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ID PMID Title PublicationDate abstract
21242512 IL-3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulat 2011 Feb 15 IL-3, a cytokine secreted by Th cells, functions as a link between the immune and the hematopoietic system. We previously demonstrated the potent inhibitory role of IL-3 on osteoclastogenesis, pathological bone resorption, and inflammatory arthritis. In this study, we investigated the novel role of IL-3 in development of regulatory T (Treg) cells. We found that IL-3 in a dose-dependent manner increases the percentage of Foxp3(+) Treg cells indirectly through secretion of IL-2 by non-Treg cells. These IL-3-expanded Treg cells are competent in suppressing effector T cell proliferation. Interestingly, IL-3 treatment significantly reduces the severity of arthritis and restores the loss of Foxp3(+) Treg cells in thymus, lymph nodes, and spleen in collagen-induced arthritis mice. Most significantly, we show that IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-α, and IL-1 and increases the production of anti-inflammatory cytokines IFN-γ and IL-10 in collagen-induced arthritis mice. Thus, to our knowledge, we provide the first evidence that IL-3 play an important role in modulation of Treg cell development in both in vitro and in vivo conditions, and we suggest its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases.
21727237 Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. 2011 Sep BACKGROUND: Rheumatoid arthritis (RA) is associated with enhanced cardiovascular (CV) risk and subclinical vascular disease. The proinflammatory milieu has been linked to premature atherosclerosis and endothelial dysfunction in RA. While interleukin 17 (IL-17) is considered pathogenic in RA, its role in determining vascular dysfunction in this disease has not been systematically assessed. OBJECTIVES: To analyse candidate variables that might determine endothelial function in various vascular territories in a cohort of patients with RA receiving treatment with biological agents, with minimal traditional CV risk factors and low disease activity score. METHODS: Patients with RA (n=50) receiving stable treatment with biological agents underwent measurement of conduit artery endothelial function by brachial artery flow-mediated dilatation; arterial compliance by pulse wave velocity (PWV) assessment; and endothelium-dependent microvascular testing with Endo-Pat2000 device to assess the reactive hyperaemia index (RHI). IL-17 was quantified by ELISA and disease activity was assessed by 28-joint count Disease Activity Score. RESULTS: IL-17 was the main determinant of lower RHI in univariate and multivariate analysis. Traditional and non-traditional CV risk variables determined PWV, with a significant positive association with IL-17 in univariate and multivariate analysis. In contrast, conduit endothelial function was mainly determined by rheumatoid factor titres in univariate and multivariate analysis. Anti-cyclic citrullinated peptide titres, specific disease-modifying antirheumatic drugs or biological agents and disease activity did not determine vascular function. CONCLUSION: In patients with RA treated with biological agents, IL-17 is a main predictor of microvascular function and arterial compliance. This study suggests that IL-17 may play a significant role in development of endothelial dysfunction and cardiovascular disease in RA.
21554150 Efficacy and safety of adalimumab treatment in patients with rheumatoid arthritis, ankylos 2011 Jul INTRODUCTION: In the last couple of years, the number of patients with chronic inflammatory rheumatic diseases being treated with TNF α antagonist has increased dramatically. Adalimumab, a fully human monoclonal antibody against TNF α, is one of the most frequently administered TNF α antagonists. Yet, unresolved issues are the long-term safety of TNF α antagonists and high treatment costs. AREAS COVERED: The authors summarize the available data on short- and long-term efficacy and safety of adalimumab in the treatment of rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. The reader will find a comprehensive overview on the safety and efficacy of adalimumab for these conditions. Clinically relevant questions of adalimumab therapy are discussed. A special focus of this review is on the safety of adalimumab therapy. EXPERT OPINION: Adalimumab is effective and reasonably safe in the short- and long-term treatment of patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis who do not respond to the standard therapy. It inhibits radiographic progression in rheumatoid and psoriatic arthritis. Treatment with a TNF α inhibitor such as adalimumab is associated with high treatment costs.
