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ID PMID Title PublicationDate abstract
22226771 Drug targeting systems for inflammatory disease: one for all, all for one. 2012 Jul 20 In various systemic disorders, structural changes in the microenvironment of diseased tissues enable both passive and active targeting of therapeutic agents to these tissues. This has led to a number of targeting approaches that enhance the accumulation of drugs in the target tissues, making drug targeting an attractive strategy for the treatment of various diseases. Remarkably, the strategic principles that form the basis of drug targeting are often employed for tumor targeting, while chronic inflammatory diseases appear to draw much less attention. To provide the reader with a general overview of the current status of drug targeting to inflammatory diseases, the passive and active targeting strategies that have been used for the treatment of rheumatoid arthritis (RA) and multiple sclerosis (MS) are discussed. The last part of this review addresses the dualism of platform technology-oriented ("one for all") and disease-oriented drug targeting research ("all for one"), both of which are key elements of effective drug targeting research.
21427755 Modeling of environmental and genetic interactions with AMBROSIA, an information-theoretic 2011 Oct To develop a model synthesis method for parsimoniously modeling gene-environmental interactions (GEI) associated with clinical outcomes and phenotypes. The AMBROSIA model synthesis approach utilizes the k-way interaction information (KWII), an information-theoretic metric capable of identifying variable combinations associated with GEI. For model synthesis, AMBROSIA considers relevance of combinations to the phenotype, it precludes entry of combinations with redundant information, and penalizes for unjustifiable complexity; each step is KWII based. The performance and power of AMBROSIA were evaluated with simulations and Genetic Association Workshop 15 (GAW15) data sets of rheumatoid arthritis (RA). AMBROSIA identified parsimonious models in data sets containing multiple interactions with linkage disequilibrium present. For the GAW15 data set containing 9187 single-nucleotide polymorphisms, the parsimonious AMBROSIA model identified nine RA-associated combinations with power >90%. AMBROSIA was compared with multifactor dimensionality reduction across several diverse models and had satisfactory power. Software source code is available from http://www.cse.buffalo.edu/DBGROUP/bioinformatics/resources.html. AMBROSIA is a promising method for GEI model synthesis.
21404581 [Measurement of NK cell and macrophage activation]. 2011 Jan FcgammaRIII(CD16), one of the low-affinity IgG Fc receptors exists in two forms. FcgammaRIIIa is expressed on NK cells, a subset of T lymphocytes, a subpopulation of monocytes and macrophages, and shows a cell type specific glycosylation pattern. FcgammaRIIIb is expressed exclusively on neutrophils in two allotypes, NA1/2, and it can be induced on eosinophils. Both FcyRIIIs are released from the cell surface. FcgammaRIIIa is released by the action of a metalloprotease upon the in vitro activation of NK cells and macrophages. FcgammaRIIIb is released upon activation and during the apoptosis of neutrophils by proteolytic activity. So, the amount of each type of soluble FcgammaRIII means the activation of each type of cell. We measured three types of soluble FcgammaRIII in plasma and also urine with newly developed anti-FcgammaRIIIa and anti-FcgammaRIIIa(Mphi) monoclonal antibodies. We found that sFcgammaRIIIa may be a novel marker of inflammatory activity in rheumatoid arthritis. sFcgammaRIIIa(M phi) may serve as predictive marker for atherosclerosis. Further, urinary sFcgammaRIIIa and sFcgammaRIIIa(Mphi) may be novel markers for the assessment of disease activity in nephritis.
