after ingestion at 10 pm), we studied the circadian dynamics of serum IL-6, other cytokines, and cortisol in 9 patients before and after 2 weeks, therapy. Significant improvements occurred in morning stiffness, pain, disease activity, and the acute-phase response. Only IL-6 showed measurable cytokine circadian variation, its high pretreatment peak was abolished, and changes in IL-6 correlated with the changes in morning stiffness. Following treatment, afternoon and evening serum cortisol was reduced, but in the early morning cortisol peak concentration increased. Thus the severity of morning symptoms is related to nocturnal serum IL-6 concentration. The specific timing of the medication, linked to the interaction between IL-6 and the hypothalamic-pituitary-adrenal (HPA) axis, may correct a postulated deficiency in HPA control in RA.
20113255 Association of the CD28/CTLA4/ICOS polymorphisms with susceptibility to rheumatoid arthrit 2010 Mar BACKGROUND: Rheumatoid arthritis (RA) is currently thought to be an immune-mediated disease where the host's genes and environmental factors interact. Some of the immuno-regulatory genes that are responsible for an individual's susceptibility to RA have been identified. The co-stimulatory receptor gene cluster on chromosome 2q33 encodes for both the positive T-cell regulators CD28 molecule (CD28) and inducible T-cell co-stimulator (ICOS), and the negative regulator cytotoxic T-lymphocyte-associated protein 4 (CTLA4). The CTLA4 gene has been implicated in several immune-mediated diseases, but it is not known whether RA is associated with any of these genes. METHODS: We conducted single nucleotide polymorphism (SNP) genotyping with direct sequencing and restriction fragment length polymorphism for 308 Korean patients with RA and 412 healthy control subjects. For the case-control analysis, SNPStats, SNPAnalyzer and Helixtree programs were used. RESULTS: Although none of the polymorphisms in CTLA4 showed a significant association with RA, CD28 and ICOS showed a significant association with RA [rs2140148 in CD28, p = 0.022, odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.07-2.40 in the dominant model, rs6726035 in ICOS, p = 0.032, OR = 1.28, 95% CI = 1.02-1.60 in the codominant model]. CONCLUSIONS: Our results suggest that CD28 and ICOS genes may be associated with a risk of RA in Koreans.
19222660 Effects of a nurse practitioner on a multidisciplinary consultation team. 2009 Mar AIM: This paper is a report of a study to evaluate the impact on office hours capacity, patient satisfaction, quality of life and costs of including a nurse practitioner in a multidisciplinary consultation team for patients with hand problems caused by rheumatoid arthritis. BACKGROUND: Over 90% of patients with rheumatoid arthritis suffer symptoms in their hand joints and may be seriously disabled in performing daily, work or leisure activities. A recent promising development in the treatment of patients with a chronic disease is the co-ordinating and accompanying role of a nurse, such as a nurse practitioner, in a multidisciplinary treatment team. METHODS: A two successive group time-series design was adopted. The intervention group (n = 78) visited a clinic with a nurse practitioner assigned to the team during 2003-2004. The control group (n = 69) was seen before inclusion of the nurse practitioner. Office hours capacity, patient satisfaction, quality of life and costs were assessed using questionnaires directly after consulting the team, and 3 and 6 months later. RESULTS: Between-group comparisons of patient satisfaction and quality of life revealed no statistically significant differences. Changes within groups over time were not demonstrable. Mean office hour capacity increased by 17% (t = -1.906, d.f. = 32.879, P = 0.065). The costs for professional home care or informal care were equal in the two groups. CONCLUSION: Evaluation of clinical practice using pre- and post-test design was impeded by changes in clinical practice, which made concrete conclusions difficult to draw. In future studies the satisfaction of participating clinicians should be evaluated, in addition to that of patients.