21041271 Beware of antibodies to dietary proteins in "antigen-specific" immunoassays! falsely posit 2011 Feb OBJECTIVE: To evaluate (1) to what extent sera from healthy subjects and patients with rheumatoid arthritis (RA) contain antibodies to bovine serum albumin (BSA); and (2) if anti-BSA antibodies interfere with results of enzyme-linked immunoassays (ELISA) containing BSA. METHODS: The ELISA used was a previously developed in-house assay of autoantibodies to tumor necrosis factor (TNF). Anti-TNF and anti-BSA antibodies were analyzed by ELISA in 189 patients with early RA and 186 healthy blood donors. TNF preparations containing either BSA or human serum albumin (HSA) as carrier proteins were used as antigens in the anti-TNF assay. The presence and levels of antibodies were analyzed in relation to disease course and to the presence/absence of rheumatoid factor (RF). RESULTS: In patients with RA, anti-TNF/BSA levels strongly correlated with anti-BSA levels (r = 0.81, p < 0.001), whereas anti-TNF/HSA did not (r = -0.09). Neither the presence nor the levels of anti-BSA in RA patients were associated with disease progression, and antibody levels were not significantly altered compared to controls (p = 0.11). IgG reactivity with TNF/HSA was neglible. In paired sera, preincubation with BSA abolished the anti-TNF/BSA reactivity. There were no indications of RF interference with anti-BSA or anti-TNF reactivity. CONCLUSION: Antibodies to BSA are common in patients with RA as well as in healthy individuals. Their presence does not seem to be associated with RA disease activity or disease course, but may severely interfere with ELISA containing BSA. The use of BSA as a "blocking agent" or carrier protein in immunoassays should therefore be avoided.
20878344 Antineutrophil cytoplasmic antibodies against myeloperoxidase, proteinase 3, elastase, cat 2011 Feb Antineutrophil cytoplasmic antibodies (ANCAs) against myeloperoxidase (MPO), proteinase 3 (PR-3), lactoferrin (LF), cathepsin G (CG) and elastase (EL) were determined to investigate whether the presence of ANCAs is closely related to extra-articular manifestations in Japanese patients with rheumatoid arthritis (RA). Antibodies against MPO, PR-3, LF, CG and EL were determined in sera from 125 patients with RA and 83 sera from patients with other rheumatic diseases by enzyme-linked immunosorbent assay. Clinical manifestations and laboratory parameters of the patients were studied from medical records. Thirty of the 125 (24.0%) RA patients were positive for ANCAs for at least one of these 5 ANCA antigens. Among the 5 ANCAs, anti-LF antibody (anti-LF) (16.8%) was most commonly observed in patients with RA. A higher joint score (JS) and an elevated ESR were demonstrated in ANCA-positive RA patients compared to those of ANCA-negative patients (40.8 ± 43.3, 24.3 ± 26.2, p < 0.05, 44.4 ± 22.4, 28.9 ± 23.6, p < 0.05, respectively). No statistical differences in the presence of interstitial pneumonia, cutaneous vasculitis, rheumatoid nodules and mononeuropathy multiplex were observed between ANCA-positive and ANCA-negative patients. The presence of anti-LF is expected to be of pathological relevance, as the action of anti-LF towards LF results in the inhibition of the anti-inflammatory activity of LF.
23090506 siRNA-based therapeutic approaches for rheumatic diseases. 2013 Jan RNA interference (RNAi) is one of the most exciting and important discoveries of the past few decades. Small interfering RNAs (siRNAs) can silence gene activity and be used to interfere with pathophysiological processes. Substantial research has focused on introducing 'drug-like' properties-stability, selectivity and potency-to RNAi molecules, and clinical trials have been initiated. Despite initial success, the current challenge that remains is to develop optimized vehicles that avoid off-target effects whilst efficiently delivering the therapeutic siRNA to specific cell types. As for many other diseases, siRNA-based therapy is emerging as a promising approach for the treatment of rheumatic disorders. Although the pathogenesis of rheumatic diseases is complex, identification of candidate genes able to influence either inflammation or structural damage has been successful. Here, we will discuss advances in the field and potential applications of siRNA therapeutics in clinical trials for rheumatic conditions.
20950869 Adjuvant-induced arthritis induces c-Fos chronically in neurons in the hippocampus. 2011 Jan Chronic pain, sickness behaviors, and cognitive decline are symptoms in rheumatoid arthritis. In the adjuvant-induced arthritis Lewis rat model, we examined the dynamics of c-Fos expression in the hippocampus, a brain region important for these symptoms. Brain sections were stained for c-Fos using immunohistochemistry. c-Fos-positive nuclei were counted in CA1, CA2, CA3 and the dentate gyrus of the dorsal hippocampi from rats receiving no treatment or base-of-the-tail injections of (1 or 2) incomplete or complete Freund's adjuvant (low- or high-dose), (3), Mycobacterium butyricum cell wall suspended in saline, or (4) saline, and sacrificed 4, 14, 21, or 126days post-immunization. Disease severity was evaluated by dorsoplantar foot pad widths and X-ray analysis. We report sustained dose- and subfield-dependent c-Fos expression with arthritis, but transient expression in nonarthritic groups, suggesting long-term genomic changes in rheumatoid arthritis that may be causal for behavioral changes, adaptation to chronic pain and/or cognitive decline associated with disease.
21688319 Volume measurement of bone erosions in magnetic resonance images of patients with rheumato 2012 Mar The volume of bone erosions in the metacarpophalangeal joints is a radiological feature that can be used to track the progression of rheumatoid arthritis. We introduce a hybrid segmentation algorithm that combines region growing and level-set segmentation algorithms to semiautomatically measure the volume of bone erosions in magnetic resonance images. A total of 40 rheumatoid arthritis patients were included in the study. The scans of eight patients were used for training, whereas the remaining 32 scans were used to determine the accuracy, precision, and speed of the technique. The reproducibility of the semiautomated technique and that of manual segmentation was defined in terms of intraclass correlation coefficients. Both techniques were equally precise with intraclass correlation coefficient values greater than 0.9. The hybrid algorithm was highly accurate: the least squares fit between the semiautomated segmentations to those manually traced by a musculoskeletal radiologist resulted in a slope of 1.030 with an x-intercept of 1.385 mm(3) and an R(2) value of 0.923. The semiautomated technique was significantly faster than manual segmentation, which took two to four times longer to complete. Our hybrid algorithm shows promise in the quantitative assessment of radiological features of rheumatoid arthritis in a clinical setting.
22537824 Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated pr 2012 Apr 26 INTRODUCTION: Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which genetic and environmental factors interact in the etiology. In this study, we investigated whether smoking and HLA-DRB1 shared-epitope (SE) alleles interact differently in the development of the two major subgroups of rheumatoid arthritis (RA), anti-citrullinated proteins antibody (ACPA)-positive and ACPA-negative disease, in a multiethnic population of Asian descent. METHODS: A case-control study comprising early diagnosed RA cases was carried out in Malaysia between 2005 and 2009. In total, 1,076 cases and 1,612 matched controls participated in the study. High-resolution HLA-DRB1 genotyping was performed for shared-epitope (SE) alleles. All participants answered a questionnaire on a broad range of issues, including smoking habits. The odds ratio (OR) of developing ACPA-positive and ACPA-negative disease was calculated for smoking and the presence of any SE alleles separately. Potential interaction between smoking history (defined as "ever" and "never" smoking) and HLA-DRB1 SE alleles also was calculated. RESULTS: In our multiethnic study, both the SE alleles and smoking were associated with an increased risk of developing ACPA-positive RA (OR SE alleles, 4.7; 95% confidence interval (CI), 3.6 to 6.2; OR smoking, 4.1; 95% CI, 1.9 to 9.2). SE-positive smokers had an odds ratio of ACPA-positive RA of 25.6 (95% CI, 10.4 to 63.4), compared with SE-negative never-smokers. The interaction between smoking and SE alleles was significant (attributable proportion due to interaction (AP) was 0.7 (95% CI, 0.5 to 1.0)). The HLA-DRB1*04:05 SE allele, which is common in Asian populations, but not among Caucasians, was associated with an increased risk of ACPA-positive RA, and this allele also showed signs of interaction with smoking (AP, 0.4; 95% CI, -0.1 to 0.9). Neither smoking nor SE alleles nor their combination was associated with an increased risk of ACPA-negative RA. CONCLUSIONS: The risk of developing ACPA-positive RA is associated with a strong gene-environment interaction between smoking and HLA-DRB1 SE alleles in a Malaysian multiethnic population of Asian descent. This interaction seems to apply also between smoking and the specific HLA-DRB1*04:05 SE allele, which is common in Asian populations but not in Caucasians.
22116079 Biologicals and switch in rheumatoid arthritis throughout time - are we being more aggress 2011 Jul OBJECTIVES: To investigate the switches performed in patients with rheumatoid arthritis under biological therapy and specifically comparing the switches from earlier days with more recent switches. PATIENTS AND METHODS: Patients with rheumatoid arthritis under biological therapy followed at Hospital Garcia de Orta, Almada, and included in the Rheumatic Diseases Portuguese Register (Reuma.Pt) were included in this study. Switches occurring before and after January 2007 were compared with respect to patients' demographic and clinical characteristics, such as disease activity and duration of biological therapy. The survival of the first biological agent was compared between patients starting biological therapy before and after 2007. EULAR response and remission rate at the last evaluation were calculated. Comparisons between groups were established using a t-test or chi--square, as appropriate. Survival curves of the first biological were compared through the logrank test. RESULTS: In total, 123 patients were included in the analysis (mean age 57.0 ± 13.1 years and mean disease duration 11.7 ± 8.0 years). A total of 85 switches were documented, 20% of which took place before 2007. Comparing the switches before and after 2007, the latter were registered among older patients (recent switches 56.2 ± 12.9 years vs older switches 48.9 ± 11.0 years, p=0.04) and with a shorter duration of the first biological agent (recent switches 461.9 ± 293.2 days vs older switches 773.7 ± 475.8 days, p=0.03). No further significant differences were found, including the disease activity. The survival of the first biological was shorter in patients starting biological therapy after 2007 (2949 days for biological onset before 2007 and 818 days for onset after 2007, p <0.001). A good EULAR response was achieved by 19% and 30% of the patients, before and after 2007, respectively (p = 0.23). Remission was achieved by 14% and 22% of the patients, before and after 2007, respectively (p = 0.30). CONCLUSIONS: Switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy. A trend towards a better and more targeted control of the disease could be discussed in light of our results. Although switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy, there is still room for improvement when aiming at remission, for example by applying a tighter therapy strategy like the "treat to target model".
23815013 [Pathophysiological advances underlying the biotherapeutic revolution in inflammatory rheu 2012 Oct Major advances have been made in the pathogenesis of rheumatoid arthritis, spondyloarthritis and connective tissue diseases, leading to new biotherapies. In rheumatoid arthritis, the discovery of anti-citrulline antibodies (ACPA, anti-citrullinatedpeptide antibodies), whose specificity is between 95% and 98% and may be present before symptom onset, allowed early diagnosis and provided new pathological insights. Studies of the role of cytokines, B cells and co-stimulation of T cells revealed novel therapeutic targets. TNF inhibitors are effective in spondyloarthritis. In lupusandSjigren'ssyndrome, genes stimulatedby IFNtypel are hyper-expressed, along with BAFF (or BLyS), a B lymphocyte-activating cytokine.
22847212 Do patients with active RA have differences in disease activity and perceptions if anti-TN 2012 Aug BACKGROUND: The chance of a good response in RA is attenuated in previous anti-TNF users who start new anti-TNF therapy compared to biologic naïve patients. In active RA, those with previous anti-TNF exposure compared to anti-TNF naïve may have different baseline disease activity and patient perceptions when starting a new anti-TNF treatment that could explain the observed response differences. MATERIAL/METHODS: The aim of this study was a post hoc analysis of baseline characteristics of patients enrolled in the Optimization of Adalimumab study that was a treat to target vs. routine care study in patients initiating adalimumab. As per the protocol, a maximum of 20% anti-TNF experienced patients were enrolled in the 300 patient trial. Twelve (4.0%) were excluded who previously used other biologics. Baseline characteristics including age, gender, tender and swollen joint counts, disease activity (DAS28), function (HAQ-DI), patient global assessment, patient satisfaction with current treatment, and inflammatory markers (CRP, ESR), were compared between previously anti-TNF experienced [etanercept or infliximab (EXP)], and anti-TNF naïve patients (NAÏVE). RESULTS: The mean (SD) age was 54.8 (13.3) years; 81.0% were female, and 237 (79.0%) were anti-TNF naïve while 51 (17.0%) patients were anti-TNF experienced (29 with etanercept, 16 with infliximab, and 6 for both). The mean (SD) baseline in EXP versus NAÏVE groups respectively was: CRP=21.7(32.9) vs. 17.5(20.7); ESR=28.7(22.5) vs. 29.8(20.4); SJC=10.5(6.0) vs. 10.7(5.6); TJC=12.8(7.1) vs. 12.3(7.3); and DAS28=6.0(1.2) vs. 5.8(1.1). None of the between-group differences were statistically significant, however, the HAQ-DI in EXP was 1.7(0.6) compared to 1.5(0.7) for the NAÏVE (P=0.021). Additionally, EXP patients had a higher patient global score [71.3(26.1) vs. 61.9(26.2), P=0.021]. CONCLUSIONS: Although anti-TNF naïve and experienced patients who initiated adalimumab were similar, with respect to several baseline characteristics, significant differences in subjective measures were observed, which may indicate more severe patient measures (function and global disease activity) in anti-TNF experienced patients.
23300855 Bone formation and resorption are both increased in experimental autoimmune arthritis. 2012 INTRODUCTION: Arthritic bone loss in the joints of patients with rheumatoid arthritis is the result of a combination of osteoclastic bone resorption and osteoblastic bone formation. This process is not completely understood, and especially the importance of local inflammation needs further investigation. We evaluated how bone formation and bone resorption are altered in experimental autoimmune arthritis. METHODS: Twenty-one female SKG mice were randomized to either an arthritis group or a control group. Tetracycline was used to identify mineralizing surfaces. After six weeks the right hind paws were embedded undecalcified in methylmethacrylate. The paws were cut exhaustively according to the principles of vertical sectioning and systematic sampling. 3D design-based methods were used to estimate the total number of osteoclasts, mineralizing surfaces, eroded surfaces, and osteoclast-covered bone surfaces. In addition the presence of adjacent inflammation was ascertained. RESULTS: The total number of osteoclasts, mineralizing surfaces, eroded surfaces, and osteoclast covered surfaces were elevated in arthritic paws compared to normal paws. Mineralizing surfaces were elevated adjacent to as well as not adjacent to inflammation in arthritic mice compared to normal mice. In arthritic mice, eroded surfaces and osteoclast covered surfaces were larger on bone surfaces adjacent to inflammation than on bone surfaces without adjacent inflammation. However, we found no difference between mineralizing surfaces at bone surfaces with or without inflammation in arthritic mice. CONCLUSIONS: Inflammation induced an increase in resorptive bone surfaces as well as formative bone surfaces. The bone formative response may be more general, since formative bone surfaces were also increased when not associated with inflammation. Thus, the bone loss may be the result of a substantial local bone resorption, which cannot be compensated by the increased local bone formation. These findings may be valuable for the development of new osteoblast targeting drugs in RA.
23204551 Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. 2013 Apr Biotherapies have revolutionized the treatment of RA. However, much work is needed to understand all the mechanisms of these biotherapies, and alternatives are needed to circumvent adverse effects and the high cost of these long-lasting treatments. In this article we outline some of the approaches we have used to target monocytes/macrophages as major components of inflammation and bone homeostasis. We also discuss how anti-TNF-α antibodies target monocytes/macrophages in the complex mechanisms contributing to inhibition of inflammation.
20921970 A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in e 2012 Apr Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.
21884601 Integrated safety in tocilizumab clinical trials. 2011 INTRODUCTION: The efficacy and safety of tocilizumab in patients with rheumatoid arthritis have been evaluated in a comprehensive phase 3 program. Patients from these randomized trials could receive tocilizumab treatment in open-label extension trials. Here, the long-term safety profile of tocilizumab, using pooled data from all of these trials, is reported. METHODS: Cumulative safety data (as of February 6, 2009) from five core phase 3 trials, two ongoing extension trials, and one clinical pharmacology study were analyzed. Two patient populations were evaluated: an all-control population (n = 4,199), which included all patients randomly assigned in the placebo-controlled portions of the five core studies, and an all-exposed population (n = 4,009), which included patients from any of the eight studies who received at least one dose of tocilizumab. RESULTS: Total exposure to tocilizumab was 8,580 patient years (PY), and total duration of observation was 9,414 PY. Overall adverse event (AE) and serious AE (SAE) rates were 278.2/100 PY and 14.4/100 PY, respectively. These events included serious infections (4.7/100 PY), opportunistic infections (0.23/100 PY), gastrointestinal perforations (0.28/100 PY), malignancy (1.1/100 PY), myocardial infarction (0.25/100 PY), and stroke (0.19/100 PY). The rates of SAEs and serious infections were stable over time; no increase with prolonged exposure was noted. CONCLUSIONS: The longer-term safety profile of tocilizumab (mean treatment duration, 2.4 years) is consistent with that observed in the phase 3 studies (duration up to 1 year).
21778898 The relationship between carotid intima-media thickness and the activity of rheumatoid art 2011 Aug BACKGROUND: Cardiovascular (CV) disease, the most common cause of mortality in patients with rheumatoid arthritis (RA), is largely attributable to accelerated atherosclerosis. Carotid intima-media thickness (cIMT) has been approved as a surrogate marker of early atherosclerosis. OBJECTIVES: The aim of the study was to assess cIMT in RA patients lacking concomitant comorbidities potentially influencing cIMT value. METHODS: The study group consisted of 74 RA patients, without diagnosed heart or kidney disease, hypertension, diabetes, obesity, or current smoking (mean age, 46.4 [SD, 10.6] years; range, 19-70 years). Assessment of cIMT was determined by high-resolution B-mode ultrasonography in RA patients and 31 control subjects (mean age, 42.6 [SD, 8.0] years; range, 27-59 years). RESULTS: The mean maximum cIMT value was significantly greater in RA patients than in control subjects (0.73 [SD, 0.14] vs 0.59 [SD, 0.12] mm; P < 0.0001). In RA patients, cIMT correlated positively with a number of immunological and inflammatory parameters and also with amino-terminal pro-brain natriuretic peptide (NT-proBNP), age, metabolic variables (serum cholesterol, creatinine, cystatin C). In multiple linear regression analysis, significant association was found between cIMT and NT-proBNP and age. Patients without atherosclerosis (cIMT <0.6 mm) were younger and had significantly lower concentrations of NT-proBNP and total cholesterol, as well as higher estimated glomerular filtration rate. The course of RA in patients without atherosclerosis was characterized by shorter disease duration, lower tender joint count, and C-reactive protein. CONCLUSIONS: Values of cIMT were significantly greater in RA compared with control subjects. Features of RA, such as extra-articular manifestations, erosions, high inflammatory parameters, and long disease duration, even in the absence of traditional clinical CV risk factors, were associated with greater cIMT, suggesting an unfavorable CV risk profile.
