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ID PMID Title PublicationDate abstract
19096851 Preliminary study on the immunologic background of good clinical outcome in rheumatoid art 2009 Jun This preliminary study focuses on early peripheral cellular immune changes after 1 month therapy with leflunomide, in 18 patients with severe rheumatoid arthritis, previously treated with methotrexate. A good clinical outcome of disease was documented and we showed that a particular target of short-time leflunomide therapy in rheumatoid arthritis was the peripheral innate immune system (NK cells and the population of granulocytes developing phagocytosis and superoxide anion production when challenged ex vivo with zymosan particles). Meanwhile, the high inter-individual variability of adaptive immunity required data analysis in subgroups of patients. We showed that the abnormal increase of peripheral leukocytes counts, or the decrease towards normal values of the CD4:CD8 lymphocytes ratio, or the inhibition of uridine uptake by ex vivo activated lymphocytes were consistent with a positive clinical evolution, proved by the reduction of tender/swollen joints, morning stiffness duration or acute phase response. We emphasized that significant benefits of short-term leflunomide therapy were associated with functional suppression of peripheral B lymphocytes. Hence, the positive evolution of rheumatoid arthritis patients seemed to be specifically linked to early drug-induced changes of trafficking or uridine metabolism of mononuclear cells.
20958321 A role for calreticulin in the pathogenesis of rheumatoid arthritis. 2010 Oct Calreticulin (CRT) plays a role in the clearance of dying cells and has been implicated in autoimmunity. Recent evidence indicates that cell surface CRT (csCRT) acts as a signal transducing receptor for the rheumatoid arthritis (RA) shared epitope (SE). The SE binding site on CRT has been mapped to amino acid residues 217-223 in the P-domain. Upon interaction with dendritic cells (DCs), the SE activates potent immune regulatory events. In CD8α(+) DCs, which express higher abundance of csCRT, the SE inhibits the tolerogenic enzyme indoleamine 2,3 dioxygenase with resultant inhibition of regulatory T (Treg) cell differentiation. In CD8α(-) DCs, the SE ligand increases secretion of IL-6 and IL-23 and facilitates generation of Th17 cells, a T cell subset known to play a role in autoimmunity. On the basis of these recent findings, we discuss the possibility that the csCRT may play a pathogenic role in RA by transducing SE-activated Th17-polarizing signals.
20179740 Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type 2010 Jul It has repeatedly been suggested that the development of complex diseases can be elucidated by gene-gene interactions. Recently, we found that HTR2A, a member of the serotonin receptor family, is associated with rheumatoid arthritis (RA). This study was aimed to investigate the possibility of a gene-gene interaction between HTR2A and the major genetic risk factor for RA, HLA-DRB1 shared epitope (SE) alleles. We studied 4095 RA cases and 3223 controls from three different populations - from Sweden, the United States and the Netherlands - to test for interaction between the protective HTR2A haplotype and HLA-DRB1 SE alleles. Further, we analyzed mRNA and/or protein expression of HTR2A and HLA-DR in biopsy samples and in synovial fibroblasts from RA patients. The interaction was defined as departure from additivity of effects using attributable proportion due to interaction. First, we could demonstrate and further replicate an interaction between a protective haplotype in HTR2A and HLA-DRB1 SE alleles regarding risk of developing autoantibody-positive RA. Second, we could show that both genes are constitutively expressed in fibroblasts from synovial tissue of RA patients, and, by double immunofluorescence staining, we demonstrated that these two proteins are colocalized in these cells. In conclusion, our data demonstrate a statistical interaction between HTR2A and HLA-DRB1 SE alleles and colocalization of the product of these two genes in inflamed synovial tissue, which suggest a possible biological relationship between these two proteins. This finding may lead to the development of treatment based on enhancing the protective features of 5-HT2A in individuals with a certain HLA genotype.
21181275 Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis 2011 Nov The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.
