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ID PMID Title PublicationDate abstract
24532832 Retinol-binding protein 4 in rheumatoid arthritis-related insulin resistance and β-cell f 2014 Apr OBJECTIVE: Retinol-binding protein 4 (RBP4), an adipokine related to impaired glucose tolerance, has been associated with insulin resistance (IR) and β-cell function in subjects with obesity or diabetes. In our study we assessed RBP4 levels in patients with rheumatoid arthritis (RA). We also determined whether any correlation exists between RBP4 levels and the presence of IR in these patients. METHODS: Plasma RBP4, insulin, C-peptide concentrations, and homeostasis model assessment (HOMA)-IR were measured in 101 patients with RA and 115 sex-matched and age-matched controls. A multivariable analysis adjusted for IR classic cardiovascular risk factors and body mass index was performed to establish the correlation between RBP4 plasma concentrations and features of IR in RA. Data were adjusted for glucocorticoid intake in patients with RA. RESULTS: Patients had higher levels of insulin, C-peptide levels, HOMA-percentage of β-cell secretion (%B) index, and HOMA-IR index than controls. RBP4 levels were significantly lower in the whole group of patients than in controls [13.99 (9.78-19.88) vs 21.50 (10.28-32.59) μg/ml, p<0.01]. However, only those who were glucocorticoid-naive showed significant difference in RBP4 plasma concentration when compared to controls [11.88 (7.93-17.96) vs 21.50 (10.28-32.59) μg/ml, p<0.01]. The HOMA-%B [log β coefficient 0.00 (0.00-0.01), p<0.01] showed positive relationships regarding RBP4 in controls. That was not the case in patients with RA [log β coefficient 0.00 (-0.0-0.00), p=0.93 for HOMA-%B]. CONCLUSION: RBP4 does not correlate with the presence of IR and β-cell function in patients with RA. The mechanisms leading to IR in RA may be different from those occurring in obesity or diabetes.
24473673 Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment 2014 May OBJECTIVE: To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. METHODS: ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2. RESULTS: 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients. CONCLUSIONS: Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.
23852694 Results from systematic screening for cardiovascular risk in outpatients with rheumatoid a 2013 Nov AIM: To investigate risk factors for the development of cardiovascular disease (CVD) and estimate the risk of cardiovascular death in rheumatoid arthritis (RA) patients in accordance with EULAR recommendations. MATERIALS AND METHODS: Outpatients with RA ≤85 years of age from a Danish hospital were invited to participate. Patients' risk of cardiovascular death was calculated according to the SCORE system, based on total cholesterol/high-density lipoprotein (HDL) ratio, smoking habits, blood pressure, age and gender. The SCORE was adjusted based on disease duration, IgM-RF/anti-CCP positivity and the presence of extra-articular manifestations. Factors such as history of CVD, hypertension or diabetes mellitus (DM), fasting glucose, exercise habits, body mass index (BMI) and waist circumference were explored. RESULTS: 836 patients participated; 71.5% women; mean (SD) age 64.3 years (12.0); 152 (19.1%) were already diagnosed with CVD and 74 (9.0%) with DM. Among the 644 patients without CVD or DM, 158 (24.5%) were smokers, 229 (35.8%) had a systolic blood pressure ≥140, 397 (65.6%) total cholesterol ≥5.0 mM/L, 326 (55.4%) low-density lipoprotein cholesterol ≥3.0 mM/L, 18 (4.0%) women and 19 (12.1%) men had a HDL-cholesterol level below 1.2/1.0 mM/L. BMI was >25 in 409 (63.8%). Waist circumference was above 80/94 cm in 297 (63.3%) of female and 111 (63.8%) of male patients, respectively, and 418 (64.9%) exercised ≤5 times a week. Among patients without DM, 14.3% had a fasting glucose ≥6.0 mmol/L. The SCORE was ≥5 in 122 (20.2%). They were referred to follow-up by their GP and community advice services. CONCLUSIONS: Systematic screening revealed several risk factors that needed medical follow-up or support to initiate lifestyle changes.