22703848 Sensitivity and specificity of ultrasonography and low-field magnetic resonance imaging fo 2012 Jul OBJECTIVES: To evaluate the value of grey-scale ultrasonography (US) including power Doppler ultrasonography (PDUS) and low-field magnetic resonance imaging (MRI) for the diagnosis of arthritis in a diagnostic phase III study. METHODS: Fifty consecutive patients with suspected arthritis were included in the study. Following a standardised protocol, US of the carpus and the metacarpophalangeal (MCP) joints of the dominant hand was performed. Subsequently, low-field MRI was done using standard sequences, with contrast agent (Gadolinium DTPA) administered to 29 patients. RESULTS: In 32 out of 50 patients a clinical diagnosis of arthritis was established. In grey-scale ultrasonography including PDUS, sensitivity and specificity were determined as 0.94 and 0.5, respectively, for synovitis (effusion and hypertrophy), 0.72 and 0.94, respectively, for Doppler signals, and 0.38 and 1.0, respectively, for bone erosions. In low-field MRI, sensitivity and specificity values were 0.77 and 0.75, respectively, for synovitis (when using contrast agent), 0.48 and 0.78, respectively, for bone marrow oedema, and 0.58 and 0.83, respectively, for bone erosion. CONCLUSIONS: Both grey-scale ultrasonography including PDUS and low-field MRI are suitable imaging methods for diagnosing arthritis at an early stage. However, PDUS displays a higher specificity and almost the same sensitivity as compared to contrast-enhanced MRI, while being a much simpler and less costly procedure.
23190940 The APOM polymorphism as a novel risk factor for dyslipidaemia in rheumatoid arthritis: a 2013 Mar OBJECTIVES: A decrease in high-density lipoprotein (HDL) cholesterol during inflammation is common in many rheumatologic diseases, including rheumatoid arthritis (RA). Apolipoprotein M (apoM) is an apolipoprotein predominantly associated with HDL cholesterol. Recently, apoM polymorphisms have been related with RA susceptibility. We investigated the possible association between an APOM polymorphism and dyslipidaemia in Korean RA patients. METHODS: Two hundred and fifteen RA patients and 215 controls that provided complete genotyping were included. Genetic distribution, RA-associated phenotype, lipid profiles, and lipoproteins were evaluated. RESULTS: RA patients had increased frequencies of the APOM C-1065A A allele compared to the controls. RA patients with A/A genotypes had lower levels of HDL cholesterol than those with C/C genotypes. After adjustment for confounding factors, the A/A genotype was a risk factor for low HDL cholesterolaemia (OR=1.070, p=0.001). Subgroup analyses according to disease activity showed that the association between APOM genotype and HDL cholesterol levels was still significant in all subgroups, indicating that this APOM polymorphism may increase the dyslipidaemia risk, independently of RA disease activity. CONCLUSIONS: These data support that the APOM C-1065A polymorphism is associated with increased risk for developing RA and dyslipidaemia in RA patients. Reduced HDL cholesterol levels are independent of disease activity but are significantly influenced by APOM genotype. These findings suggest that a specific genetic factor for RA could be linked to dyslipidaemia and this could increase the risk of atherosclerosis in RA patients.
22342143 Discovery of a series of imidazopyrazine small molecule inhibitors of the kinase MAPKAPK5, 2012 Mar 15 MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
22138674 Genetic polymorphisms of the DNA repair gene UNG are associated with the susceptibility of 2012 Dec The involvement of uracil-DNA glycosylase (UNG) in the pathogenesis of cancer is well documented. In contrast, the role of this protein in rheumatoid arthritis (RA) development is not well defined, although previous studies suggest a possible link between autoimmune diseases and malignancy. Therefore, we aimed to examine whether there is a link between UNG genetic polymorphisms and RA. Our present study investigated the effects of UNG (rs3219218 and rs246079) single nucleotide polymorphisms (SNPs) on RA among Taiwan's Han Chinese population. Polymorphism of the UNG gene was analyzed in 192 controls and 183 RA patients. Genotyping for UNG SNPs was performed by restriction fragment length polymorphism assay. Our data confirmed statistically significant variations in genotype frequency distributions at rs246079 SNP between RA patients and controls (P = 3.05 × 10(-4)). The G allele at rs246079 SNP is a high-risk factor in developing RA (odds ratio [OR] = 1.77; 95% confidence interval [CI] = 1.290-2.42). A comparison of haplotype frequencies between the case and the control revealed that RA patients with the Ht2 haplotype are at additional risk for RA development (P = 0.042). Our data yielded new information on UNG polymorphisms associated with RA development and as RA molecular markers. The polymorphisms revealed by the present study merit further investigation.