20116334 Raised serum level of APRIL in patients with systemic lupus erythematosus: correlations wi 2010 Apr The aim of the present study is to assess serum APRIL levels in SLE patients versus rheumatoid arthritis (RA) patients and normal control and to correlate serum APRIL levels in SLE patients with disease activity indices. Serum APRIL levels was measured in 40 SLE patients, 20 patients with RA and 20 healthy volunteers who served as control group. Disease activity in SLE patients was assessed by the British Isles Lupus Assessment Group (BILAG) index and SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Significantly higher serum APRIL levels was observed in SLE patients compared to RA patients and normal controls (p=0.003 and p < or = 0.001, respectively). Positive correlations were found between serum APRIL levels and total BILAG index (r=0.486 and p=0.001), BILAG musculoskeletal score (r=0.848 and p < or = 0.001) and BILAG cardiorespiratory score (r=0.326 and 0.04). Serum APRIL was higher in SLE patients compared to RA patients and normal control subjects and positively correlates with BILAG index and higher levels may be associated with musculoskeletal manifestations of the disease. APRIL antagonism could be a potential therapeutic target in SLE.
20444268 Peripheral blood gene expression patterns discriminate among chronic inflammatory diseases 2010 May 5 BACKGROUND: Chronic inflammatory diseases including inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis and rheumatoid arthritis (RA) afflict millions of people worldwide, but their pathogenesis is still not well understood. It is also not well known if distinct changes in gene expression characterize these diseases and if these patterns can discriminate between diseased and control patients and/or stratify the disease. The main focus of our work was the identification of novel markers that overlap among the 3 diseases or discriminate them from each other. METHODS: Diseased (n = 13, n = 15 and n = 12 in IBD, psoriasis and RA respectively) and healthy patients (n = 18) were recruited based on strict inclusion and exclusion criteria; peripheral blood samples were collected by clinicians (30 ml) in Venous Blood Vacuum Collection Tubes containing EDTA and peripheral blood mononuclear cells were separated by Ficoll gradient centrifugation. RNA was extracted using Trizol reagent. Gene expression data was obtained using TaqMan Low Density Array (TLDA) containing 96 genes that were selected by an algorithm and the statistical analyses were performed in Prism by using non-parametric Mann-Whitney U test (P-values < 0.05). RESULTS: Here we show that using a panel of 96 disease associated genes and measuring mRNA expression levels in peripheral blood derived mononuclear cells; we could identify disease-specific gene panels that separate each disease from healthy controls. In addition, a panel of five genes such as ADM, AQP9, CXCL2, IL10 and NAMPT discriminates between all samples from patients with chronic inflammation and healthy controls. We also found genes that stratify the diseases and separate different subtypes or different states of prognosis in each condition. CONCLUSIONS: These findings and the identification of five universal markers of chronic inflammation suggest that these diseases have a common background in pathomechanism, but still can be separated by peripheral blood gene expression. Importantly, the identified genes can be associated with overlapping biological processes including changed inflammatory response. Gene panels based on such markers can play a major role in the development of personalized medicine, in monitoring disease progression and can lead to the identification of new potential drug targets in chronic inflammation.
19539516 Anti-TNFalpha blockers, autoantibodies and autoimmune diseases. 2009 Jul Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.
19483410 [B cell targeting therapy using the anti-CD20 antibody in autoimmune diseases]. 2009 Jun Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are representative autoimmune diseases thought to involve disturbances in T and B cell functions. Immune complexes consisting of antigens and autoantibodies secreted from activated B cells cause severe inflammation in various organs. Since often patients with RA and SLE are refractory to these conventional treatments such as immunosuppressants and corticosteroids, innovative approaches need to be developed. CD20 is a surface molecule specific for B cells and rituximab is a chimeric antibody specific for human CD20 and is known to deplete B cells. Recently, the potential efficacy of B-cell depletion therapy with rituximab has been reported in several autoimmune diseases. Rituximab is now approved for use in combination with methotrexate in refractory RA patients in the United States and EU. We reported that SLE patients with organ-threatening disorders that are resistant to intensive conventional therapies, were treated by once a week administration of anti-CD20 antibody rituximab, and that sufficient evidence concerning the excellent tolerability and high efficacy of rituximab therapy was obtained in both a pilot study and a nation-wide phase I/II clinical examination Moreover, a rapid and marked reduction in the expression of the co-stimulatory molecules CD40 and CD80 on B-cells was found in SLE patients, implying that reduction of both the quantity and the quality of B-cells by rituximab could improve the disease course in refractory SLE. Therefore, targeting B-cells may have potential interests by bringing about a breakthrough in the treatment of RA, SLE and other autoimmune diseases.