25028371 The effect of different remission definitions on identification of predictors of both poin 2014 Aug OBJECTIVE: Predictors of remission in rheumatoid arthritis (RA) have been defined in cross-sectional analyses using the 28-joint Disease Activity Score (DAS28), but not with newer composite disease activity measures or using the more clinically relevant state of sustained remission. We have evaluated predictors of remission using cross-sectional and longitudinal durations of disease state, and by applying additional definitions of remission [American College of Rheumatology/European League Against Rheumatism Boolean, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI)]. METHODS: Individuals in the Alberta Biologics Pharmacosurveillance Program were classified for the presence of remission (point and/or sustained > 1 yr) by each of the 4 definitions. Multivariate models were constructed including all available variables in the dataset and refined to optimize model fit and predictive ability to calculate OR for remission. RESULTS: Nonsmoking status independently predicted point remission by all definitions (OR range 1.20-2.71). Minority ethnicity decreased odds of remission by DAS28 (OR 0.13) and CDAI (OR 0.09) definitions. Male sex was associated with DAS28 remission (OR 2.85), whereas higher baseline physician global (OR 0.67) and erythrocyte sedimentation rate values (OR 0.98) decreased odds of DAS28 remission. Higher baseline patient global score (OR 0.77) and swollen joint counts (OR 0.93) were negative predictors for CDAI remission. Higher baseline Health Assessment Questionnaire (OR 0.62) reduced odds for remission by the SDAI definition, and educational attainment increased these odds (OR 2.13). Sustained remission was negatively predicted by baseline physician global for the DAS28 (OR 0.80), and higher tender joint count (OR 0.96) for the CDAI. CONCLUSION: We demonstrate the influence of duration of remission state and remission definition on defining independent predictors for remission in RA requiring anti-tumor necrosis factor therapy. These predictors offer improved applicability for modern rheumatology practice.
23710583 Efficiency of adalimumab, etanercept and infliximab in rheumatoid arthritis patients: dosi 2013 Jul OBJECTIVES: This retrospective, multicentre, observational study aimed to assess the mean annual doses and associated costs of three anti-tumour necrosis factor agents in daily clinical practice in rheumatoid arthritis patients, correlating these costs with disease activity. METHODS: Adult rheumatoid arthritis patients were treated and followed at the Rheumatology departments of two Spanish hospitals for at least 6 months, with adalimumab, etanercept or infliximab over a 4-year period. ANOVA and multivariate statistical analyses of dosing patterns, disease activity and annualised costs were carried out. RESULTS: A total of 198 patients, comprising 215 cases, met the inclusion criteria (73 on adalimumab, 81 etanercept and 61 infliximab). Compared to recommended doses, mean doses of adalimumab and etanercept decreased by 7% and 19%, respectively, while the mean dose of infliximab increased by 36%. There were no statistical differences between treatments in terms of clinical effectiveness. The hazard of dose escalation was significantly higher for either adalimumab (4.4-fold) or infliximab (11.8-fold) compared to etanercept (p<0.05). Clinical control was achieved and maintained in more than half of the patients treated with reduced doses of etanercept. Associated mean patient-year costs were significantly higher in adalimumab patients (€11.962.58) (etanercept €9.594.73; infliximab €10.094.53; [p<0.05]). CONCLUSIONS: In rheumatoid arthritis patients, it is possible to reduce doses and associated costs of biological therapies while controlling disease activity. Mean doses used in our clinical practice were significantly lower with etanercept than with the anti-TNF monoclonal antibodies, adalimumab and infliximab. Dose differences impact directly on associated patient-year costs, and thus on treatment efficiency.