21474486 Longitudinal association between coping and psychological distress in rheumatoid arthritis 2011 Jul OBJECTIVE: To examine the longitudinal association between coping and psychological distress in rheumatoid arthritis (RA). METHODS: Bibliographic databases up to July 2010 were searched for longitudinal studies with a follow-up of ≥6 months. Two reviewers assessed the methodological quality of the included studies. Study characteristics, coping strategies and coping-psychological distress associations were extracted. Coping strategies were categorised using a hierarchical taxonomy. A best-evidence synthesis determined the level of evidence for a prognostic association of coping with depression, anxiety and general distress. RESULTS: From an initial set of 2605 potentially relevant studies, 19 studies (14 cohorts) met the predefined selection criteria. In all, 10 studies were of 'high quality' (≥12 of 18 quality criteria). Unadjusted bivariate correlations showed that baseline approach-oriented coping correlated with lower psychological distress (r between 0.007-0.46, p values <0.05) and baseline avoidant-oriented coping correlated with higher psychological distress (r between 0.29-0.64, p values <0.05) at follow-up. Adjusted for baseline psychological distress, limited evidence was found that avoidant-oriented coping was longitudinally associated with an increase in psychological distress. Specifically, the categories helplessness, avoidance and wishful thinking were prognostically associated with increased general psychological distress. Approach-oriented coping was not associated with subsequent psychological distress. CONCLUSIONS: The prognostic value of coping strategies for later psychological distress in RA is weak. Limited evidence suggests that avoidant-oriented coping is associated with increased subsequent psychological distress. No evidence was found that approach-oriented coping protects against an increase of psychological distress.
21864284 Selenium and clinical trials: new therapeutic evidence for multiple diseases. 2011 The understanding of the essential role of selenium (Se) in human health has increased substantially in recent decades. Micronutrient deficiencies are very common in the general population and may be even more common in patients with different pathologies due to genetic or environmental causes and prescription drug use. Selenium is used by people in the prevention and/or treatment of different disorders including cardiovascular disease, osteoarthritis, rheumatoid arthritis, hypothyroidism, stroke, atherosclerosis, cancer susceptibility and treatment, HIV, AIDS, neuronal diseases such as Alzheimer or amyotrophic lateral sclerosis, pancreatitis, depression, and diabetes amongst others. Several mechanisms have been suggested to mediate the biological effects of Se and these include antioxidant defence systems, synthesis and stability of metabolites that act as intermediates implicated in diverse selenoproteins expression pathways oxidative metabolism, immune system modulation, DNA intercalators, kinase regulation, enzymatic cofactor, and gene expression. A number of clinical trials in recent years have provided convincing evidence of the central role of this element, either alone or in combination with other micronutrients or antioxidants, in the prevention and treatment of multiple diseases. Based on these studies this review focuses on the advances made so far in the study of mechanisms and applications of selenium compounds that could be suitable for chronic diseases.