19590933 Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti 2009 The introduction of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) has brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). Although these anti-TNF agents have excellent efficacy against RA, a substantial number of patients still show inadequate responses. In Western countries, such patients are already being treated with new classes of antirheumatic drugs such as abatacept and rituximab. Tocilizumab (TCZ) is a humanized monoclonal antibody developed in Japan against the human interleukin-6 (IL-6) receptor. TCZ does not only alleviate the signs and symptoms of RA but also seems to prevent progressive bone and joint destruction. However, there is a concern that TCZ might increase the risk of adverse events such as infections since IL-6 plays a pivotal role in the immune system. Calculating the relative risks of specific adverse outcomes with TCZ use remains difficult, due to insufficient patient numbers enrolled in clinical trials to date. This review presents tentative guidelines for the use of TCZ for RA patients prepared by the Japan College of Rheumatology and based on results of clinical trials in Japan and Western countries. The guidelines are intended as a guide for postmarketing surveillance and clinical practice, and will be revised periodically based on the surveillance.
19877057 Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with 2009 Nov Progressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000-mg infusions administered 2 weeks apart) over a period of approximately 40 months, during a phase III trial and safety extension study. PML was diagnosed approximately 18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.
19368701 Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor ther 2009 Conventional disease-modifying antirheumatic drugs such as methotrexate are the mainstay of treatment for rheumatoid arthritis. More recently, biologic agents such as etanercept, infliximab and adalimumab, which act by inhibiting tumour necrosis factor (TNF), have become available. TNF inhibitors have proved to be very effective in patients not responding to conventional disease-modifying antirheumatic drugs. However, about 20% to 40% of patients treated with a TNF inhibitor fail to achieve a 20% improvement in American College of Rheumatology criteria, and more lose response over time (secondary failure or acquired therapeutic resistance) or experience adverse events following treatment with a TNF inhibitor. In this group of patients, therapeutic options were limited until recently and an established treatment approach was to switch from one TNF inhibitor to another. In recent years, therapeutic options in these patients have increased with the introduction of biologic agents with novel mechanisms of action, such as rituximab and abatacept. This review outlines the current evidence in support of the available treatment strategies in patients with an inadequate response or intolerance to an initial TNF inhibitor.
20133791 Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid a 2010 Feb 9 Rheumatoid arthritis (RA) is a systemic autoimmune disease involving inflammation of the joints. Among the autoantibodies described in RA, anticitrullinated protein antibodies (ACPAs) are highly specific and predictive for RA. In addition, ACPAs have been implicated in the pathogenesis of RA. However, a direct functional response of immune cells from ACPA(+) RA patients toward citrullinated proteins has not been demonstrated. In this study, we show that exposure to citrullinated antigens leads to activation of basophils from ACPA(+) RA patients within 20 minutes. This was not observed after exposure of basophils to noncitrullinated control antigens or after stimulation of basophils from ACPA(-) RA patients and healthy controls. Basophil activation was correlated with the binding of citrullinated proteins to basophils. Furthermore, serum from ACPA(+) RA patients in contrast to that from ACPA(-) RA patients could specifically sensitize human FcepsilonRI expressing rat basophil cells (RBL), enabling activation by citrullinated proteins. Mast cell degranulation products such as histamine levels were enhanced in synovial fluid of ACPA(+) RA patients as compared with ACPA(-) RA and osteoarthritis patients. In addition, histamine levels in synovial fluid from ACPA(+) RA patients correlated with IgE levels, suggesting degranulation of mast cells by cross-linking IgE. Immunohistochemistry on synovial biopsies demonstrated an increased number of degranulated CD117(+) mast cells in ACPA(+) RA patients; IgE and FcepsilonRI expression in synovial mast cells from ACPA(+) RA patients was increased. In conclusion, our results show an immunological response of immune cells from ACPA(+) RA patients in a citrulline-specific manner. Moreover, these data indicate a role for IgE-ACPAs and FcepsilonRI-positive cells in the pathogenesis of RA.
20570093 Occlusion of the artery of Adamkiewicz after hip and knee arthroplasty. 2011 Apr The artery of Adamkiewicz is the most significant tributary of the anterior spinal artery in the midthoracic region; the occlusion of this artery results in a well-described phenomenon consisting of paraplegia with loss of the sensation of pain, temperature, and touch as well as loss of sphincter control. Proprioception and vibration sense are typically preserved. Although this phenomenon has been associated with several surgeries as well as preexisting aortic abnormalities, the literature thus far has not reported this as a complication of hip or knee arthroplasty. Two case histories are presented.