22859946 Biomarkers of good EULAR response to the B cell depletion therapy in all seropositive rheu 2012 OBJECTIVE: To find out whether a high number of auto-antibodies can increase the probability of a "good-EULAR response" and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT). PATIENTS AND METHODS: One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT. The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy. The IL6 and BAFF levels were also determined. RESULTS: At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response. Having up to 5-AABs positivity increased the chances for treatment response. After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count <1875/uL (OR = 10.74), a RF-IgG level >52.1 IU/ml (OR = 8.37) and BAFF levels <1011 pg/ml (OR = 7.38). When all the AABs, except for RF-IgM and ACPA-IgG, were left in the analysis, the two final predictors were no-steroid therapy and low lymphocyte count. DISCUSSION: The number of AABs increased the chances of being a "good-EULAR" responder. The only predictors, however, at the baseline of a good response in this seropositive cohort of RA patients were 2 simple variables--no steroids and lymphocyte count--and two laboratory assays--IgG-RF and BAFF.
22885420 Lack of association between the CC genotype of the rs7903146 polymorphism in the TCF7L2 ge 2012 Aug INTRODUCTION: TCF7L2 is a transcription factor involved in Wnt/beta-catenin signaling and which has a variant known to be consistently associated with type 2 diabetes risk and some studies have also indicated its association with risk of certain types of cancer. OBJECTIVE: Since this pathway may be involved in the pathophysiology of other chronic inflammatory diseases such as rheumatoid arthritis, we aimed to investigate the effect of TCF7L2 polymorphism rs7903146 on rheumatoid arthritis severity in a Brazilian population. PATIENTS AND METHODS: This polymorphism was genotyped in 208 patients with rheumatoid arthritis and in 104 healthy controls. We also analyzed the association of this polymorphism to smoking history, functional status classification and radiological indicators of disease severity. RESULTS: The distribution of CC, CT and TT genotypes of SNP rs7903146 of the TCF7L2 gene was not different between patients and controls, and no association between the genotype and indicators of disease severity or smoking history was found. When data were evaluated using the dominant model, in which carriers of the CT and TT genotypes were grouped, an increase in the T allele was observed in patients positive for rheumatoid factor and erosions, although this was not significant. The frequency of T allele was also increased in patients with functional class II compared to class I (P = 0.032). CONCLUSION: It is possible that the small number of patients included in this study may have restrained additional findings. Further studies are therefore needed to investigate the role of TCF7L2 gene variants in the risk of rheumatoid arthritis and its severity.
21328055 Receptor activator of nuclear factor kappa B ligand serum and synovial fluid level. A comp 2012 Jun To assess the levels of receptor activator of NF-κB ligand (RANKL) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to correlate its levels with disease activity and severity. Serum and SF levels of RANKL were measured in 24 patients with RA (Group I) and 20 patients with OA (Group II); patients were selected according to the ACR criteria, and serum RANKL was measured in 13 healthy controls. All patients were subjected to full rheumatological assessment. In RA group, serum level of RANKL was significantly higher than control group (P = 0.01), but not correlated with disease activity and severity parameters apart from number of tender joints (P = 0.03). SF level of RANKL was significantly correlated with disease duration (P = 0.02), number of tender (P = 0.002) and swollen joints (P = 003), ESR (P = 0.01), CRP (P = 0.000), DAS-28 (P = 0.004), and SENS (P = 0.03). In patients with OA, serum level of RANKL was significantly higher than the control group (P < 0.001), and it was statistically insignificant with clinical, laboratory, or radiological data, while SF level of RANKL was statistically significantly higher in patients with Heberden and Bouchard nodes (P = 0.007), Kellgren-Lawrence score (P = 0.002), and with the erosive changes of hands (P = 0.006). The mean serum RANKL in RA group was insignificant with that of total OA group. SF level of RANKL was significantly higher in RA than erosive OA patients and in erosive than non-erosive OA with (P = 0.001, in each one). The SF level of RANKL is an important marker of both disease activity and severity in RA patients; while in OA patients, it is an important marker of disease severity especially in erosive than non-erosive types. Serum level of RANKL may be of low benefit in disease activity and severity of both rheumatoid arthritis and osteoarthritis.