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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
16963793 Methotrexate in rheumatoid arthritis. 2006 Jul A variety of disease-modifying antirheumatic drugs (DMARDs) are available to control the clinical activity of rheumatoid arthritis (RA). Methotrexate (MTX), an analogue of folic acid and of aminopterin, is the most commonly used DMARD and is now prescribed worldwide to at least 500,000 patients with RA. The mechanism by which MTX used at a low dose modulates inflammation in RA is still unknown. Monitoring of the therapy in terms of MTX concentration in patients with RA seems not to have a significant influence on the effectiveness of the treatment. Two meta-analyses showed that MTX has one of the best efficacy/toxicity ratios. It should be the first DMARD used in the majority of patients with RA at this time. However, a significant number of patients treated only with MTX fail to achieve optimal disease control, so there are many combinations of DMARD regimes. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission. The therapy of RA is a dynamic process and requires maintaining a delicate balance between benefits and risks. Even with the newer biological agents, MTX continues to serve as a reference point and there is still a role for MTX in the treatment of RA patients.
16978150 Plasmid DNA acquires immunogenicity on exposure to singlet oxygen. 2006 Aug In the present study, the effect of singlet oxygen (1O2) (generated by ultraviolet (UV) irradiation of methylene blue) on plasmid DNA has been analyzed by UV spectroscopy, fluorescence spectroscopy, and S1 nuclease digestibility. Both native and 1O2-modified plasmid DNA were treated with a number of restriction enzymes to map out the sites damaged by 1O2. It was also observed that, on exposure to 1O2, native plasmid DNA that is non-immunogenic acquired the ability to elicit an immune response in experimental animals. However, the induced antibodies exhibited appreciable cross reactivity with various polynucleotides and nucleic acids. The data indicate that the antibodies, though cross-reactive, preferentially bind 1O2-modified epitopes on plasmid DNA. Gel retardation assay further substantiated the enhanced recognition of 1O2-modified plasmid DNA over the native form. The antibodies developed were then subjected to competition ELISA with sera from various diseases such as systemic lupus erythematosus, rheumatoid arthritis, and cancer. These results suggest that upon exposure of DNA to 1O2, neo-epitopes are generated, which may be one of the factors for the induction of circulating autoantibodies in the three diseases.
17044206 Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis. 2006 Oct SETTING: A major concern surrounding the use of tumor necrosis factor-alpha (TNF-alpha) inhibitors is their potential to increase the risk of opportunistic infections, particularly tuberculosis (TB). OBJECTIVE: To estimate the incidence of active TB in patients with rheumatic diseases receiving anti-TNF drug therapy and to evaluate the effectiveness of an antituberculosis chemoprophylaxis regimen. DESIGN: Retrospective study of the files of 613 patients with rheumatic diseases who had received anti-TNF agent (etanercept, infliximab and adalimumab) therapy from July 2000 to June 2004 at the Aristotle University of Thessaloniki, Greece. All patients had a tuberculin skin test (TST) and a postero-anterior chest radiograph (CXR) prior to anti-TNF therapy. When indicated (TST > or =10 mm and/or fibrotic lesions on CXR), treatment for latent TB was established (6 months isoniazid [INH] or 3 months INH and rifampicin [RMP]). Anti-TNF agent therapy was started again 2 months later. RESULTS: Of 45 patients who fulfilled the criteria for chemoprophylaxis, only 36 were treated correctly. Eleven patients developed active TB 2-35 months after the beginning of anti-TNF therapy. Six patients developed pulmonary and five extra-pulmonary TB. Eight of these had received infliximab and three adalimumab. CONCLUSION: The incidence of active TB in this study population was estimated at 449 cases per 100,00 population annually. Anti-tuberculosis chemoprophylaxis was only of partial preventive success in these patients.
15821736 MHC2TA is associated with differential MHC molecule expression and susceptibility to rheum 2005 May Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a -168A --> G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-gamma. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.