19266397 Disseminated Mycobacterium marinum infection in a patient with rheumatoid arthritis receiv 2009 Tumor necrosis factor-alpha inhibitors are important adjunctive therapies for rheumatologic diseases. These agents increase the risk for granulomatous disease. We present a case of a woman with severe rheumatoid arthritis on infliximab who developed multiple nodular skin lesions. Biopsies grew Mycobacterium marinum. New lesions developed through therapy, necessitating surgical debulking.
19411782 [Clinical significance of dense fine speckled pattern in anti-nuclear antibody test using 2009 Apr BACKGROUND: Dense fine speckled (DFS) pattern in antinuclear antibody (ANA) test using indirect immunofluorescence method became to be known recently and it is detected in patients with various chronic inflammatory diseases as well as in healthy individuals. We investigated the relation between DFS pattern and various diseases. METHODS: ANA tests by indirect immunofluorescence method using HEp-2 cell line slide (Kallestad; Bio-Rad, USA) were performed in 2,654 patients for screening of systemic autoimmune diseases. The frequencies of ANA and DFS positivity were analyzed according to sex, age, clinical department and disease. RESULTS: ANA was positive in 13.3% (352/2,654) of the total patients, and the frequency of DFS pattern was observed in 3.8% (101/2,654) of the total patients and in 28.7% (101/352) of the patients with ANA positivity. Higher frequency of DFS positivity was observed in patients referred from Departments of Rheumatology and Nephrology, but there was no difference in the frequencies of DFS positivity among the patients with ANA positivity. The frequency of DFS pattern was higher in seborrheic dermatitis (14.3%), herpes zoster (11.1%), rheumatoid arthritis (16.9%), systemic lupus erythematosus (15.4%) and Sjogren syndrome (14.3%). CONCLUSIONS: The DFS pattern is a frequent finding (about 28% of ANA positivity) in ANA test using indirect immunofluorescence method. Relatively high frequency of DFS pattern was observed in autoimmune diseases, contrary to the previous observations that DFS pattern is not related with autoimmune diseases. Further studies including the confirmation tests of anti-DFS70 are needed for the identification of relation between DFS pattern and particular diseases.
20437913 Supporting safe driving with arthritis: developing a driving toolkit for clinical practice 2010 Mar We conducted a series of focus groups to explore the information needs of clinicians and consumers related to arthritis and driving. An open coding analysis identified common themes across both consumer and clinician-based focus groups that underscored the importance of addressing driving-related concerns and the challenges associated with assessing safety. The results revealed that although driving is critical for maintaining independence and community mobility, drivers with arthritis experience several problems that can affect safe operation of a motor vehicle. Findings from this study are part of a broader research initiative that will inform the development of the Arthritis and Driving toolkit. This toolkit outlines strategies to support safe mobility for people with arthritis and will be an important resource in the coming years given the aging population.
19286844 Plasma 25,OH vitamin D concentrations are not associated with rheumatoid arthritis (RA)-re 2009 May OBJECTIVE: To evaluate the association between rheumatoid arthritis (RA)-related autoantibodies and plasma 25,OH vitamin D in subjects at risk for RA. METHODS: In 1210 subjects without RA, 76 were positive for anti-cyclic citrullinated peptide antibodies or for at least 2 rheumatoid factors (RF; by nephelometry: RF-IgM, RF-IgG, RF-IgA). 25,OH vitamin D was measured in these cases and 154 autoantibody-negative controls from this cohort. RESULTS: 25,OH vitamin D levels did not differ between cases and controls (adjusted OR 1.23, 95% CI 0.93-1.63). CONCLUSION: Vitamin D concentrations are not associated with RA-related autoimmunity in unaffected subjects at increased risk for RA.