19220542 Leflunomide use in New Zealand. A national prospective post-marketing study. 2009 Feb BACKGROUND: This post-marketing study aimed to record rates of retention, adverse effects and efficacy of leflunomide in the treatment of rheumatoid arthritis (RA). The secondary objectives were to make a semi-quantitative assessment of response to treatment and to examine the effect of a loading dose on adverse events and treatment duration. METHODS: Rheumatologists in New Zealand contributed to a prospective leflunomide treatment registry. Baseline data were collected on leflunomide initiation and information about treatment experience was sought every 6 months. Each patient was followed for 2 years. Kaplan-Meier analysis was used to evaluate differences in stopping rates between lack of efficacy and adverse effects. Hazard analysis was used to evaluate the effect of using a loading dose on retention rate. RESULTS: Three hundred and eight patients were enrolled in the study; complete follow-up data were available for 244 patients. Retention of patients on leflunomide was 64% at 12 months and 49.4% at 2 years. Reasons for stopping were adverse events (54 patients), loss of effect (25 patients) and miscellaneous reasons (14 patients). Use of a loading dose had no effect on retention; there was no difference in treatment duration between those who stopped from adverse effects or loss of efficacy. CONCLUSION: Leflunomide was effective in treating RA in a group that had longer duration of disease and greater prior use of disease-modifying agents than the groups studied in clinical trials. Rates of withdrawal were lower than those reported in other post-marketing studies, but were higher than those from phase III clinical trials.
19366498 Economic evaluation of nonsteroidal anti-inflammatory drug strategies in rheumatoid arthri 2009 Apr OBJECTIVES: Although disease modifying antirheumatic drugs (DMARDs) are the first choice drugs in the treatment of rheumatoid arthritis, many patients still take nonsteroidal anti-inflammatory drugs (NSAIDs) as well. These drugs may cause serious gastric adverse events with continuous usage. Cyclooxygenase-2 (COX2) inhibitors were supposed to have a gastrointestinal (GI) friendly side effect profile. The aim of the study is to compare three therapeutic strategies: conventional NSAIDs, NSAID in combination with proton pump inhibitors (PPIs), and the selective COX2 inhibitor therapy (celecoxib). METHODS: A decision tree model was developed, for 1 year, to simulate cohorts within the three arms (NSAIDs, NSAID + PPI, celecoxib). The efficacy of the different active agents of NSAIDs in therapeutically relevant doses was assumed to be the same, consequently differences can be seen in the side effect profile of the drugs. Medical costs, the costs of the side effects (GI, cardiovascular [CV] events), and quality-adjusted life-years (QALYs) were calculated to gain an incremental cost-effectiveness ratio (ICER). Evaluations were made from a third party payer's perspective. We performed one-way deterministic sensitivity analyses; the results were displayed in tornado diagrams. RESULTS: Our model indicates that NSAID + PPI offers extra health gain for extra costs compared with conventional NSAIDs (ICER:14,287 euro/QALY), while it dominates celecoxib because of celecoxib's higher costs and lower effectiveness. According to the sensitivity analyses, QALYs had the highest influence on ICER. CONCLUSIONS: Although COX2 inhibitors have elevated GI efficacy compared with NSAIDs, celecoxib seems to be an adequate choice only for a limited group of patients with specific conditions because of the significantly higher price and CV risk profile.