15640272 Prescription practice of biological drugs in rheumatoid arthritis during the first 3 years 2005 Aug BACKGROUND: The study was based on the Danish DANBIO and the Norwegian NOR-DMARD databases. OBJECTIVE: To investigate changes in prescription practice during the first 3 years of post-marketing use of biological drugs, and to determine the proportion of patients who would not have received tumour necrosis factor (TNF) blocking agents if the prescription guidelines of the UK and the Netherlands had been applied. METHODS: Patients with rheumatoid arthritis (RA) receiving TNF blocking agents from Denmark (n = 823, median age 56.0, 72.2% women) and Norway (n = 371, median age 52.5, 75.4% women) were studied. Prescription guidelines in the UK and the Netherlands were applied to the data. RESULTS: Baseline disease activity and number of previous DMARDs declined significantly during the 3 years (median baseline DAS28 decreased from 5.8 to 5.2 in Denmark (p<0.001) and from 6.0 to 5.6 in Norway (p<0.01)). 47.9% and 41.3% of the Norwegian and Danish patients, respectively, did not meet the UK criteria for using TNF blocking agents, and 10.5% and 5.7% did not meet the Dutch criteria. CONCLUSION: Danish and Norwegian prescription practices of biological treatments in RA were similar, and became less stringent from 2000 to 2003. Prescriptions agreed well with the Dutch guidelines, but almost half the patients did not meet the UK guidelines.
17075829 Activation of nitric oxide signaling by the rheumatoid arthritis shared epitope. 2006 Nov OBJECTIVE: Susceptibility to rheumatoid arthritis (RA) is closely associated with HLA-DRB1 alleles encoding a shared epitope (SE) in positions 70-74 of the HLA-DRbeta chain. The mechanistic basis for this association is unknown. Given the proposed pathogenic role of nitric oxide (NO) in RA, this study was undertaken to examine whether the SE can trigger NO signaling events. METHODS: The intracellular levels of NO were measured with the fluorescent NO probe 4,5-diaminofluorescein diacetate and by the 2,3-diaminonaphthalene method. NO synthase activity was determined by measuring the rate of conversion of radioactive arginine to citrulline. Levels of cGMP were measured with a commercial enzyme-linked immunosorbent assay, and the cytolytic activity of T cells was measured using a standard (51)Cr release assay. RESULTS: Lymphoblastoid B cell lines carrying SE-positive HLA-DR alleles displayed a higher rate of spontaneous NO production compared with SE-negative cells. L cell transfectants expressing SE-positive DR molecules on their surface also generated higher levels of NO. Tetrameric HLA-DR molecules containing a DRbeta-chain encoded by the SE-positive DRB1*0401 allele stimulated fibroblast cells to produce higher levels of NO compared with cells stimulated with a control HLA-DR tetramer. Multimeric hepatitis B core proteins engineered to express region 65-79 encoded by the DRB1*0401 allele, but not the same region encoded by the control allele DRB1*0402, stimulated NO production in fibroblasts. Similarly, synthetic 15-mer peptides corresponding to the region 65-79 encoded by SE-positive alleles triggered increased NO levels when incubated with class II major histocompatibility complex-negative cells. The signaling pathway was found to involve NO synthase activation, followed by increased production of cGMP. SE-triggered increased NO levels inhibited cytolytic elimination of target cells. CONCLUSION: The SE can trigger NO-mediated signaling events in opposite cells, and may thereby contribute to RA pathogenesis.
16282192 Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medici 2006 Jan OBJECTIVES: To assess the efficacy of a cannabis-based medicine (CBM) in the treatment of pain due to rheumatoid arthritis (RA). METHODS: We compared a CBM (Sativex) with placebo in a randomized, double-blind, parallel group study in 58 patients over 5 weeks of treatment. The CBM was administered by oromucosal spray in the evening and assessments were made the following morning. Efficacy outcomes assessed were pain on movement, pain at rest, morning stiffness and sleep quality measured by a numerical rating scale, the Short-Form McGill Pain Questionnaire (SF-MPQ) and the DAS28 measure of disease activity. RESULTS: Seventy-five patients were screened and 58 met the eligibility criteria. Thirty-one were randomized to the CBM and 27 to placebo. Mean (S.D.) daily dose achieved in the final treatment week was 5.4 (0.84) actuations for the CBM and 5.3 (1.18) for placebo. In comparison with placebo, the CBM produced statistically significant improvements in pain on movement, pain at rest, quality of sleep, DAS28 and the SF-MPQ pain at present component. There was no effect on morning stiffness but baseline scores were low. The large majority of adverse effects were mild or moderate, and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group. CONCLUSIONS: In the first ever controlled trial of a CBM in RA, a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment. Whilst the differences are small and variable across the population, they represent benefits of clinical relevance and show the need for more detailed investigation in this indication.
