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ID PMID Title PublicationDate abstract
22275188 CXCR4 and vascular cell adhesion molecule 1 are key chemokine/adhesion receptors in the mi 2012 Jul OBJECTIVE: To examine the migratory properties of cytokine-activated T (Tck) cells. METHODS: Tck cells were generated by culture of peripheral blood T cells in the presence of interleukin-6 (IL-6), tumor necrosis factor α, and IL-2. Changes in cell surface phenotype were analyzed by flow cytometry. Chemotactic responsiveness was measured using in vitro chemotaxis assays and transendothelial migration through human umbilical vein endothelial cell monolayers. Levels of vascular cell adhesion molecule 1 (VCAM-1) were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: Cytokine stimulation up-regulated the expression of chemokine receptors and integrins on Tck cells, including CXCR4, very late activation antigen 4 (VLA-4), and lymphocyte function-associated antigen 1. Increased expression of CXCR4 and VLA-4 integrin resulted in concentration-dependent chemotaxis to their ligands, stromal cell-derived factor 1 (SDF-1) and VCAM-1, which could be selectively blocked using a specific CXCR4 inhibitor and antibodies against VLA-4. Increased expression of VLA-4 also resulted in increased transendothelial migration of Tck cells, which could be abrogated using blocking antibodies against VLA-4. Tck cells also showed an increased chemotactic response to rheumatoid arthritis (RA) fibroblast-like synoviocytes cultured in vitro, which could be blocked using inhibitors against VLA-4 and CXCR4. CONCLUSION: The activated phenotype of Tck cells results in increased migratory responsiveness to SDF-1 and soluble VCAM-1, which are among the chemokines and proteins found elevated in the RA synovial joint environment. Cytokine-dependent activation may contribute to RA pathogenicity by promoting T cell recruitment to and retention in the joint, perpetuating the inflammatory cascade in RA.
22426852 Kinematics of a highly congruent mobile-bearing total knee prosthesis. 2012 Dec PURPOSE: Limited or absent axial rotation of the mobile insert of total knee prostheses could lead to high contact stresses and stresses at the bone-implant interface, which in turn might lead to implant loosening. The aim of this study was to assess knee kinematics and muscle activation and their possible change over time in patients with a highly congruent, mobile-bearing total knee prosthesis. METHODS: A prospective series of 11 rheumatoid arthritis patients was included to participate in this fluoroscopic and EMG study; only 7 patients completed the study. Kinematic evaluations took place 7 months, 1 and 2 years post-operatively. Repeated measurements ANOVA and linear mixed-effects model for longitudinal data were used to compare the differences between the follow-ups. RESULTS: There are no significant changes in axial rotations between follow-up moments for the femoral component as well as the mobile insert. The insert remained mobile and followed the femoral component from 0° until approximately 60° of knee flexion. Diverging and reversed axial rotations and translations were seen during the dynamic motions. CONCLUSIONS: Knee kinematics and muscle activation do not appear to change in the first 2 post-operative years. Reversed and divergent axial rotations with increasing knee flexion indicate that as soon as the congruency decreases, the femoral component is no longer forced in a certain position by the insert and moves to a self-imposed position. At lower knee flexion angles, the femoral component might be obstructed by the highly congruent insert and therefore might not be able to move freely. LEVEL OF EVIDENCE: Therapeutic study, Level IV.