25410066 Horsetail mixture on rheumatoid arthritis and its regulation on TNF-α and IL-10. 2014 Nov Taking autoimmune inflammation of rheumatoid arthritis as entry point, this paper discussed the clinical effect of horsetail mixture on rheumatoid arthritis (RA) and its mechanism. A total of 60 cases of patients with RA were randomly divided into experimental group and control group using randomized controlled trial. We observed its biochemistry, TNF-α and IL-10 before and after treatment, and then systematically assessed the clinical effect of horsetail on RA. Results showed that the total effective rate of experimental group was 80%, while that of control group was 16.67%. After statistical treatment, the differences between two groups were significant (p<0.01). Comparison of the difference value of TNF-α (p<0.05) and IL-0.05 in serum between groups before and after treatment, there were significant differences. Comparison of CRP within group before and after treatment was significantly different (p<0.05), while comparison of CRP between groups was not significantly different (p>0.05). Comparison of ESR and RF within group before and after treatment was significantly different (p<0.01), and comparison of them between groups was also significantly different (p<0.05). Comparison of difference values within group before and after treatment were also significantly different (p<0.01). It was concluded that horsetail mixture has remarkable curative effect on rheumatoid arthritis, and its clinical application is safe and reliable. It has obvious down regulatory effect on cell factor TNF-α related to RA, that is, it can down regulate the level of pre-inflammatory factor TNF-α as well as the level of anti-inflammatory factor IL-10. Therefore, it is considered that the regulating effect of horsetail mixture on TNF-α and IL-10 is one of the mechanisms of its treatment on RA.
24167138 [Extract of Herba Siegesbeckiae on mouse rheumatoid arthritis induced by anthrogen-CIA mon 2013 Sep OBJECTIVE: To investigate the anti-inflammatory effect of Herba Siegesbeckiae extracts on mouse rheumatoid arthritis induced by arthrogen-CIA monoclonal antibody. METHODS: The rheumatoid arthritis was induced by arthrogen-CIA arthritogenic monoclonal antibody in mice. The sandwich enzyme-linked immunosorbent assay was used to determine the concentration of IL-1βin mouse serum,and the content of IL-6,IL-17 and MMP-3 in supernatant of tissue homogenate of hind limb below the stifle of mice. One-way ANOVA was used for data analysis. RESULTS: The toe swelling was attenuated in Siegesbeckiae group than that in model group [(0.218 ± 0.0307)cm(3) compared with (0.2545 ± 0.0179)cm(3), P<0.05]. The serum IL-1β level in Siegesbeckiae group was lower than that in model group [(63.74 ± 21.74)pg/ml compared with (104.96 ± 31.22)pg/ml, P<0.01]. The contents of IL-6, IL-17 and MMP-3 in tissue supernatants of Siegesbeckiae group were all lower than those of model group [(171.10 ± 48.35)pg/ml compared with (249.64 ± 75.08)pg/ml, P<0.05; (115.42 ± 56.52)pg/ml compared with (208.40 ± 88.54)pg/ml, P<0.05;(3660.31 ± 1680.99) pg/ml compared with (5420.79 ± 1201.43)pg/ml, P<0.05, respectively]. CONCLUSION: The extract of Herba Siegesbeckiae has anti-inflammatory effect on mouse rheumatoid arthritis induced by mixed arthrogen monoclonal antibody.
23746537 Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab 2013 Jul OBJECTIVES: Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro. METHODS: Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected. RESULTS: After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 ± 0.9 to 5.9 ± 1.3 mmol/L; p < 0.001), LDLc by 22% (3.0 ± 0.6 to 3.6 ± 0.8 mmol/L; p < 0.001) and HDLc by 17% (1.4 ± 0.4 to 1.7 ± 0.7 mmol/L; p < 0.016). Fasting triglycerides (TG) increased by 48% (1.0 ± 0.4 to 1.4 ± 0.8 mmol/L; p = 0.011), whereas postprandial incremental area under the curve TG increased by 62% (p = 0.002). Lipid changes were unrelated to the change in disease activity or inflammatory markers. No difference in HDL antioxidative capacity was found. In vitro, LDLr expression in cultured liver cells was significantly decreased following TCZ incubation (P < 0.001). CONCLUSIONS: TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials.