15661933 A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and 2005 Feb 1 According to the current model for tissue-specific homing, specificity is conferred by the selective recruitment of lymphocyte populations from peripheral blood, based on their expression of chemokine and adhesion receptors (endothelial selection). In this study, we provide evidence for an alternative stromal induction mechanism that operates in chronic inflammation. We show that the human rheumatoid synovial microenvironment directly induces functional inflammatory (CCR5 and CXCR3) and constitutive (CCR7 and CXCR4) chemokine receptors on infiltrating CD4(+) T cells. Expression of the corresponding inflammatory chemokine ligands (CCL5 and CXCL11) was confined to stromal areas in the synovium. However, expression of the constitutive ligands (CCL19 and CXCL12) was inappropriately high on both vascular and lymphatic endothelium, suggesting that the vascular to lymphatic chemokine gradient involved in lymphatic recirculation becomes subverted in the rheumatoid synovium. These results challenge the view that leukocyte trafficking is regulated solely by selective recruitment of pre-existing chemokine receptor-positive cells from peripheral blood, by providing an alternative explanation based on aberrant lymphocyte retention and compromised lymphatic return.
16579668 Factors affecting physical activity behavior in urban adults with arthritis who are predom 2006 Apr BACKGROUND AND PURPOSE: Physical activity and exercise play a critical role in the management of arthritis. Understanding the factors affecting physical activity and exercise behavior is a necessary first step toward identifying the needs of, and intervention strategies for, people with arthritis. The purpose of this study was to identify factors affecting physical activity and exercise behavior in urban subjects with osteoarthritis (OA) and rheumatoid arthritis (RA). SUBJECTS: Seventy-two consecutive subjects were recruited from the rheumatology clinic at a large urban public hospital. The sample was predominantly African American (92%), female (87%), and not working (90%). The subjects' average age was 60.9 years (SD=13.9, range=30-90). METHODS: Time per day spent sitting or lying down and time per week spent in exercise, leisure, and household activities were determined by individual interview. Self-efficacy, outcome expectations, disability, pain, body mass index, and social support were measured as possible explanatory factors. RESULTS: The average daily total activity time was 3.1 hours. Household and leisure activities accounted for 85% of that time. Explanatory factors for physical activity behavior were not the same for subjects with OA and RA, despite similar between-group characteristics. Self-efficacy was present in all of the significant explanatory models. DISCUSSION AND CONCLUSION: The results indicate that factors that affect physical activity behavior among urban and predominantly African-American adults are dependent upon the type of physical activity and are different for people with OA and RA. Self-efficacy was the most consistent explanatory factor.
15953059 Clinical profiles of vitiligo in China: an analysis of 3742 patients. 2005 Jul Very few articles have aimed to illuminate the clinical profiles of vitiligo in China. We conducted this retrospective survey involving 4118 outpatients with vitiligo in order to identify the differences among various clinical types of vitiligo and their associated disorders. Completed questionnaires (3742) were validated and analysed. Of this large cohort, 1565 (41.8%) individuals presented vitiligo vulgaris, followed by focal, segmental, acrofacial, and universal, in that order. The mean age of vitiligo onset was 18.88 years. More than 60% of the patients were affected before 20 years of age. Patients with segmental vitiligo were affected earlier than those with other types of vitiligo (15.55 years; (P < 0.001). More than 74% of the patients presented with focal vitiligo at onset. After 3-5 years, 99% of active vitiligo was worse and shifted from one clinical type to another. However, there was no transformation between acrofacial vitiligo and segmental vitiligo. Compared with the general population, the patients with vitiligo were more likely to be affected by rheumatoid arthritis (P < 0.01), ichthyosis (P < 0.01), chronic urticaria (P < 0.01), or alopecia areata (P < 0.01).