22422501 Levels of plasma-soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are co 2012 May OBJECTIVE: To determine whether levels of plasma-soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) are elevated in patients with rheumatoid arthritis (RA) and whether levels are correlated with disease activity and other variables. METHODS: Our study included 71 patients with RA and 50 age- and sex-matched healthy controls. Clinical characteristics and laboratory measures, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and 28-joint Disease Activity Score (DAS28) were assessed. Plasma levels of sTREM-1 and tumor necrosis factor-α (TNF-α) were measured by ELISA. RESULTS: Patients with RA had significantly higher plasma sTREM-1 levels than healthy controls (170.10 ± 84.71 pg/ml vs 97.41 ± 40.64 pg/ml; p < 0.001). In patients with RA, plasma sTREM-1 levels were found to be correlated with DAS28, ESR, CRP, white blood cell counts, neutrophil counts, and plasma TNF-α levels (r = 0.329, p = 0.005; r = 0.241, p = 0.043; r = 0.314, p < 0.001; r = 0.261, p = 0.028; r = 0.278, p = 0.019; and r = 0.313, p = 0.009, respectively). Plasma sTREM-1 levels in patients with active disease status (DAS28 > 3.2) were significantly higher than in those with low disease status (DAS28 ≤ 3.2; 208.89 ± 100.14 pg/ml vs 150.29 ± 68.70 pg/ml; p = 0.005). CONCLUSION: Patients with RA had higher plasma sTREM-1 levels than healthy controls, and plasma sTREM-1 levels were correlated with disease activity measures, suggesting that plasma sTREM-1 could play a role in the inflammatory process associated with TNF-α, and that it may be a useful disease activity marker in RA.
21859690 Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substra 2012 Jan OBJECTIVE: To define the relationship between autoantigen citrullination and different peptidylarginine deiminase (PAD) enzymes in rheumatoid arthritis (RA). METHODS: Citrullinated autoantigens were identified by immunoblotting control and ionomycin-activated human primary neutrophil lysate with RA sera. Autoantigen identity and citrullination sites were defined by mass spectrometry. PAD isoenzyme expression in human neutrophils was determined by immunoblotting. PAD substrate specificity was addressed in HL-60 cell lysates co-incubated with human recombinant PAD2, PAD3 and PAD4. RESULTS: Although prominent protein citrullination is observed in ionomycin-activated neutrophils, RA sera only recognised a limited number of these citrullinated molecules. Among these, the authors identified that β and γ-actins are citrullinated on at least 10 arginine residues, generating a novel 47 kDa species that is frequently recognised by RA autoantibodies. Interestingly, the authors showed that the PAD enzymes expressed in human neutrophils (ie, PAD2, PAD3 and PAD4) have unique substrate specificities, independent of their subcellular distribution. Thus, only PAD2 was able to citrullinate native β/γ-actin, while histone H3 was only citrullinated by PAD4. CONCLUSION: These studies identified β and γ-actins as novel citrullinated autoantigens in RA, allowing enzyme specificity against intracellular substrates to be addressed. The studies provide evidence that PAD enzymes have the intrinsic capacity to select unique protein targets. The authors propose that unique PAD specificity may play a role in autoantigen selection in RA.
21125264 Power estimation using a population pharmacokinetics model with optimal design by clinical 2011 Mar OBJECTIVES: The aim of this article was to determine the power for pharmacokinetic interaction investigations using population a pharmacokinetic modelling approach with optimal sampling designs and clinical trial simulations. METHODS: A clinical trial simulation approach was proposed to estimate the power for pharmacokinetic effects in drug-drug interaction (DDI) studies. This approach consisted of: (1) population pharmacokinetic (PK) model(s) was characterised for the drug(s) studied; (2) D-optimal design strategy was applied based on these model(s) to determine optimal sampling times for DDI investigation; (3) clinical trial simulations under particular study designs, for example a randomised parallel design, were used to evaluate the sample size needed for studying PK interaction. The approach was described using an example investigating the impact of a new anti-inflammatory drug on methotrexate (MTX) exposure in rheumatoid arthritis (RA) patients. RESULTS: The power for evaluating PK interaction largely depended on the interindividual variability (IIV) in PK parameters. Residual variability was also influential to a lesser degree in the sample size determination using the proposed approach. It required 40-60 participants for scenarios where IIV was relatively low in order to achieve 90% power. However, a sample size of 80 individuals was required to reach 90% power where both IIV and residual variances were high. Under the same IIV assumptions, the proposed approach in general required a smaller sample size compared with the standard noncompartmental analysis method with intensive blood samples to attain the target power. When IIV was low, the difference in the power between the two approaches was relatively small. CONCLUSIONS: Population PK modelling with optimal design and clinical trial simulation to determine sample size when designing drug-drug interaction studies was efficient and cost effective.