25535750 Diabetes mellitus risk factors in rheumatoid arthritis: a systematic review and meta-analy 2015 Jan OBJECTIVES: The aim of this study was to investigate the relationship between rheumatoid arthritis (RA) and the occurrence of diabetes mellitus (DM). METHODS: A meta-analysis was conducted to explore the risk of DM in RA patients. All relevant studies were identified by searching PUBMED, EMBASE and MEDLINE database prior to 1 January 2014. Pooled risk estimates were calculated with random-effects models using STATA 11.0. RESULTS: A total of 11 case-control studies and 8 cohort studies were included in the final analysis. The pooled risk estimate of 11 case-control studies showed a statistically significant increased risk of DM prevalence among RA individuals (OR=1.40, 95% CI: 1.34-1.47). The pooled risk estimate of 8 cohort studies also showed a statistically significant increasing risk of DM (RR=1.43, 95%CI: 1.38-1.47). In a subgroup analysis for case-control studies, the pooled risk estimate of individuals with RA increased the incidence of T1DM (type 1 diabetes mellitus) and the incidence of T2DM (type 2 diabetes mellitus) (OR, 4.78 vs. 1.41). In a subgroup analysis for cohort studies, RA was also found to have a statistically significant increasing risk of T2DM (RR=1.24, 95%CI: 1.14-1.35). Begg funnel plot and Egger test showed no evidence of publication bias. CONCLUSIONS: RA is associated with increased risk of DM, including T1DM and T2DM.
23618456 The modified Clayton-Mannerfelt arthrodesis of the wrist in rheumatoid arthritis: operativ 2013 May Arthrodesis of a painful and destroyed wrist is one of the key operations in patients with rheumatoid arthritis. Clayton is given credit for the first description of an operative technique of wrist arthrodesis by means of an intramedullary Steinmann pin. Mannerfelt popularized this technique by using a Rush pin and additional fixation with staples. The aim of the present article is to give a detailed description of the operative technique used in our hospital. Over a period of 13 years, 104 modified Clayton-Mannerfelt arthrodeses were performed in 87 patients with rheumatoid arthritis. Ninety-three wrists were reviewed clinically and radiographically. The patients had high fusion rates and a reliable reduction in preoperative pain, with a low rate of complications. The pin technique is more versatile than standard wrist arthrodesis plates, and the wrist can be positioned according to the needs of the patient. This technique seems to be a good alternative to conventional wrist arthrodesis using an arthrodesis plate in wrists destroyed by rheumatoid arthritis, even in situations with difficult bone stock. In most cases, it is not necessary to remove the hardware.
25148371 TL1A increases expression of CD25, LFA-1, CD134 and CD154, and induces IL-22 and GM-CSF pr 2014 Elevated levels of the cytokine TL1A is associated with several autoimmune diseases e.g. rheumatoid arthritis and inflammatory bowel disease. However, the exact role of TL1A remains elusive. In this study, we investigated the function of TL1A in a pro-inflammatory setting. We show that TL1A together with IL-12, IL-15 and IL-18 increases expression of the co-stimulatory molecules CD154 (CD40 ligand) and CD134 (OX40) on previously activated CD4+ T cells. This indicates that TL1A functions as a co-stimulatory molecule, decreasing the activation threshold of T-cells. We have previously shown that TL1A co-stimulation strongly induces IL-6 in human healthy leukocytes. Interestingly, the cytokine-activated effector T-cells did not produce IL-6 in response to TL1A, indicating distinct effects of TL1A on different cell populations. We further show that this co-stimulation increases the expression of CD25 (IL-2Rα) and CD11a (α-chain of LFA-1) on CD4 T-cells, likely governing increased IL-2/IL-15 sensitivity and cell-cell contact. Along with this, TL1A co-stimulation caused a specific induction of IL-22 and GM-CSF from the activated T-cells. These results substantially contribute to the explanation of TL1A's role in inflammation. Our results suggest that TL1A should be considered as a target for immunotherapeutic treatment of rheumatoid arthritis and inflammatory bowel disease.