17043378 CD8-positive T cell-induced liver damage was found in a patient with polymyositis. 2006 We describe a case of polymyositis (PM) with liver injury that occurred in a patient with rheumatoid arthritis (RA). A 74-year-old woman who had a 12-year history of RA was admitted to our hospital because of muscle weakness and liver dysfunction. CD8-positive T cell infiltration was found in the interstitium of both the liver and muscle. In addition to the administration of a large amount of prednisolone (PSL), high-dose intravenous immunoglobulin (IVIG) successfully improved myositis and hepatitis. Our case indicates the pathogenic potential of CD8-positive T cells in PM-associated liver injury.
16220211 Association of mannose-binding lectin gene (MBL2) polymorphisms with rheumatoid arthritis 2005 Single nucleotide polymorphisms in the mannose-binding lectin (MBL2) gene, as well as the serum MBL2 level, have been associated with various autoimmune diseases. We investigated whether such polymorphisms and/or the serum MBL2 level were associated with rheumatoid arthritis (RA) in an Indian population. The frequency of the B variant (codon 54) of the MBL2 gene was quite frequent in the healthy Indian population and was significantly (P=6.35x10(-6)) lower in RA patients. We replicated this association (P=1.78x10(-5)) in an independent cohort of control individuals. Promoter polymorphism at -550 nt showed a significant overrepresentation (P=0.003) of the minor allele G in severe RA patients compared with the less severe group. Haplotype LYA frequency was significantly (P=0.03) high in the less severe group, while the frequency of the HYA haplotype was significantly (P=0.04) increased in the severe RA patients. No statistically significant difference in serum MBL2 was observed as a whole, but the individuals homozygous for the LYA haplotype had significantly lower (P=0.017) serum MBL2 levels compared with individuals homozygous for the HYA haplotype. Therefore, the B variant of the MBL2 gene may be associated with protection from RA in our study population, and the promoter polymorphism (-550 nt) seems to have some role in disease progression.
15934058 Violation of the intent-to-treat principle and rate of missing data in superiority trials 2005 Jun OBJECTIVE: To evaluate the methodologic quality of and identify methodologic issues in superiority trials assessing structural outcomes in rheumatic diseases. METHODS: We searched Medline and the Cochrane Central Register of Controlled Trials for reports of randomized controlled trials assessing structural outcomes in osteoarthritis (OA), rheumatoid arthritis (RA), and osteoporosis (OP) published between January 1994 and December 2003 in high-impact factor general medical and specialty journals. One reader extracted data (quality assessment, intent-to-treat analysis [ITT analysis], rate of missing data, and methods of handling missing data), using a standardized form. RESULTS: A total of 81 reports were included in the analysis (37 on OP, 34 on RA, and 10 on OA). The mean +/- SD methodologic quality scores on the Jadad scale (possible range 0-5) and the Delphi list (possible range 0-9) were 2.9 +/- 1.2 and 6.4 +/- 1.3, respectively. Although it was reported in 54 articles (66.7%) that the analysis was done on an ITT basis, full ITT analysis was performed in only 6 of the studies (7.4%), modified ITT analysis in 11 (13.6%), and case-complete analysis in 48 (59.3%); the analysis was unclear in 16 articles (19.8%). The rate of missing data on structural outcomes could be determined in only 63 articles (77.8%) and was >20% in approximately one-third of these reports. Methods for handling missing data on structural outcomes were described in 19 articles (23.5%) and were, in general, inappropriate. CONCLUSION: Lack of ITT analysis and a high rate of missing data in superiority trials assessing structural outcomes may bias results from such trials. Our recommendations for improving these shortcomings may help researchers plan, analyze, and report the results of such trials.
16309943 Genetic basis of rheumatoid arthritis. 2005 Dec Rheumatoid arthritis (RA) is a multifactorial disease due to a combination of genetic and environmental factors. Identification of the genetic factors involved in the pathogenesis of RA should open up avenues for developing radical treatment strategies directed at the cause of the disease. The Association de Recherche sur la Polyarthrite (ARP) supports research in this field, in which our group has been involved since 1993. Thanks to this support, considerable progress has been made. Several combinations of susceptibility alleles of various genes are probably involved in the development of RA. Although HLA-DRB1 is the main RA gene, it accounts for only part of the familial risk for RA. HLA-DRB1 alleles are neither necessary nor sufficient to cause the development of RA in a given individual. Several genome scans conducted in populations from France, Japan, North America and UK have confirmed the role of the HLA region and suggested several other susceptibility loci. Association studies support a role for several genes, including TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22. However, the imperfect matching of cases and controls requires that confirmation of these results be obtained. To confirm that a gene confers susceptibility to RA, the association must be replicated in several independent studies and, more importantly, evidence of genetic linkage must be obtained in family studies. The identification of genetic factors conferring susceptibility to RA will open up new avenues toward radical treatments for RA and may help to optimize the diagnostic, prognostic, and pharmacogenetic management of today's patients with RA.
16669210 Mixed aetiology leg ulcers. 2006 Apr 18 Irene Anderson and Brenda King outline the causes of mixed aetiology leg ulcers and the treatment of these complex wounds.
16622718 Lack of increase in postoperative complications with low-dose methotrexate therapy in pati 2006 To determine the potential contribution of intermittent low-dose methotrexate (MTX) treatment (2-8 mg/week) to postoperative complications, we studied 122 patients with rheumatoid arthritis (RA) who had 201 surgical procedures. The patients with treatment with MTX were allocated to two groups: those who continued MTX (group A, 77 procedures) and those who discontinued MTX more than 1 week (group B, 21 procedures). The patients who had no treatment with MTX were allocated to group C (103 procedures). The incidence of postoperative infection, poor wound healing, and flare-up of RA was compared between the three groups. Postoperative infection occurred in 3.9%, 4.8%, and 3.9% in groups A, B, and C, respectively. Poor wound healing was experienced in 1.3%, 9.5%, and 7.8% in groups A, B, and C, respectively. At 4 weeks postoperatively, 3.9%, 14.3%, and 6.8% of flares were seen in groups A, B, and C, respectively. No significant difference was found in the patients with or without perioperative use of MTX. From these results, it is unlikely that continuation of intermittent low-dose MTX treatment increases the risk of postoperative complications in patients with RA. Continued treatment with MTX during perioperative period could suppress disease flares, especially in severe RA patients.
15870027 Angiopoietin-like-4 is a potential angiogenic mediator in arthritis. 2005 Apr Our previous studies of gene expression profiling during collagen-induced arthritis (CIA) indicated that the putative angiogenic factor Angptl4 was one of the most highly expressed mRNAs early in disease. To investigate the potential involvement of Angptl4 in CIA pathogenesis, Angptl4 protein levels were assessed at early stages of disease and its cellular sources were determined. In addition, the functional effects of mouse Angptl4 on endothelial cells were assessed. Angptl4 protein levels were higher in arthritic joints as compared to normal joints. In situ hybridization localized Angptl4 mRNA to stromal fibroblast-like cells within the inflamed synovium. Temporal expression of Angptl4 mRNA during CIA was similar to that of key angiogenic factors, including structurally related angiopoietin 1. Recombinant mouse Angptl4 promoted endothelial cell survival and formation of tubule-like structures. These functional effects of Angptl4, combined with very high expression at early stages of CIA, suggest a role for Angptl4 in angiogenesis in arthritis.
16987426 Identification of a human peripheral blood monocyte subset that differentiates into osteoc 2006 Increased bone resorption mediated by osteoclasts causes various diseases such as osteoporosis and bone erosion in rheumatoid arthritis (RA). Osteoclasts are derived from the monocyte/macrophage lineage, but the precise origin remains unclear. In the present study, we show that the purified CD16- human peripheral blood monocyte subset, but not the CD16+ monocyte subset, differentiates into osteoclast by stimulation with receptor activator of NF-kappaB ligand (RANKL) in combination with macrophage colony-stimulating factor (M-CSF). Integrin-beta3 mRNA and the integrin-alpha(v)beta3 heterodimer were only expressed on CD16- monocytes, when they were stimulated with RANKL + M-CSF. Downregulation of beta3-subunit expression by small interfering RNA targeting beta3 abrogated osteoclastogenesis from the CD16- monocyte subset. In contrast, the CD16+ monocyte subset expressed larger amounts of tumor necrosis factor alpha and IL-6 than the CD16- subset, which was further enhanced by RANKL stimulation. Examination of RA synovial tissue showed accumulation of both CD16+ and CD16- macrophages. Our results suggest that peripheral blood monocytes consist of two functionally heterogeneous subsets with distinct responses to RANKL. Osteoclasts seem to originate from CD16- monocytes, and integrin beta3 is necessary for osteoclastogenesis. Blockade of accumulation and activation of CD16- monocytes could therefore be a beneficial approach as an anti-bone resorptive therapy, especially for RA.
16142748 Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study. 2005 Sep OBJECTIVE: Interleukin-15 (IL-15) is a proinflammatory, innate response cytokine that mediates pleiotropic effector function in rheumatoid arthritis (RA) inflammatory synovitis. Our objective was to study the ability of HuMax-IL15, a human IgG1 anti-IL-15 monoclonal antibody, to neutralize exogenous and endogenous IL-15 activity in vitro and to perform a phase I-II dose-escalation trial with HuMax-IL15 in patients with active RA. METHODS: Mononuclear cells from blood and synovial fluid (SF) of RA patients were isolated and cultured in vitro under experimental conditions involving the addition of HuMax-IL15. HuMax-IL15 was administered to 30 RA patients who received no other disease-modifying antirheumatic drugs in a 12-week, dose-ascending, placebo-controlled, double-blind, phase I-II proof-of-concept study. RESULTS: In vitro studies showed that HuMax-IL15 suppressed proliferation and induced apoptosis in an IL-15-dependent cell line, BDB2, and was capable of suppressing the release of interferon-gamma by synovial fluid mononuclear cell (SFMC) cultures induced by exogenous IL-15. Furthermore, HuMax-IL15 F(ab')2 fragments suppressed exogenous IL-15-induced CD69 expression in RA peripheral blood mononuclear cells and SFMCs, which indicates that HuMax-IL15 can specifically neutralize several biologic effects of IL-15 in synovial tissue in vitro. In a phase I-II clinical trial, HuMax-IL15 was well tolerated clinically, with no significant effects on T lymphocyte subset and natural killer cell numbers. Substantial improvements in disease activity were observed according to the American College of Rheumatology criteria for 20% improvement (63% of patients), 50% improvement (38%), and 70% improvement (25%). CONCLUSION: These clinical data suggest for the first time that IL-15 could represent a novel therapeutic target in RA.
15509629 Increase of peripheral CXCR3 positive T lymphocytes upon treatment of RA patients with TNF 2005 Feb OBJECTIVE: To explore the regulation of factors involved in lymphocyte trafficking in patients with rheumatoid arthritis (RA) undergoing treatment with tumour necrosis factor alpha (TNF-alpha) inhibitors. METHODS: We examined 14 consecutive patients with RA according to ACR criteria prior to and during treatment with TNF-alpha inhibitors (seven etanercept, seven infliximab) and determined disease activity using the Disease Activity Score (DAS-28). Peripheral blood mononuclear cells were isolated before and after 6 and 14 weeks of treatment and analysed immediately for CD3, CD4 and CD8, expression of chemokine receptors CXCR3 and CCR4, CD45RO phenotype and for expression of interferon gamma (IFN-gamma) and interleukin 4 (IL-4) using four-colour flow cytometry. RESULTS: We found significant increases in CD4 and CD8 T lymphocytes expressing CXCR3 after 6 and 14 weeks. The overall proportion of T lymphocytes expressing CCR4 appeared unchanged. More than half of peripheral CD4 T lymphocytes showed a memory phenotype (CD45RO), with a non-significant increase under TNF-alpha inhibition. Upon activation, up to 30% of CXCR3(+)/CD4 T cells expressed IFN-gamma, while IL-4-expressing cells were rare. There was a robust negative correlation between CXCR3(+)/CD4 T lymphocytes and DAS-28. CONCLUSIONS: TNF-alpha inhibition with infliximab and etanercept results in sustained accumulation of CXCR3 positive T lymphocytes in the peripheral blood of RA patients. This suggests altered lymphocyte trafficking during TNF-alpha inhibition.