22584154 High-density lipoprotein cholesterol subfractions HDL2 and HDL3 are reduced in women with 2012 May 14 INTRODUCTION: Higher levels of high density lipoprotein (HDL) subfractions HDL3-chol and particularly HDL2-chol protect against cardiovascular disease (CVD), but inflammation reduces the HDL level and may impair its anti-atherogenic effect. Changed HDL composition through the impact of inflammation on HDL subfractions may contribute to the excess risk of CVD in rheumatoid arthritis (RA). In this study, we investigated whether HDL2-chol and HDL3-chol concentrations differ between RA patients and healthy controls, and whether these levels are related to the level of RA disease activity. METHODS: Non-fasting blood samples were collected from 45 RA patients and 45 healthy controls. None of the participants had a history of CVD, diabetes, or used lipid-lowering drugs. HDL2-chol and HDL3-chol concentrations were obtained by ultracentrifugation. Regression modeling was used to compare HDL subfraction levels between RA patients and healthy controls, and to analyze the effect of disease activity on HDL2-chol and HDL3-chol. RESULTS: HDL2-chol and HDL3-chol were significantly lower in RA patients compared to healthy controls (P = 0.01, P = 0.005, respectively). The HDL2:HDL3 ratio was significantly lower in patients compared to controls (P = 0.04). Reduced HDL2-chol and HDL3-chol levels were primarily present in female RA patients and not in male RA patients. A modest effect of the disease activity score in 28 joins ( DAS28) on HDL2-chol concentrations was found, after correction for disease duration, glucocorticosteroid use and body mass index (BMI), with a 0.06 mmol/L decrease with every point increase in DAS28 (P = 0.05). DAS28 did not significantly affect HDL3-chol concentrations (P = 0.186). CONCLUSIONS: Both HDL subfractions but particularly HDL2-chol concentrations were decreased in RA, primarily in women. This seems to be associated with disease activity and is of clinical relevance. The reduction of the HDL subfraction concentrations, particularly the supposedly beneficial HDL2-chol, may negatively impact the cardiovascular risk profile of women with RA.
23053963 Associations between interleukin-23 receptor polymorphisms and susceptibility to rheumatoi 2012 Dec The aim of this study was to determine whether interleukin-23 receptor (IL-23R) polymorphisms confer susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the IL-23R rs1343151, rs10489629, rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA using (1) allele contrast, (2) the recessive model, (3) the dominant model, and (4) the additive model. A total of 13 studies from eight articles involving 10,016 RA patients and 11,967 controls were considered in the meta-analysis. Meta-analysis identified a significant association between RA and the A allele of the rs1343151 polymorphism in the overall population (OR = 1.110, 95 % CI = 1.056-1.168, p = 4.7 × 10(-6)). Stratification by ethnicity identified a significant association between this polymorphism and RA in Europeans (OR = 1.105, 95 % CI = 1.049-1.163, p = 1.4 × 10(-5)). An association was also found between RA and the A allele carrier of the rs1343151 polymorphism in Europeans (OR = 1.135, 95 % CI = 1.058-1.217, p = 4.0 × 10(-5)). Meta-analysis revealed a significant association between RA and the A allele of the rs10489629 polymorphism in the overall population (OR = 1.079, 95 % CI = 1.029-1.131, p = 0.002) and in Europeans (OR = 1.092, 95 % CI = 1.038-1.149, p = 0.001). Meta-analyses of recessive, dominant, and additive models showed the same pattern as the meta-analysis of the A allele of the rs10489629 polymorphism, that is, a significant association with RA in Europeans. However, no association was found between the IL-23R rs7517847, rs11209026, rs1004819, and rs2201841 polymorphisms and RA susceptibility. This meta-analysis shows that the IL-23R rs1343151 and rs10489629 polymorphisms are associated with the development of RA in Europeans. These findings suggest that the IL-23R genes confer susceptibility to RA in the European population, but further study of this association is required in other ethnic groups.
22342385 Dampened ERK signaling in hematopoietic progenitor cells in rheumatoid arthritis. 2012 Apr In rheumatoid arthritis (RA), hematopoietic progenitor cells (HPC) have age-inappropriate telomeric shortening suggesting premature senescence and possible restriction of proliferative capacity. In response to hematopoietic growth factors RA-derived CD34(+) HPC expanded significantly less than age-matched controls. Cell surface receptors for stem cell factor (SCF), Flt 3-Ligand, IL-3 and IL-6 were intact in RA HPC but the cells had lower transcript levels of cell cycle genes, compatible with insufficient signal strength in the ERK pathway. Cytokine-induced phosphorylation of ERK1/2 was diminished in RA HPC whereas phosphorylated STAT3 and STAT5 molecules accumulated to a similar extent as in controls. Confocal microscopy demonstrated that the membrane-proximal colocalization of K-Ras and B-Raf was less efficient in RA-derived CD34(+) cells. Thus, hyporesponsiveness of RA HPC to growth factors results from dampening of the ERK signaling pathways; with a defect localized in the very early steps of the ERK signaling cascade.
22994423 Development and psychometric testing of the Swedish version of the Body Awareness Question 2013 Jul AIM: This paper is a report of the development and psychometric testing of the Swedish version of the Body Awareness Questionnaire to measure bodily focus of attention. BACKGROUND: The Body Awareness Questionnaire has been identified as an instrument with excellent psychometric properties within the concept of body awareness. It has been used in both research and clinical settings in different contexts. However, a validated Swedish version is not available. METHOD: A cross-sectional design was applied for adaptation of the Body Awareness Questionnaire and psychometric validation. Data were collected between autumn 2009 and spring 2011 from 120 patients diagnosed with rheumatoid arthritis, and from 120 students. The 'concurrent think aloud' method was used in a pre-test to determine the usability of the questionnaire. Cronbach's alpha was used to test the internal consistency, and confirmatory factor analysis was performed to test the construct validity. RESULTS: According to the confirmatory factor analysis, neither the one-factor model nor the four-factor model tested in this study fulfilled the pre-specified criteria in accordance with the Comparative Fit Index, Standardized Root Mean Squared Residual and the Root Mean Square Error of Approximation. The value of Cronbach's alpha for the Swedish version of the Body Awareness Questionnaire was satisfactory. CONCLUSION: Our results indicate that the two models tested in this study do not provide a good fit to the observed data. Further refinement and testing of the Swedish version of the Body Awareness Questionnaire is therefore required. The concept of body awareness may be useful in the management of chronic disease and can be addressed in nursing.
21506097 The interaction between HLA shared epitope alleles and smoking and its contribution to aut 2011 Jul OBJECTIVE: Recent data suggest that a gene-environment interaction between smoking and the HLA shared epitope alleles plays a role in shaping the autoimmune reaction to specific citrullinated antigens. This study was undertaken to determine the effects of HLA shared epitope alleles and tobacco exposure on the immune response against various citrullinated antigens. These associations were analyzed in the anti-citrullinated protein antibody (ACPA)-positive stratum to control for the possibility that the associations found are explained by the known interaction between HLA shared epitope alleles and tobacco exposure on ACPA status. METHODS: In 661 patients with rheumatoid arthritis, reactivity against several citrullinated antigens from vimentin, fibrinogen, enolase, and myelin basic protein was determined by enzyme-linked immunosorbent assay. The effects of the HLA shared epitope alleles and tobacco exposure were assessed by logistic regression analysis. Biologic interaction was analyzed by investigating whether the effects of the risk factors combined exhibited departure from additivity. RESULTS: A significant interaction between tobacco exposure and HLA shared epitope alleles was found for the presence of ACPA as reported previously. When these interaction effects were studied for several ACPA "fine specificities," significant interactions were noted for several citrullinated peptides. However, these interactions were not present after stratification for ACPA status, indicating that the interaction between tobacco exposure and HLA shared epitope alleles influences autoimmunity not to specific citrullinated antigens, but rather to ACPA development. CONCLUSION: Our data indicate that the gene-environment interaction between HLA shared epitope alleles and smoking does not appear to shape the reactivity of the ACPA response. These data suggest that smoking promotes nonspecific citrullination rather than citrullination of specific antigens.
22370364 Intramedullary fibular and impaction allografting in revision total elbow arthroplasty wit 2012 Mar One of the many reasons for failed revision elbow replacement is loss of the normally irregular shape of the endosteal surface leading to reduced ability to provide rotational control of the humeral or ulnar component within the intramedullary canal. The endosteal bone loss of the distal humerus or proximal ulna compromises the rotational stability of the stem in the intramedullary canal. In these cases, impaction cancellous allografting techniques, similar to the ones used in revision total hip arthroplasties, are commonly used to address the osseous deficiency, but these methods are not optimal for providing rotational control of the prosthetic stem. We describe a technique of restoring the irregular shape of the endosteal bone using intramedullary fibular allografting to enhance the rotational control of the prosthetic stem within the intramedullary bone canal.
22147320 The use of sex hormones in women with rheumatological diseases. 2011 Dec A number of rheumatological diseases predominantly affect women of reproductive age. There has always been concern that the use of oestrogen-containing agents such as combined hormonal contraception and hormone therapy might aggravate these conditions. This article reviews the up-to-date evidence regarding the safety of using these agents in women with various rheumatological diseases, with emphasis on systemic lupus erythematosus and rheumatoid arthritis. In the absence of antiphospholipid antibody or other prothrombotic risk factors, combined hormonal contraception is not contra-indicated in most rheumatological conditions including inactive systemic lupus erythematosus. Moreover, hormone therapy is generally not contra-indicated except for women with active systemic lupus erythematosus disease where its effect on disease flare is less clear and individual judgement is required.
21418785 Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in p 2011 Mar OBJECTIVES: To evaluate long-term safety and efficacy of etanercept (ETN) in patients with rheumatoid arthritis (RA) without concomitant disease-modifying antirheumatic drug therapy. METHODS: A total of 549 patients enrolled in this 5-year, open-label extension after completing 1 of 2 randomised controlled studies; all patients received ETN 25 mg twice weekly during the extension. Safety assessments included physical exams, adverse events (AEs), vital signs, laboratory tests, and autoantibody evaluations. Key efficacy endpoints included numbers of responders achieving the American College of Rheumatology (ACR) criteria, low disease activity scores, and disease remission. RESULTS: Three hundred and eight (56%) patients completed the 5-year extension study. Total ETN exposure, including that received during the double-blind studies was 2212 patient-years. Withdrawals for efficacy- and safety-related reasons were 12% and 19%, respectively. The most common AE was upper respiratory infection (44%). Rates of serious infections decreased over the 5-year period; one case of suspected tuberculosis was reported. Rates of malignancies remained generally consistent during the 5-year period. There were no reports of demyelinating disease, serious blood dyscrasias, or opportunistic infections. The relationship between autoantibody titres and clinical events was not statistically significant. Less than 5% of patients tested positive for anti-etanercept antibodies and all antibodies were non-neutralising. After 5 years, ACR 20, 50, and 70 response rates were 78%, 51%, and 32%, respectively; the mean percentage of patients achieving low disease activity score (DAS ≤ 2.4) and remission (DAS ≤ 1.6) were 44% and 20%, respectively. CONCLUSIONS: ETN maintained a favourable safety profile and consistent efficacy throughout the 5-year study duration.
23057341 [Middle- and long-term effectiveness of primary total hip arthroplasty for patients with c 2012 Sep OBJECTIVE: To evaluate the middle- and long-term effectiveness of primary total hip arthroplasty (THA) in patients with chronic autoimmune inflammatory diseases. METHODS: Between January 1990 and June 2006, 42 patients (51 hips) with chronic autoimmune inflammatory diseases underwent THA. There were 15 males (18 hips) and 27 females (33 hips) with an average age of 36.9 years (range, 22-70 years). The locations were the left side in 29 hips and the right side in 22 hips. Of 42 cases, there were 11 cases of systemic lupus erythematosus (13 hips), 16 cases of rheumatoid arthritis (22 hips), and 15 cases of ankylosing spondylitis (16 hips). The causes of THA included avascular necrosis of the femoral head in 26 cases (34 hips), ankylosis of the hip in 15 cases (16 hips), and fracture of the femoral neck in 1 case (1 hip). The Harris score was 32.49 +/- 9.50. The physical component summary (PCS) and mental component summary (MCS) of short form 36 health survey scale (SF-36) scores were 25.53 +/- 4.46 and 42.28 +/- 6.27, respectively. RESULTS: All incisions healed primarily. All 42 patients were followed up 5-21 years (mean, 9.1 years). At last follow-up, the Harris score was 89.25 +/- 8.47; PCS and MCS of the SF-36 were 51.35 +/- 4.28 and 55.29 +/- 8.31, respectively; and significant differences in the scores were found between pre- and post-operation (P < 0.05). Complications included limp (4 cases), prosthesis dislocation (2 cases, 2 hips), periprosthetic fracture (1 case, 1 hip), aseptic loosening (2 cases, 2 hips), and ectopic ossification (3 cases, 3 hips). CONCLUSION: THA seems to be a good choice for patients with chronic autoimmune inflammatory diseases.
21747955 Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the tr 2011 BACKGROUND: The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis. CONCLUSIONS/SIGNIFICANCE: The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo.
22974474 Development of a new humanized mouse model to study acute inflammatory arthritis. 2012 Sep 13 BACKGROUND: Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis. METHODS: One to two-day old irradiated NOD-scid IL2rγ(null) (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund's adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically. RESULTS: Humanized mice were established with high reconstitution rates and were able to spontaneously produce human immunoglobulins as well as specific IgG in response to immunization. Intraperitoneal injection of thioglycolate or injection of complete Freund's adjuvant into joints resulted in migration of human immune cells to the injected sites. Arthritic humanized mice treated with Etanercept had markedly less inflammation, which was associated with decreased total numbers of human CD45+ cells, including human lymphocytes and neutrophils. CONCLUSIONS: The humanized mouse model is a new model to study inflammatory arthritis disease using human leukocytes without rejection of engrafted tissue. Future studies may adapt this system to incorporate RA patient cord blood and develop a chimeric animal model of inflammatory arthritis using genetically predisposed immune cells.
22942265 Increasing treatment in early rheumatoid arthritis is not determined by the disease activi 2012 Nov OBJECTIVE: To determine the factors most strongly associated with an increase in therapy of early rheumatoid arthritis (ERA). METHODS: Data from the Canadian Early Arthritis Cohort (CATCH) were included if the patient had ≥ 2 visits and baseline and 6 months data. A regression analysis was done to determine factors associated with treatment intensification. RESULTS: Of 1145 patients with ERA, 790 met inclusion criteria; mean age was 53.4 years (SD 14.7), mean disease duration 6.1 months (SD 2.8), 75% were female, baseline Disease Activity Score-28 (DAS28) was 4.7 (SD 1.8) and 2.9 (SD 1.8) at 6 months for included patients. Univariate factors for intensifying treatment were physician global assessment (MDGA; OR 7.8 and OR 7.4 at 3 and 6 months, respectively, p < 0.0005), swollen joint count (SJC; OR 4.7 and OR 7.3 at 3 and 6 months, p < 0.0005), and DAS28 (OR 3.0 and OR 4.6 at 3 and 6 months, p < 0.0005). In the regression model only MDGA was strongly associated with treatment intensification (OR 1.5 and OR 1.2 at 3 and 6 months, p < 0.0005); DAS28 was not consistently predictive (OR 1.0, p = 0.987, and OR 1.2, p = 0.023, at 3 and 6 months). DAS28 was the reason for treatment intensification 2.3% of the time, compared to 51.7% for SJC, 49.9% for tender joint count, and 23.8% for MDGA. For the same SJC, larger joint involvement was more likely to influence treatment than small joints at 3 months (OR 1.4, p = 0.027). CONCLUSION: MDGA was strongly associated with an increase in treatment at 3 and 6 months in ERA, whereas DAS28 was not. Physicians rarely stated that DAS28 was the reason for increasing treatment.