22824238 The effect of smoking and alcohol consumption on markers of systemic inflammation, immunog 2012 Jul 23 INTRODUCTION: The purpose of this research was to study the influence of cigarette smoking and alcohol consumption on immune response to heptavalent pneumococcal conjugate vaccine, immunoglobulin levels (Ig) and markers of systemic inflammation in patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA). METHODS: In total, 505 patients were vaccinated. Six pre-specified groups were enrolled: RA on methotrexate (MTX) treatment in some cases other disease-modifying antirheumatic drugs (DMARDs) (I); RA on anti-tumour necrosis factor (TNF) as monotherapy (II); RA on anti-TNF+MTX+ possibly other DMARDs (III); SpA on anti-TNF as monotherapy (IV); SpA on anti-TNF+MTX+ possibly other DMARDs (V); and SpA on nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesics (VI). Smoking (pack-years) and alcohol consumption (g/week) were calculated from patient questionnaires. Ig, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at vaccination. IgG antibodies against serotypes 23F and 6B were measured at vaccination and after four to six weeks using standard ELISA. Immune response (ratio between post- and pre-vaccination antibodies; immune response (IR)) and positive immune response (≥2-fold increase in pre-vaccination antibodies; posIR) were calculated. RESULTS: Eighty-eight patients (17.4%) were current smokers. Smokers had higher CRP and ESR, lower IgG and lower IR for both serotypes (P between 0.012 and 0.045). RA patients on MTX who smoked ≥1pack-year had lower posIR for both serotypes (P = 0.021; OR 0.29; CI 0.1 to 0.7) compared to never-smokers. Alcohol consumption was associated with lower CRP (P = 0.05) and ESR (P = 0.003) but did not influence IR or Ig levels. CONCLUSION: Smoking predicted impaired immune response to pneumococcal conjugate vaccine in RA patients on MTX. Smokers with arthritis had higher inflammatory markers and lower IgG regardless of diagnosis and treatment. Low to moderate alcohol consumption was related to lower levels of inflammation markers but had no impact on immune response. TRIAL REGISTRATION: EudraCT EU 2007-006539-29 and NCT00828997.
23090510 Possible roles of IL-12-family cytokines in rheumatoid arthritis. 2013 Apr The IL-12 family members, IL-12, IL-23, IL-27 and IL-35, are heterodimeric cytokines that share subunits and have important roles in autoimmunity. As well as their structural relationship the IL-12 family cytokines share some biological characteristics but have functional differences. These cytokines contribute to immune-mediated inflammation and our improved knowledge of their actions has led to alteration of the T(H)1-T(H)2 paradigm. In rheumatoid arthritis (RA), leukocyte migration, bone erosions and angiogenesis are modulated by an IL-23-IL-17 cascade, which can be negated in part by IL-12, IL-27 and IL-35 function. However, the IL-12 family members are a relatively new area of research and data have been generated mostly at the preclinical stage. Further studies in patients with RA are, therefore, required to determine whether these cytokines are valid targets for RA therapy.
22939106 Surgical treatment of hindfoot inflammatory diseases: 107 arthrodesis. 2012 Oct INTRODUCTION: In rheumatoid diseases, hindfoot arthrodesis abolishes pain and corrects deformity. The choice between selective and double arthrodesis depends on whether the hindfoot malalignment is fixed or not. Indications for surgery are well codified. The various types of arthrodesis have never been assessed together on a large series. We here report a series that is substantial in numbers and in follow-up. MATERIALS AND METHODS: A continuous single-center retrospective study included patients with native hindfoot inflammatory disease treated by arthrodesis between 1996 and 2009. RESULTS: Around 80% of patients were followed up, for a mean 7 years. Fifty-four isolated talonavicular arthrodeses, 14 talocalcaneal arthrodeses and 39 double arthrodeses were performed. 96% of patients had rheumatoid arthritis and 4% spondylarthritis. 62% were completely pain-free at follow-up. The satisfaction rate was 91% and mean AOFAS score 70%. 6% of patients showed symptomatic non-union, mainly associated with talonavicular arthrodesis. In 22% of double arthrodeses and 11% of talonavicular arthrodeses, ankle status required surgical revision. In double arthrodesis, there was no correlation between hindfoot deviation and secondary deterioration in ankle status. Talocalcaneal arthrodesis was associated with radiologic hindfoot varus, both preoperatively and at follow-up. DISCUSSION: Non-union was the main complication in talonavicular arthrodesis. The rate of secondary ankle surgery was significantly elevated in double arthrodesis. These findings support Suckel's cadaver studies, which, in 2007, reported early deterioration in ankle status in double arthrodesis, due to mechanical overloading. Talocalcaneal arthrodesis proved reliable and simple, free of major complications and with a 100% satisfaction rate. CONCLUSION: Double arthrodesis showed the greatest benefit in terms of restoring foot architecture, but was associated with a higher rate of deterioration in ankle status. Preventive double arthrodesis is not recommended in case of isolated arthritis with reducible hindfoot malalignment.