23724971 Vaccination against seasonal influenza is effective in Japanese patients with rheumatoid a 2013 OBJECTIVE: To investigate the effectiveness of influenza vaccination in patients with rheumatoid arthritis (RA) from a large practice-based cohort. METHOD: Patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort completed self-administered questionnaires as part of the April IORRA surveys of 2001, 2002, 2003, and 2007, which included their influenza vaccination status and occurrence of an actual influenza attack. Vaccine coverage rate and attack rates were calculated in each season. Relative risks (RRs) of vaccination for an actual influenza attack were evaluated and risk factors for influenza infection were determined by multiple logistic regression analysis. RESULTS: Data from 3529, 4518, 4816, and 4872 patients in the 2000/01, 2001/02, 2002/03, and 2006/07 seasons, respectively, were analysed. Coverage rates were increased from 12.2% in the 2000/01 season to 38.7% in the 2006/07 season. For each season, the attack rates in vaccinated patients trended lower than the rates in unvaccinated patients but the differences were not significant; however, by combining these four seasonal results, the attack rate was significantly lower for vaccinated patients [RR 0.83, 95% confidence interval (CI) 0.71-0.95, p < 0.01]. Male gender [odds ratio (OR) 1.48, 95% CI 1.25-1.76, p < 0.001] was associated with increased risk whereas vaccination was associated with reduced risk for influenza attack (OR 0.76, 95% CI 0.63-0.91, p < 0.01). There were no associations between influenza attacks and RA disease activity, treatment with methotrexate (MTX) or corticosteroids. CONCLUSION: Influenza vaccination was effective in patients with RA regardless of disease activity or treatment.
24950016 SDF-1 signaling: a promising target in rheumatic diseases. 2014 Sep INTRODUCTION: Stromal cell-derived factor 1 (SDF-1) is a potent chemoattractant cytokine with various biological functions such as stem cell mobilization, inflammatory cell infiltration and angiogenesis. Therefore, it has also been implicated in several pathological processes, from ischemic conditions to cancer. Remarkably, SDF-1 and its receptors, CXCR4 and CXCR7, are also present in joint tissues, where they play a role in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). AREAS COVERED: This review summarizes the physiological and pathological role of SDF-1 signaling and its involvement in RA and OA. That includes synovial inflammation, bone erosion, cartilage degradation and increased bone turnover. Although this cytokine could play different roles in these rheumatic diseases, specific and differentiated therapeutic targets in each process can be identified. Current therapeutic strategies to block SDF-1 signaling in several diseases and their possible use in rheumatic diseases are also discussed. EXPERT OPINION: Emerging drugs that block CXCR4 or CXCR7 in different disorders may represent promising therapies for rheumatic disease via inhibition of key pathological events involved in the progression of RA and OA.
24001261 Redefined by illness: meta-ethnography of qualitative studies on the experience of rheumat 2014 PURPOSE: To synthesize published qualitative studies concerning the lived experience of rheumatoid arthritis (RA). To compare the conceptual features of qualitative studies covering two different time periods. METHODS: In 2002, 24 items published 1975-2001 were identified in comprehensive literature searches and assessed by multiple reviewers. In 2010, the first author found 28 articles published 2002-2009 in a simple search of the Medline database and synthesized them alone. Articles were synthesized using meta-ethnography. RESULTS: Both syntheses found that the main symptoms of RA are variable and unpredictable. However, in the first synthesis a sociological model dominated where RA was seen as an assault on self-identity with devastating social consequences. The main concepts were biographical disruption, role incompetence and the dread of dependency on others. In the second synthesis, the findings produced a model for health care practitioners tied to perceptions of control and incorporating a career-adaptation model of the experience of RA. CONCLUSIONS: We recommend that future synthesizers and primary qualitative health researchers focus more on non-hospital based populations and non-English language articles or study participants. The implications for rehabilitation follow from reflecting the findings of the synthesis against existing psychological models of coping and adaptation in RA. Implications for Rehabilitation Coping and adaptation are biographical processes, although the relative importance of active "disease mastery" versus more passive "getting used to it" is unclear. The uncertainty and fluctuating nature of symptoms and disease course presents existential challenges for people with RA in relation to maintaining physical functioning and social roles. Within a social model of disability, these findings point to potential intervention sites in society and relationships that would benefit people living with RA.
24014567 A redundant epistatic interaction between IRF5 and STAT4 of the type I interferon pathway 2013 Nov OBJECTIVE: Two transcription factors in the type I interferon pathway, IRF5 and STAT4, have been genetically associated with susceptibility to both systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). This study aimed to determine whether these two genes interact with each other to affect the disease susceptibilities. METHODS: The genetic interactions between IRF5 and STAT4 polymorphisms in SLE and RA susceptibility were examined using the epistasis options in PLINK software. This study analyzes the genetic data from 2558 unrelated Korean participants including 589 SLE patients, 987 RA patients, and 982 controls. RESULTS: All 12 polymorphisms were individually associated with SLE susceptibility (p = 2.49 × 10(-8) to 0.00360). Among the three SLE-associated polymorphisms of IRF5, rs77571059, alternatively called CGGGG(3-4) indel, exhibited the lowest p value (4.60 × 10(-5)) and accounted for the observed associations of the other two single-nucleotide polymorphisms (SNPs). Among the nine SLE-associated SNPs of STAT4, rs16833215 exhibited the lowest p value (2.49 × 10(-8)) and accounted for all the other associations. These two polymorphisms, rs77571059 of IRF5 and rs16833215 of STAT4, interacted with each other for SLE susceptibility in a redundant manner (ORinteraction = 0.77, P epistasis = 0.040). Furthermore, these two polymorphisms, which had been individually associated with RA susceptibility, also interacted for RA susceptibility in the same manner (ORinteraction = 0.75, P epistasis = 0.014). CONCLUSIONS: A redundant interaction between IRF5 and STAT4 polymorphisms was found in susceptibility to the type I interferon pathway-associated rheumatic autoimmune diseases, SLE and RA, calling for further studies on confirmation of these findings.
23651021 GWAS replication study confirms the association of PDE3A-SLCO1C1 with anti-TNF therapy res 2013 May AIM: The present study was undertaken to replicate the association of candidate genes for anti-TNF response in rheumatoid arthritis. Candidate genes were selected from a recent genome-wide association study on anti-TNF response performed in a population from Denmark. MATERIALS & METHODS: Genomic DNA was obtained from 315 Spanish rheumatoid arthritis patients having received an anti-TNF agent as their first biological therapy. SNPs from NR2FR2, MAP2K6, CBLN2 and PDE3A-SLCO1C1 candidate loci were genotyped. RESULTS: The PDE3A-SLCO1C1 locus rs3794271 SNP showed a highly significant association with anti-TNF treatment response (p = 1.74 × 10⁻⁵). Combining the statistical evidence from the Spanish and Danish rheumatoid arthritis cohorts, the associated rs3794271 SNP reached a genome-wide significance level of association (p = 3.3 × 10⁻¹⁰). CONCLUSION: The present findings establish the PDE3A-SLCO1C1 locus as a strong genetic marker of anti-TNF therapy response.
24241034 α9β1 integrin acts as a critical intrinsic regulator of human rheumatoid arthritis. 2014 Mar OBJECTIVE: The role of the joint tissue microenvironment in the pathogenesis of human RA has recently attracted much attention. The present study investigated the roles of α9β1 integrin and its ligands in synovial specimens of human RA patients in generating the unique human arthritic tissue microenvironment. METHODS: Synovial fibroblasts and macrophages were isolated from the synovial tissue of patients with RA or OA. The expression of α9β1 integrin was analysed using FACS with multicolour staining. The production of MMPs and proinflammatory cytokines was analysed in cultures of synovial fibroblasts and macrophages with α9β1 integrin ligands. RESULTS: Synovial fibroblasts and macrophages derived from arthritic joints spontaneously secreted tenascin-C and osteopontin. Synovial fibroblasts and macrophages obtained from patients with RA expressed α9β1 integrins, a common receptor for osteopontin and tenascin-C. In the synovial fibroblasts of RA, the amount of tenascin-C protein produced was much greater than that of osteopontin in synovial fibroblasts of RA. Importantly, autocrine and paracrine interactions of α9β1 integrin and tenascin-C induced the expression of MMPs and IL-6 in synovial fibroblasts, as well as TNF-α and IL-1β in synovial macrophages. CONCLUSION: These findings indicate that autocrine and paracrine interaction of α9β1 integrin and tenascin-C in the joint tissue microenvironment contributes to the pathogenesis of RA. Therefore α9β1 integrin may become a potential therapeutic target for RA.
22215041 Fibronectin molecular status determination useful to differentiate between rheumatoid arth 2013 Jan To find whether the plasma fibronectin (FN) molecular status can be useful to differentiate between rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The expression of plasma FN domains was determined by ELISA using monoclonal domain-specific antibodies. FN molecular forms were revealed by immunoblotting and analyzed by densitometry. The following findings were found: (1) Mean values of (Fibrin-Heparin)FN concentration were lower in SLE and RA patients than in normal plasmas. The cut off points at 31 mg/l in SLE and at 45 mg/l in RA showed a sensitivity and specificity of 54, 55 and 75%, respectively. (2) Mean values of concentrations of (CBD)FN and (Ct)FN were lower in SLE than those in normal and RA plasmas. Quantified data showed the cut off points of (CBD)FN and (Ct)FN at 200 mg/l (58% of sensitivity, 56% of specificity) and 350 mg/l (58% of sensitivity, 58% of specificity) in SLE, as well as at 295 mg/l (52% of sensitivity, 51% of specificity) and 460 mg/l in RA (70% of sensitivity, 73% of specificity). (3) The plasma FN immunopatterns, characterized by the presence of high-molecular (260-310 kDa) and/or low-molecular (158-209 kDa) FN bands, were specific only for SLE samples. The analysis of plasma FN status revealed by its Fibrin-Heparin-, CBD- and Ct-domain reactivity with monoclonal antibody and immunoblotting can be helpful to differentiate the SLE in respect to RA and normal plasmas.
25060537 From the era of genome analysis to the era of genomic drug discovery: a pioneering example 2014 Nov Although we have obtained comprehensive catalogs of genetic risk loci that are linked to human diseases, little is known regarding how to devise a systematic strategy to integrate genetic study results with diverse biological resources. Such strategies will be crucial for providing novel insights into disease biology and for aiding drug discovery as an ultimate goal. Here we describe the current progress in this field using a pioneering example of large-scale genetic association studies on rheumatoid arthritis (RA), an autoimmune disease characterized by inflammation and destruction of joints. Through functional and bioinformatic annotations of risk single nucleotide polymorphisms (SNPs) and genes from >100 RA risk loci identified by genome-wide association study (GWAS) meta-analysis, we found novel biological insights into RA pathogenicity. Further, by integrating RA genetic findings with the complete catalog of approved drugs for RA and other diseases, we provide empirical data to indicate that human genetic-based approaches may be useful for supporting 'genetics-driven genomic drug discovery' efforts in complex human traits and suggest that further development of integrative approaches should be undertaken.
22833372 Granulocyte-macrophage colony-stimulating factor is a key mediator in inflammatory and art 2013 Feb OBJECTIVES: Better therapies are needed for inflammatory pain. In arthritis the relationship between joint pain, inflammation and damage is unclear. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is important for the progression of a number of inflammatory/autoimmune conditions including arthritis; clinical trials targeting its action in rheumatoid arthritis are underway. However, its contribution to inflammatory and arthritic pain is unknown. The aims of this study were to determine whether GM-CSF controls inflammatory and/or arthritic pain. METHODS: A model of inflammatory pain (complete Freund's adjuvant footpad), as well as two inflammatory arthritis models, were induced in GM-CSF(-/-) mice and development of pain (assessment of weight distribution) and arthritic disease (histology) was assessed. Pain was further assessed in a GM-CSF-driven arthritis (methylated bovine serum albumin/GM-CSF) model and the cyclooxygenase-dependence determined using indomethacin. RESULTS: GM-CSF was absolutely required for pain development in both the inflammatory pain and arthritis models, including for IL-1-dependent arthritic pain. Pain in a GM-CSF-driven arthritis model, but not the disease itself, was abolished by the cyclooxygenase inhibitor, indomethacin, indicating separate pathways downstream of GM-CSF for pain and arthritis control. CONCLUSIONS: GM-CSF is key to the development of inflammatory and arthritic pain, suggesting that pain alleviation could result from trials evaluating its role in inflammatory/autoimmune conditions.