19595060 [T cell proliferative response and antibody formation to citrullinated collagen type II in 2009 Mar 17 OBJECTIVE: To investigate the T cell proliferative response and antibody formation to citrullinated collagen type II (Cit-CII) in patients with rheumatoid arthritis (RA), and explore whether autoreactive T cells responding to Cit-CII plays a role in the pathogenesis of RA. METHODS: Arginine residues of bovine collagen type II (CII) were converted to citrulline residues by peptidylarginine deiminase (PAD). Peripheral blood samples were collected from 34 RA patients, and 18 sex- and age-matched controls, including 6 osteoarthritis patients and 12 healthy blood donors. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with Cit-CII, CII, or fetal bovine serum RPMI 1640 fluid, phytohemagglutinin (PHA), or citrullinated buffer as controls. Cellular reactivity levels against Cit-CII and CII were investigated by measuring the proliferation of PBMCs to calculate the stimulation index (SI). ELISA was used to detect the presence of antibodies against Cit-CII and CII. RESULTS: The positive rate of T cell proliferative response to Cit-CII of the RA group was 32.4% (11/34), significantly higher than that of the control group (0, P < 0.05). The positive rate of T cell proliferative response to CII of the RA group was 35.3% (12/34), significantly higher than that of the control group (11.1%, P < 0.05). Interestingly, Cit-CII could not elicit a better T cell proliferative response than CII did. In the RA patients, the anti-Cit-CII antibody positive rate was 52.9% (18/34), significantly higher than that of the anti-CII antibody positive rate [32.4% (11/34), P < 0.05). The serum IgG anti-CII antibody positive rate of the patients with positive T cell responses to CII was 58.3% (7/12), significantly higher than that of the patients with negative T cell responses to CII [18.2% (4/22), P < 0.05]. The serum IgG anti-CII antibody positive rate of the patients with positive T cell responses to Cit-CII was 72.7% (8/11), significantly higher than that of the patients with negative T cell responses to Cit-CII [43.5% (10/23), P < 0.05]. CONCLUSION: The recognition of Cit-CII by circulating IgG antibodies is a RA-specific serological phenomenon. The formation of CII antibody in the RA patients may be related to B cell activation mediated by CII specific T cells. The role of Cit-CII in RA cellular immune need be further studied.
21193999 The effect of body mass index on the spread of spinal block in patients with rheumatoid ar 2011 Apr PURPOSE: Body mass index (BMI) has a significant effect on the spread of sensory spinal block in rheumatoid patients. We tried to achieve the same spread of spinal block for patients in three different BMI groups and, on the basis of the results from a preliminary study, used a simple method feasible for clinical practice. We hypothesized that BMI-related inverse dosing of plain bupivacaine according to low, normal, and high BMI would result in no difference in block extent. METHODS: Together 75 patients with seropositive rheumatoid arthritis were included in three equal-sized groups according to BMI: low (<23 kg/m(2)), normal (23-28 kg/m(2)), and high (>28 kg/m(2)). Spinal anesthesia was induced with plain bupivacaine using doses 3.3, 3.0, and 2.7 ml, respectively. The spread of sensory block was recorded 30 min after injection of bupivacaine by use of a pin-prick test and a cold ice-filled container. RESULTS: Spreads of sensory block were different in low, normal, and high BMI groups (mean (SD); 14.0 (2.6), 14.5 (2.5), and 16.3 (2.5) dermatomes, respectively, P = 0.006) because of greater block extent in the high-BMI group. CONCLUSIONS: Despite three-step dosing of plain bupivacaine inversely related to BMI (low, normal, or high), comparable block extent was not achieved because of greater spread in the high-BMI group. Adjustment of plain bupivacaine dose according to BMI could be used to achieve a more predictable spread of spinal block, but further reduction of dose is needed in patients with high BMI.
20493342 Musculoskeletal disorders. 2010 Jun Musculoskeletal system complaints are one of the most common reasons that patients seek medical care. A significant number of these patients use complementary and alternative medicine. This article discusses the most common musculoskeletal problems for which patients present to a physician's office. These include osteoarthritis, rheumatoid arthritis, low back pain, neck pain, and myofascial pain syndrome.