21422077 Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus ery 2011 May The underlying mechanisms for the subsets of self-limiting, intermittent or chronic and deforming arthritis in systemic lupus erythematosus (SLE) are not well understood. We performed a cross-sectional analysis of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8 and TNF-α) and joint status in 47 SLE patients (79% females, age 42 years, disease duration 8.6 years). All cytokines levels were significantly elevated in SLE patients compared with controls, but only IL-2 and IL-8 levels were higher than in patients with rheumatoid arthritis. SLE patients with ongoing synovitis (19%) and joint deformities (11%) had increased erythrocyte sedimentation rate (ESR), IL-6 and anti-dsDNA Ab levels. IL-6 levels correlated with ESR, anti-dsDNA Ab and haemoglobin, but not with C-reactive protein levels. Arthritis constitutes a considerable burden of disease in SLE over time, and joint deformations are associated with longstanding disease and arthritis flare rates. IL-6 is a potential biomarker and therapeutic target in the prevention of joint damage in SLE arthritis.
21404654 [The clinical application of quantiferon TB-2G: its usefulness and limitations]. 2011 Feb QuantiFERON TB-2G (QFT) is widely used in clinical settings for the identification of tuberculosis infection because of its high level of utility. It is well known that QFT stimulates peripheral blood lymphocytes in vitro by means of M. tuberculosis-specific protein, and that infection is identified by measuring the interferon-gamma released. Interpretation of QFT results is therefore difficult in immunosuppressed subjects in whom the function of immunocompetent cells, including lymphocytes, is suppressed, making it difficult for them to produce interferon-gamma. There is a high incidence of tuberculosis among hemodialysis patients. It has been conjectured that the use of powerful immunosuppressive agents following kidney transplantation results in a high risk of tuberculosis. How QFT results change immediately following kidney transplantation is an extremely interesting question. In recent years, an increasing number of institutions have been using TNF-alpha inhibitors to treat rheumatoid arthritis patients. Is QTF useful for identifying whether patients have latent tuberculosis infection before the administration of anti-TNF antibodies? In particular, many rheumatoid arthritis patients may have been given methotrexate or glucocorticoids, which suppress the immune system, prior to the administration of TNF-alpha inhibitors, possibly making it difficult to interpret the QFT results. We must be aware of this limitation when performing QFT on immunosuppressed patients. It is also important that we understand the clinical parameters influencing QFT results (such as lymphocyte counts). The morbidity rate of tuberculosis is high among healthcare workers, particularly nurses. A number of studies have reported that QFT is useful in hospital infection control for tuberculosis, but the effectiveness of QFT for monitoring the health of healthcare workers is still not fully understood. In this symposium, we will debate how far QFT can be used and the extent of its usefulness under exceptional circumstances. (1) How do we manage kidney transplant recipients with latent tuberculosis infection?: Norihiko GOTO (Transplant Surgery, Nagoya Daini Red Cross Hospital) It is unclear whether QuantiFERON-second generation (QFT-2G) is useful for diagnostic screening and follow up of latent tuberculosis infection (LTBI) in immunosuppressed kidney transplant (KTx) recipients. The QFT-2G assay that included response to mitogen stimulation was performed before and 6 months after KTx. Non responder was 0 (0%) at baseline, 3 (3%) at 6 months. Response to mitogen stimulation was 9.7 +/- 5.3 IU/mL at baseline vs. 10.4 +/- 5.0 IU/mL at 6 months after KTx (p = 0.29). QFT-2G is a useful screening test for LTBI and active tuberculosis (TB) even during maintenance of immunosuppression of KTx. (2) QuantiFERON-TB Gold in Japanese rheumatoid arthritis patients for assessing latent tuberculosis infection prior treatment of anti-tumor necrosis factor antibody: Shogo BANNO (Division of Rheumatology and Nephrology, Department of Internal Medicine, Aichi Medical School of Medicine) To determine the positive rate of LTBI in RA patients using the QFT-2G test, we divided RA patients into two groups: with or without old TB findings by chest CT. With a cutoff level set at 0.35 