19809821 Regulation of TNFalpha and IL1beta in rheumatoid arthritis synovial fibroblasts by leukotr 2010 Jul Arachidonic acid metabolites, such as leukotriene B4 (LTB4), are known to play an important role in pathogenesis of rheumatoid arthritis (RA). Apart from leukocytes, RA synovial fibroblasts (RASF) produce a broad array of inflammatory mediators to recruit, retain and activate immune cells and resident mesenchymal cells in the joints to promote ongoing inflammation and tissue destruction. To determine how LTB4 may contribute to this process, RASF was cultured from synovial tissues collected from RA patients undergoing total knee replacement. The level of LTB4 in culture medium was determined using ELISA, and expression of LTB4 receptors (BLT1 and BLT2) by RT-PCR. In the presence of exogenous LTB4, mRNA and protein levels of tumor necrosis factor-alpha (TNFalpha) and interleukin 1beta (IL1beta) were determined by real-time PCR and ELISA. Furthermore, we examined the effects of leukotrienes synthesis inhibitors, MK886 and bestatin, on mRNA and protein levels of TNFalpha and IL1beta in RASF. We found that LTB4 was present at a low concentration in the culture medium of RASF, and the major LTB4 receptor expressed in RASF was BLT2. LTB4 synthesis was activated by treatment with LIT (LPS, ionomycin and thapsogargin), and suppressed by MK886 and bestatin. Exogenous LTB4 remarkably increased the expression of TNFalpha and IL1beta at both the mRNA level and the protein level. In contrast, MK886 and bestatin significantly inhibited their expression. These data suggested that LTB4 contributed to RA by regulating the expression of TNFalpha and IL1beta in RASF. BLT2 was probably the major receptor mediating such effects.
20511610 Are switches from oral to subcutaneous methotrexate or addition of ciclosporin to methotre 2010 Oct OBJECTIVE: To investigate the effects of a switch from oral methotrexate (MTX) to subcutaneous MTX (scMTX) or adding ciclosporin to oral MTX with a simultaneous reduction of the MTX dose, in case of adverse events (AE) or insufficient effect (IE) in rheumatoid arthritis (RA). METHODS: The tight control treatment arm of the Computer Assisted Management in Early RA (CAMERA) trial was evaluated. The change in 28-joint Disease Activity Score (DAS28) after taking scMTX (over 1 month) or adding ciclosporin (over 3 months) was compared to the average monthly change in the preceding 3 months. Analyses were performed separately for strategy steps because of AE or IE. RESULTS: Of 151 patients, 57 needed the scMTX strategy step (21 because of AE, 36 because of IE) and 40 the following ciclosporin strategy step (20 and 20, respectively). The decrease in DAS28 after taking the scMTX strategy step was 0.30 points (p<0.05); no significant change in DAS28 was seen after the ciclosporin strategy step. In both strategy steps for AE or IE, quite similar observations were made. Of the patients who took the scMTX strategy step, 63% showed improvement. CONCLUSION: scMTX seems a useful treatment step after oral MTX in a tight control strategy, whereas the ciclosporin step seems ineffective.
20860837 Validity of the work productivity and activity impairment questionnaire--general health ve 2010 INTRODUCTION: The Work Productivity and Activity Impairment (WPAI) questionnaire is a well validated instrument to measure impairments in work and activities. However, its validation among patients with rheumatoid arthritis (RA) has not been well established. The present study's purpose is to evaluate the construct validity of the WPAI-general health version among RA patients and its ability to differentiate between RA patients with varying health status. METHODS: Patients who were enrolled in the Early Rheumatoid Arthritis Network cohort and were employed at their most recent follow-up were recruited into this sub-study. A questionnaire battery incorporating the WPAI was administered along with a number of health outcomes including the Multidimensional Health Assessment Questionnaire, fatigue and patient assessment of disease activity. The construct validity of the WPAI was tested by the correlations between the WPAI and the health outcomes and other measures of productivity. Student's t tests were used to identify whether the WPAI outcomes differed between the two levels of heath status based on the median of health outcomes. RESULTS: A total of 150 patients completed the WPAI questionnaire. The average age was 52 years old and the disease duration was 37.5 months since the first rheumatology visit. Of the 137 patients who were working for pay, 26 reported missing work in the past week due to their health problem, accounting for 45.5% of their working time (absenteeism). While 123 patients were working, 24% of their work was impaired due to their health problem (presenteeism). In addition, 33% of the patients' regular daily activities (activity impairment) had been prevented due to their health problems. There were moderate correlations between the WPAI absenteeism and function, pain, fatigue, and disease severity (r = 0.34 to 0.39). The WPAI presenteeism and activity impairment were strongly correlated with the health outcomes (0.67 to 0.77). Patients with more severe disease status (for example, low/high functional disability by median) had significantly higher absenteeism (4%/15%), presenteeism (15%/39%), and activity impairment (19%/53%) than those with less severe disease status. CONCLUSIONS: The WPAI is a valid questionnaire for assessing impairments in paid work and activities in RA patients and for measuring the relative differences between RA patients with different health status.
19706160 Reduced Fas ligand-expressing splenic CD5+ B lymphocytes in severe collagen-induced arthri 2009 INTRODUCTION: The objective was to study immune regulation in a mouse model of rheumatoid arthritis that exhibits considerable heterogeneity of disease activity. METHODS: T-cell receptor transgenic mice, in which nearly all CD4+ T cells recognize a single peptide of type II collagen, were immunized with collagen and observed for development of arthritis for 4 weeks. At 28 days post-immunization, splenocytes were analyzed by flow cytometry and in vitro assays for markers of immune activation and regulation. RESULTS: Disease severities ranging from 0 to 12 (on a 12-point scale) were observed. Among splenic lymphocyte populations, only the CD5+ B-cell subset displayed a decrease in relative numbers as arthritis severity increased. Splenic CD5+ B cells expressed higher levels of Fas ligand (FasL) than did CD4+ T cells or CD5- B cells in all mice, and antigen-dependent T-cell death correlated with higher levels of CD5+ B cells in cocultures. Ratios of interleukin (IL)-17 to interferon-gamma production were higher in antigen-driven cultures of splenocytes from severely arthritic mice compared to mildly or nonarthritic mice. A correlation was established between the reduced production of IL-17 in antigen-driven T-cell/B-cell cocultures and FasL, but not IL-10. Confirmation of the direct killing effect of B cells on T cells was demonstrated using an antigen-specific T hybridoma cell line. CONCLUSIONS: Reduced numbers of splenic FasL+ CD5+ B cells correlated with increasing arthritis severity and decreased T-cell death in a T-cell receptor transgenic mouse model of collagen-induced arthritis. These 'killer' B cells may provide a novel mechanism for inducing T-cell death as a treatment for arthritis.
19066178 FOXP3 expression in blood, synovial fluid and synovial tissue during inflammatory arthriti 2009 Dec OBJECTIVE: To analyse the distribution of FOXP3+CD25+CD4+ regulatory T cells (Treg) in peripheral blood, synovial fluid and tissue of patients with rheumatic disease during relapse and after local treatment. METHODS: FOXP3 expression was assessed by flow cytometry, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR). The functional suppressive capacity of Treg was analysed after co-culture with effector CD4+CD25- T cells through assessment of proliferation and cytokine secretion. RESULTS: It was shown that FOXP3 protein and mRNA expression in synovial fluid T cells was not confined solely to CD25(bright) T cells as seen in blood, but included CD25(intermediate) and even CD25(neg) T cells. Indeed, synovial fluid CD25(high) T cells showed similar suppressive capacity as CD25(bright) T cells, indicating the presence of functional Treg in T cells with lower intensity of CD25. In synovial tissue, FOXP3+ cells were present in low numbers within T-cell infiltrates and decreased further after intra-articular glucocorticosteroid administration, in parallel with the general reduction in inflammation. CONCLUSIONS: Identification of synovial fluid FOXP3+ Treg with varying intensities of CD25 opens up possibilities for thorough characterisation of this important T-cell subset in the inflammatory compartment. However, only scarce synovial membrane expression of FOXP3 was found even in the absence of overt inflammation, suggesting that the synovial membrane is a site that would benefit therapeutically from Treg expansion.