22392766 Decision tool to improve the quality of care in rheumatoid arthritis. 2012 Jul OBJECTIVE: Despite the importance of achieving tight control, many patients with rheumatoid arthritis (RA) are not effectively treated with disease-modifying antirheumatic drugs. The objective of this study was to develop a decision support tool to inform RA patients with ongoing active disease about the risks and benefits related to biologic therapy. METHODS: We developed a balanced, web-based, decision support tool. Options, values, and probabilistic information were described using theoretically supported formulations. We conducted a pre-/posttest study to assess preliminary evidence of the tool's efficacy in improving knowledge related to biologics, clarity of values, willingness to take a biologic, and informed choice. RESULTS: We interviewed 104 subjects (mean age 62 years, 84% women, 87% white, and median duration of RA 8 years). Knowledge (coded on a 0-20 scale) and willingness to take a biologic (coded on a 0-10 scale) significantly increased after viewing the tool (mean differences 2.3 and 1.4, respectively; P < 0.0001 for both). Perceived knowledge and values clarity (coded on 0-100 scales) also significantly improved (mean differences 20.4 and 20.8, respectively; P < 0.0001 for both). The proportion of subjects making an informed value-concordant choice increased substantially from 35% to 64%. CONCLUSION: A tool designed to effectively communicate the risks and benefits associated with biologic therapy increased knowledge, patient willingness to escalate care, and the likelihood of making an informed choice. The results of this study support the need for a clinical trial to examine the impact of the tool in clinical practice.
21547439 Inverse correlation of programmed death 1 (PD-1) expression in T cells to the spinal radio 2011 Sep Programmed death 1 (PD-1) has been shown to be involved in the negative regulation of the immune response. However, the role of PD-1 in ankylosing spondylitis (AS) has not been studied. Therefore, we analyzed the expression of PD-1 in peripheral blood mononuclear cells (PBMC) from patients with AS. Twenty-three AS patients, 20 rheumatoid arthritis (RA) patients, and 25 normal healthy subjects were recruited. The percentage of the PBMC and PD-1 levels in these subjects were measured by flow cytometry. A higher percentage of CD4+ T cells was noted in AS patients than in healthy controls (37.53±1.65% vs. 31.55±0.92%, P<0.01), but a similar result was not observed with regard to CD3+ T lymphocytes, CD4+CD25 high+regulatory T cells, CD19+ B cells, and CD14+ and CD16+ monocytes/macrophages. PD-1 levels in PBMC were not significantly higher in AS patients than in RA patients or age- and gender-matched healthy controls and were also not correlated to the erythrocyte sedimentation rate, C-reactive protein, limitation of back flexion, and chest expansion in patients with AS. Of interest, the percentages of PD-1+CD3+ T cells and PD-1+CD4+ T cells were significantly lower in AS patients with higher modified Stokes Ankylosing Spondylitis Spinal Scores (mSASSS ≥30) than in those with lower mSASSS (<30; 0.07±0.04% vs. 0.42±0.14%, P<0.05; 0.06±0.03% vs. 0.40±0.14%, P<0.05, respectively). These results have suggested that the increased number of T helper cells lacking PD-1 may contribute to the spinal radiologic changes in AS patients.
21324962 Expression of Toll-like receptors and their signaling pathways in rheumatoid synovitis. 2011 May OBJECTIVE: Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters. METHODS: TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining. RESULTS: In RA, ß-actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells. CONCLUSION: RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.