IU/ml, the positive rate of QFT-2G in LTBI was detected only 5.8%, when setting cutoff at 0.1 IU/ml (lower cutoff level), 23.1% was detected in LTBI patients. The positive TST results were significantly increased in non-LTBI patients compared than in LTBI patients. The QFT-2G test was not affected by the treatment of MTX, and the incidence of indeterminate result was low. The QFT-2G was useful compared to TST before administration of TNF inhibitors in RA patients, because of superior specificity of QFT-2G. (3) Clinical parameters that influence the sensitivity of T-cell assays: Haruyuki ARIGA (National Hospital Organization Tokyo National Hospital) The detection of tuberculosis (TB) infection in compromised hosts is essential for TB control, but T cell assay might be influenced by the degree of cell-mediated immunosuppression. The relationship between immunocompetence and specific interferon (IFN)-gamma response in whole blood QuantiFERON-TB Gold (QFT) is uncertain. Immune-related clinical indicators associated with the degree of antigen-specific IFN-gamma production were analysed using a large immunologically-unselected population with obvious TB infection. The absolute number of blood lymphocyte in TB patients was significantly associated with specific IFN-gamma production in a linear regression model. Sensitivity of 2 IFN-gamma Release Assays, QFT and ELISPOT, partly depends on peripheral lymphocyte counts. At low lymphocyte count conditions, ELISPOT assay is superior to whole blood QFT for detecting tuberculosis infection. (4) QuantiFERON TB-2G among staffs in the hospitals of Nationao Hospital Organization: Susumu OGURI, Chihiro NISHIO, Kensuke SUMI, Masayoshi MINAGUCHI, Tomomasa TSUBOI, Atuo SATOU, Osamu TOKUNAGA, Takeshi MIYAMOMAE, Takuya KURASAWA (National Hospital Organization Minami-Kyoto National Hospital) PURPOSE: To investigate the infection rate of tuberculosis among staffs working in the hospitals of NHO. METHOD: Questionnaires were sent to the hospitals and the responses were analyzed. RESULT: Among the staffs working in the hospitals with tuberculosis wards, positive rate of QuantiFERON TB-2G was 6.9%, probable positive rate was 5.6%. On the other hand, among the staffs working in the hospitals without tuberculosis wards, positive rate was 4.4%, probable positive rate was 3.9%. CONCLUSION: It is necessary to monitor the infection rate among hospital staffs.
21614018 Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susc 2011 Oct Most of the genetic risk for rheumatoid arthritis (RA) is conferred by 'shared epitope' (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2-5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6-3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.
22847245 Discontinuation of anti-TNF-α therapy in a Chinese cohort of patients with rheumatoid art 2012 Nov The aim of this retrospective study was to examine the predictors of discontinuation of anti-tumor necrosis factor (TNF) therapy due to adverse events in Chinese patients with rheumatoid arthritis (RA). Anti-TNF-related adverse events were recorded and analyzed in 217 consecutive patients with RA followed in our institution from 2003 to 2010. Time to discontinuation of anti-TNF-α therapy was estimated using survival analysis techniques. The anti-TNF agents administered were etanercept in 181 patients and adalimumab in 36 patients. The mean age at diagnosis was 45.2 ± 13.5 years, and mean age at initiation of anti-TNF therapy was 51.8 ± 13.0 years. The mean duration of anti-TNF agent use was 36.0 ± 26.5 months (range, 1.4-87.0; median, 26.4 months). Of the 217 patients, 39 (18.0 %) developed adverse events [etanercept in 34 (18.8 %] and adalimumab in 5 (13.9 %)] during the treatment period (tuberculosis in 5, bacterial infections in 19, virus infection in 7, neuropathy in 3, malignancy in 3, other drug-related events in 1, and appendicitis in 1). In patients with RA, older age (≥55 years) at initiation of anti-TNF therapy [odds ratio (OR), 3.20; 95 % confidence interval (CI), 1.67-6.20; p < 0.001], Cr ≥1.5 mg/dL (OR, 5.72; 95 % CI, 1.17-27.90; p = 0.031), and occurrence of adverse events (OR, 3.82; 95 % CI, 1.75-8.35; p = 0.001) were associated with increased likelihood of discontinuation of anti-TNF treatment. In the present study, a significant proportion (7.8 %, 17/217) of patients with RA discontinued anti-TNF treatment because of adverse events. In the elderly and in patients with renal insufficiency, caution is needed when starting anti-TNF treatment.