20156606 Ten-year probability of osteoporotic fracture in 2012 Polish women assessed by FRAX and no 2010 Jun PURPOSE: The aim of the cross-sectional study was to establish the degree of conformity between 10-year probability of osteoporotic fracture, assessed by FRAX, and using the nomograms, as proposed by Nguyen at al. METHODS: Postmenopausal Polish women (2012) were examined in their mean age of 68.5+/-7.9 years (age range 55-90 years). Fracture probability by FRAX was based on age, BMI, prior fracture, hip fracture in parents, steroid use, rheumatoid arthritis, alcohol use, secondary osteoporosis and T-score for femoral neck BMD. Fracture probability by Nguyen's nomograms was based on age, the number of prior fractures, the number of falls and T-score for femoral neck BMD. RESULTS: The mean conformity rate was 79.1% for any fracture risk (for threshold 20%) and 79.5% for hip fracture (threshold 3%). Any and hip fracture risks were significantly higher for both methods in women with fracture history in comparison to those without fracture and increased with ageing. The influence of prior fracture and ageing was more evident in Nguyen's nomograms. ROC analyses of any fracture risk in FRAX and Nguyen's methods demonstrated the area under curve (AUC) at 0.833 and 0.879, respectively. Similar analyses for hip fracture demonstrated AUCs for FRAX and Nguyen's technique at 0.726 and 0.850, respectively. The AUCs for Nguyen's nomograms were significantly larger than the AUCs for FRAX (p<0.0001). CONCLUSION: The mean conformity for any fracture risk is 79.1% and 79.5% for hip fracture. Nguyen's nomograms seem to be more efficient in fracture risk assessment, especially for hip fractures, due to a higher accuracy of the method. The information on the number of falls during the last year and multiple fractures ought to be incorporated into the method of fracture risk prediction. MINI-ABSTRACT: The degree of conformity was assessed in a group of 2012 women between 10-year FRAX prognosis of fracture and Nguyen et al.'s nomograms. The mean conformity for any fracture risk is 79.1% and 79.5% for hip fracture. Nguyen's nomograms seem to be more efficient in fracture risk assessment due to higher accuracy.
19191254 Reliability, validity and responsiveness of a new leisure index: the Patient-Specific Leis 2009 Sep OBJECTIVES: To investigate the reliability, validity and responsiveness of a new Patient-Specific Leisure Scale (PSLS), constructed to identify goals and outcomes for individual patients with rheumatoid arthritis (RA). METHODS: Forty-nine patients with RA were used to evaluate test-retest reliability, and 100 consecutive RA patients were used for construct validity. Twenty-five RA patients, commencing with treatment on tumour necrosis factor (TNF) inhibitors, were evaluated before the start and after three months of therapy, to test responsiveness. The most important leisure activity (as judged by the patients) was used when evaluating reliability and validity. The perceived difficulty with each activity was scored from 0 to 10 (0 = able to perform activity without difficulty, 10 = unable to perform activity). RESULTS: Test-retest reliability indicated a good agreement (0.62-0.87) using weighted kappa. Construct validity was demonstrated by modest positive correlation between leisure activity and Health Assessment Questionnaire (HAQ) (r(s) = 0.27, p = 0.005) visual analogue scale (VAS) pain (r(s) = 0.28, p = 0.004) VAS global (r(s) = 0.22, p = 0.027), VAS fatigue (r(s) = 0.24, p = 0.013), joint index of 28 swollen joints (r(s) = 0.22, p = 0.027) and negative correlations with short-form-36 (SF-36) physical functioning (r(s) = -0.18, p = 0.008), bodily pain (r(s) = -0.31, p < 0.001), general health (r(s) = -0.23, p = 0.019), vitality (r(s) = -0.31, p < 0.001), social function (r(s) = -0.24, p = 0.016) and role-emotional (r(s) = -0.28, p = 0.005). Mean improvement for the most important leisure activity was 1.36, (p = 0.036, 95% confidence interval 0.10-2.62). Standardized response mean and effect size for the most important activity in PSLS was 1.05 and 0.72, respectively, and for HAQ 0.34 and 0.28, respectively. CONCLUSIONS: PSLS appears to be feasible, reliable, valid and responsive for measuring leisure activities in RA. It provides both an individual result which is useful in clinical work, and results at a group level.
19820942 Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in on 2010 Nov The aim of the present study was to determine the drug survival during 2 years' follow-up in patients (n = 104) with active rheumatoid arthritis (RA) or spondyloarthropathy (SpA) who were treated with infliximab as their first biological anti-rheumatic drug in a single rheumatological center. According to the national guidelines, infliximab was added to the treatment with combinations of traditional disease-modifying anti-rheumatic drugs (DMARD). Patients' records were analyzed at baseline and after 2 years of follow-up. The response to treatment was determined inadequate if the response was lower than ACR50 (American College of Rheumatology 50) in RA or the reduction of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was lower than 50% or 2 cm in SpA. Drug survival in infliximab-treated patients after 2 years was 40%, and among those who continued with the therapy the prednisolone dose has been reduced by 52%. Discontinuation rate was 60% during 2 years of follow-up, where 7% achieved remission and 22% of the patients were regarded as poor responders. As much as 24% of the patients discontinued due to an adverse event, mainly infections and hypersensitivity reactions. Two drug-related leukopenias were diagnosed. In the present study, infliximab therapy was initiated in RA or SpA patients who had active disease despite ongoing treatment with combinations of DMARDs. The drug survival with infliximab was 40% after 2 years of follow-up. During the 2-year follow-up, 60% discontinued infliximab treatment, mainly due to unsatisfactory or waning efficacy or a severe adverse event.