21937456 IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytoki 2011 Nov Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.
21979320 [Treat-to-target from the patient perspective]. 2011 Oct The international treat-to-target initiative including rheumatoid arthritis (RA) patients has defined remission or alternatively low disease activity as treatment goals. In Germany representatives of the medical profession, such as doctors, nurses and including the Deutsche Rheuma-Liga, are deliberating how to adapt and realize these goals in practice. The patient's perspective has to be taken into consideration as an outcome variable. Until now no combined patient reported outcome (PRO) score exists which is generally accepted by the scientific community and which puts the patient's perspective as the main primary outcome.Patients and doctors ought to decide jointly about the therapy goal remission/low disease activity and about other PROs and the planned strategy to achieve these goals. A precondition is that a sufficient timeframe is still available for this. The joint target of the medical profession and the Deutsche Rheuma-Liga is 1 rheumatologist per 50,000 adult inhabitants. An interdisciplinary and multidisciplinary treatment of RA patients is just as imperative as the expansion of patient training, information and self-management programs.
22569225 Investigation of single nucleotide polymorphisms and biological pathways associated with r 2012 Aug OBJECTIVE: Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs and the possible biological pathways associated with the treatment response to TNFα inhibitors. METHODS: TNFα-naive patients with RA, who had available DNA and initiated TNFα inhibitor therapy between 1999 and 2008, were identified in the DANBIO registry and genotyped using the Illumina HumanHap550K Duo array. The associations between SNPs and changes in the absolute and the relative Disease Activity Score, and European League Against Rheumatism good versus no response after 14 weeks of treatment were tested. SNP data were combined with two independent cohorts in a meta-analysis. A gene-set enrichment analysis (GSEA) was carried out to identify the biological pathways associated with the treatment response. RESULTS: After genotyping and quality control, 486 450 SNPs were analyzed in 196 Danish patients with moderate to severe RA treated with infliximab (n=142), etanercept (n=12), and adalimumab (n=42). None of the previously identified SNPs were confirmed in our dataset or in meta-analyses of available studies. Other potential SNPs were identified, but none achieved genome-wide significance. A GSEA identified the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways to have a potential influence on the treatment response. CONCLUSION: In a genome-wide association study of 196 genetically homogenous Danish patients with RA and in a meta-analysis, we found no SNPs associated with treatment response to TNFα inhibitors. A GSEA suggested that the transforming growth factor β, TNF, mitogen-activated protein kinase, and mammalian target of rapamycin pathways may be associated with treatment response.
21708868 Utilizing qualitative data from nominal groups: exploring the influences on treatment outc 2012 Jan The nominal group technique generates quantitative data through a process of experts ranking items of interest. This article focuses on the additional collection of qualitative data from nominal groups with rheumatoid arthritis (RA) patients, used to explore the influences on prioritizing treatment outcomes. Across all groups, the top five outcomes with the highest importance scores were identified as: pain; joint damage; fatigue; activities of daily living; and mobility. Qualitative findings showed that the personal impact of RA influenced decisions on how to rank specific outcomes through four domains: disease impact; adaptation to illness; external resources and stressors; and social expectations.