20205706 TRAF1/C5 polymorphism is not associated with increased mortality in rheumatoid arthritis: 2010 INTRODUCTION: Recently an association between a genetic variation in TRAF1/C5 and mortality from sepsis or cancer was found in rheumatoid arthritis (RA). The most prevalent cause of death, cardiovascular disease, may have been missed in that study, since patients were enrolled at an advanced disease stage. Therefore, we used an inception cohort of RA patients to investigate the association between TRAF1/C5 and cardiovascular mortality, and replicate the findings on all-cause mortality. As TRAF1/C5 associated mortality may not be restricted to RA, we also studied a large cohort of non-RA patients. METHODS: 615 RA patients from the Leiden Early Arthritis Clinic (EAC) (mean follow-up 7.6 years) were genotyped for rs10818488. In addition 5634 persons enrolled in the PROspective Study of Pravastatin in the Elderly at Risk (mean follow-up 3.2 years) were genotyped for rs2416808 (R(2) >0.99 with rs10818488). The life/death status was determined and for the deceased persons the cause of death was ascertained. Cox proportional hazards and regression models were used to assess hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Seventy-seven RA patients died. The main death causes in RA patients were cardiovascular diseases (37.7%), cancer (28.6%) and death due to infections (9.1%). No association was observed between the rs10818488 susceptible genotype AA and cardiovascular mortality (HR 1.08 95%CI 0.54 to 2.15) and all-cause mortality (HR 0.81 95%CI 0.27 to 2.43). Similar findings were observed for rs2416808 susceptible genotype GG in the non-RA cohort (HR 0.99; 95%CI 0.79 to 1.25 and HR 0.89; 95%CI 0.64 to 1.25, respectively). CONCLUSIONS: The TRAF1/C5 region is not associated with an increased mortality risk.
20080907 Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-gl 2010 Mar OBJECTIVE: Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. METHODS: One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio). RESULTS: The disease activity of enrolled patients was 5.8 +/- 1.2 (mean +/- SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. CONCLUSION: Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment.
20448287 Rapid reduction in tenosynovitis of the wrist and fingers evaluated by MRI in patients wit 2010 Jun OBJECTIVE: To assess the efficacy of etanercept in reducing tenosynovitis evaluated by MRI of the hand (h-MRI) in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drug (DMARD) after 6 weeks of treatment. METHODS: 31 patients with active RA defined by a disease activity score (DAS28) >3.2 and synovitis in the hands were randomised into two groups: 19 patients received 50 mg weekly subcutaneous etanercept added to previous DMARD treatment and 12 patients continued with previous DMARD therapy. Clinical evaluation, blood tests, functional capacity evaluation and h-MRI were performed at the start of the investigation and at week 6. Tenosynovitis was evaluated on T1-weighted sequences with fat suppression after gadolinium as the presence of a peritendinous signal enhancement on axial images using a new method including wrist and finger tendons. The reliability, sensitivity to change and responsiveness of this method were also evaluated. RESULTS: Scores for tenosynovitis showed a significant reduction in the etanercept group compared with placebo (p=0.01) after 6 weeks of treatment. Adding MRI joint synovitis to tenosynovitis scores gave an even higher significant reduction in the etanercept group (p=0.007). A positive and statistically significant correlation between tenosynovitis and DAS28, erythrocyte sedimentation rate and C-reactive protein was found, but not with functional capacity. Responsiveness for tenosynovitis was small but was higher when joint synovitis scores were added. CONCLUSION: Addition of etanercept significantly reduced MRI tenosynovitis of the wrist and fingers in patients with active RA refractory to DMARD treatment. The method of scoring tenosynovitis showed good reliability and moderate responsiveness.
18701555 Disease activity as a risk factor for myocardial infarction in rheumatoid arthritis. 2009 Aug OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (