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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
17967722 Lymphoid tissue reactions in rheumatoid arthritis. 2007 Nov Frequently, the immune cell infiltrate of chronically inflamed tissues develops functional germinal centres and acquires structural features of secondary lymphoid organs. Ectopic lymphoid structures occur in peripheral tissues not only during autoimmune diseases but also in tumors (reactive infiltrate), chronic infections and graft rejection, indicating a strong link between lymphoid neogenesis and persistent antigen driven immune/inflammatory responses. There has been a renewed interest in ectopic lymphoid neogenesis, as better understanding of the mechanisms underpinning this process could contribute to elucidate the bio-pathological mechanisms involved in transition from acute-self resolving to chronic immunological aggression as well as identify novel therapeutic targets. Here we critically review recent clinical and biological studies addressing the role of ectopic lymphoid neogenesis specifically in rheumatoid arthritis.
16652439 Crossroads of B cell activation in autoimmunity: rationale of targeting B cells. 2006 May B cells have historically been considered as not preferentially involved in the immunopathogenesis of inflammatory joint diseases, in particular rheumatoid arthritis (RA), despite the notion that autoantibodies and immune complexes were involved in pathogenesis and served as diagnostic and classification markers. Following initial reports that patients with non-Hodgkin's lymphoma (NHL) and coexisting RA showed improvement in signs and symptoms of RA after anti-CD20 therapy, the role of B cells in autoimmune diseases was reexamined. Potential mechanisms can be inferred from what is known about the role of B cell functions, in particular antigen-experienced memory B cells. Activation of these cells can be dependent on T lymphocytes or independent of them. Once activated, the cells can efficiently act as antigen-presenting cells, can produce inflammatory cytokines, and may alternatively differentiate into antibody-producing plasma cells. These processes contribute to the activation of other immune cells and ultimately to joint destruction in RA. The development and maintenance of RA may be related to both direct and indirect involvement of these B cell-dependent processes. In systemic lupus erythematosus (SLE), the central pathogenic importance of autoimmune B cells is well recognized, based on early recognition of numerous autoantibodies and clinically important immune complexes. Based on the evidence supporting B cell involvement in the pathophysiology of autoimmune diseases, investigations are evaluating the clinical impact of B cell targeted therapies. B cell targeted therapies in human trials include an anti-B lymphocyte stimulator protein agent, belimumab; an anti-CD20 agent, rituximab; and an anti-CD22 antibody, epratuzumab.
18713230 Cutaneous events during treatment of chronic inflammatory joint disorders with anti-tumour 2008 Dec BACKGROUND: Anti-tumour necrosis factors (anti-TNF) are more and more used, but the rate of skin adverse events is not known. OBJECTIVE: The aim was to assess the number of skin infections and other dermatoses in patients treated with anti-TNFalpha. PATIENTS AND METHODS: One hundred eighty-seven patients suffering from rheumatoid arthritis or ankylosing spondylitis underwent a dermatological exam. Patients with anti-TNF were compared with those without this treatment in a prospective transversal study. RESULTS: Among them, 59 patients were treated with anti-TNFalpha and steroids were prescribed in 100 cases. There was no difference in the prevalence of skin infections or eczema or tumours. Skin drug reactions were observed in six patients. Infections by dermatophytes appear very frequent, approaching 70% in both groups. CONCLUSIONS: This study shows that skin infections (or other skin diseases) are not more frequent in these patients. No differences were observed in infections (bacterial fungal, parasital or viral), tumours, psoriasis or the manifestations of atopic dermatitis. Nonetheless, a long-term survey might be interesting, especially about skin tumours.
16947783 Relationship between genetic variants in the adenosine pathway and outcome of methotrexate 2006 Sep OBJECTIVE: Among patients with rheumatoid arthritis (RA), there is a high degree of interindividual variability in the degree of response to methotrexate (MTX) treatment. This study was undertaken to explore polymorphisms in genes contributing to antiinflammatory adenosine release as novel predictors of MTX treatment outcome. METHODS: In 205 patients with newly diagnosed RA, 5 polymorphisms in 5 genes coding for enzymes related to the release of adenosine were analyzed. All patients received standardized MTX treatment (up to 25 mg per week orally), combined with folic acid. MTX efficacy was evaluated by the Disease Activity Score (DAS) and compared among genotypes. The association between MTX-related adverse events and genotype was also assessed. The following polymorphisms were determined: AMPD1 34C>T, ATIC 347C>G, ITPA 94C>A, MTR 2756A>G, and MTRR 66A>G. When significant differences were found by chi-square analysis, odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS: Patients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of < or =2.4 (OR [95% confidence interval] 2.1 [1.0-4.5], 2.5 [1.3-4.7], and 2.7 [1.1-8.1], respectively). The likelihood of a good clinical response was increased if patients possessed all 3 favorable genotypes (OR 27.8 [95% confidence interval 3.2-250]). Regarding toxicity, only ATIC G allele carriers experienced a greater frequency of adverse events (OR 2.0 [95% confidence interval 1.1-3.7]). CONCLUSION: Polymorphisms in the AMPD1, ATIC, and ITPA genes are associated with good clinical response to MTX treatment. These findings indicate that genotyping may help in the identification of patients who will benefit most from MTX treatment and may assist clinicians in making treatment decisions regarding patients with recent-onset RA.
18350722 [Amyloidosis--life threatening complication in rheumatoid arthritis patients]. 2007 Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease leading to severe disability. A secondary amyloidosis (AA amyloidosis) affecting RA patient is a life threatening clinical complication of the illness. The most common symptoms of secondary amyloidosis include: proteinuria, erythrocyturia, abdominal pain and chronic diarrhoea. It is essential to carry out regular screening tests, especially abdominal fat tissue biopsy, to early diagnose and properly manage patients with the condition. Effective anti-inflammatory therapy of RA and eradication of coexisting infections seem to be the best way to decrease the risk of development and prevent progression of the secondary amyloidosis.
16956432 Recommendations for the use of biologic (TNF-alpha blocking) agents in the treatment of rh 2006 Jul The present report is devoted to drawing up and disseminating specific recommendations for the use of anti-TNF-alpha therapies in patients with rheumatoid arthritis (RA) in Italy. The document reports and discusses the published literature concerning the criteria for inclusion, assessment of response and for withdrawal of treatment with TNF blocking agents in RA. Several specific points concerning more sensitive warnings are discussed: tuberculosis, hepatitis, lymphoma, and cardiovascular risk and induction of autoimmunity. The recommendations are summarized in an 8-point table approved by the executive committee of the Italian Society for Rheumatology.
16374248 Reversible visual loss in a patient with rheumatoid arthritis and the role of vascular ima 2006 Feb Spontaneous vertebral artery dissection is a condition that can have lethal consequences. The condition should be considered in young male patients who present with a stroke. At presentation, headaches, cerebral ischaemic episodes and oculosympathetic paresis are the most commonly encountered manifestations. The diagnosis is confirmed with angiography. Here, we present a middle-aged male gardener with rheumatoid arthritis and signs of vertebral artery dissection to highlight the importance of diagnosis and discuss the controversies in management.
18203761 Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumat 2009 Jan BACKGROUND: Tumour necrosis factor alpha blockers in rheumatoid arthritis are known to increase the risk of serious infections defined as life-threatening, requiring hospitalisation or intravenous antibiotics. Recently, new biological agents have become available. Their safety is an important issue. PURPOSE: To assess if biological agents, ie rituximab, abatacept and anakinra increase the risk of serious infections in patients with rheumatoid arthritis in published randomised controlled trials. DATA SOURCE: A systematic review of the literature using PUBMED, EMBASE, Cochrane library and abstracts databases (American College of Rheumatology and European League Against Rheumatism annual meetings) was performed up to October 2007. This search was completed with data from the Food and Drug Administration, the European Agency for the Evaluation of Medicinal Products and manufacturers. DATA EXTRACTION: Three fixed-effect meta-analyses were performed to compare serious infection rates between each biological agent and placebo. Pooled odds ratios (ORs) were calculated, using the Mantel-Haenszel method with a continuity correction. DATA SYNTHESIS: Twelve randomised controlled trials with data concerning serious infections were analysed (three for rituximab, five for abatacept and four for anakinra). They included 745 patients, 1960 patients, 2062 patients and 2112 patients treated by rituximab, abatacept, anakinra and placebo respectively. The overall pooled ORs did not reveal a statistically significant increased risk of serious infection for abatacept and rituximab; this risk was increased for high doses of anakinra (> or =100 mg daily) versus low dose and placebo (ORs = 9.63 (95% CI, 1.31 to 70.91) and 3.40 (95% CI, 1.11 to 10.46) respectively). CONCLUSIONS: These meta-analyses did not reveal a significant increase in the risk of serious infections during rituximab or abatacept treatments in patients with rheumatoid arthritis; however, high doses of anakinra may increase this risk, especially when patients have comorbidity factors. Large studies must be performed to confirm this safety profile in daily practice.
18156150 Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis. 2008 Feb OBJECTIVE: To analyse the relationship between the presence of auto-antibodies [rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)], HLA-DRB1 alleles and PTPN22 1858 C/T polymorphism and test the value of their combination as susceptibility markers for rheumatoid arthritis (RA). METHODS: Patients with early arthritis were included. At entry in the cohort or during follow-up, 191 patients fulfilled the criteria for RA and 184 individuals suffered from other arthropathies. RF was measured by nephelometry and anti-CCP antibody by enzyme-linked immunosorbent assay. HLA class II alleles were determined by polymerase chain reaction. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination assay. RESULTS: The presence of shared epitope (SE) alleles was strongly associated with anti-CCP and RF-positive RA [P = 7.05 x 10(-10), odds ratio (OR) 4.57, 95% confidence interval (CI) 2.76-7.57 and P = 1.68 x 10(-6), OR 2.99, 95% CI 1.89-4.74, respectively). The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10(-5), OR 10.05, 95% CI 1.88-53.73). CONCLUSION: The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.
16899107 Interleukin-6 and chronic inflammation. 2006 Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response as defined by a variety of clinical and biological features such as the production of acute phase proteins. IL-6 in combination with its soluble receptor sIL-6Ralpha, dictates the transition from acute to chonic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages). In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus favoring chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling led to effective prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases.
16674119 Nanobacteria-like particles in human arthritic synovial fluids. 2006 May We investigated the existence of nanosize particles in synovial fluids of rheumatoid arthritis and osteoarthritis patients. These specimens were cultured under mammalian cell culture conditions (37 degrees C; 5% CO2/95% air) for a long period. After about 2 months, many nanoparticles appeared and they gradually increased in number and in size. The nanobacteria-like particles exist in synovial fluids of arthritis patients. The possibility of their existence and pathogenesis in various diseases should be verified cautiously.
17302286 [Pharmacogenomics of antirheumatic drugs and personalized medicine for rheumatoid arthriti 2007 Feb Rheumatoid arthritis (RA) is a chronic inflammatory disease of the joints. The inflammatory process causes a significant disability and may involve internal organs. The efficacy of disease modifying anti rheumatic drugs is widely accepted. However, the outcome of the treatment with these agents is known to vary among patients. Recently, the pharmacogenomic studies on methotrexate, sulfasalazine and tumor necrosis factor-alpha inhibitors have been reported, suggesting that the pharmacogenomic approach may be useful for the treatment of RA. Although there are points to be considered before the translation of the pharmacogenomic date into clinical practice, pharmacogenomics is considered to be an important tool for development of individualized medicine in the treatment of RA.
18346410 [Determinants of carotid subclinical atherosclerosis in patients with rheumatoid arthritis 2008 Feb 23 BACKGROUND AND OBJECTIVE: Rheumatoid arthritis (RA) is characterized by high cardiovascular (CV) mortality, which seems related to systemic inflammation. Our aim was to quantify carotid atherosclerosis in RA and its relationship with the disease. PATIENTS AND METHOD: 73 RA patients and the same number of sex and age matched controls were enrolled, without history of cardiovascular events. Carotid intima-media thickness (IMT) and plaques were measured by ultrasonography. Its relationship with risk factors (RF), rheumatic disease characteristics, and inflammatory markers were analysed. RESULTS: Controls showed higher body mass index (BMI) and dyslipidemia. There were no differences in other risk factors or IMT. Age (p = 0.001), sex (p = 0.02), BMI (p = 0.002), waist perimeter (p = 0.001), and hypertension (p = 0.005) had a relationship with IMT. Among disease characteristics, only time elapsed since RA diagnosis was associated with IMT. CONCLUSIONS: There was not an increased carotid subclinical atherosclerosis in patients with RA, beyond the effects of classical RF.
17366020 Fatal Salmonella enteritidis septicaemia in a rheumatoid arthritis patient treated with a 2007 We report a patient with a rare presentation of extra-intestinal salmonellosis after infliximab therapy for rheumatoid arthritis. We discuss the increasing incidence of primary infections and reactivation of intracellular microorganisms after treatment with TNF-alpha blockage, with emphasis on salmonellosis.
17024457 [Imaging in the early diagnosis of changes in the hand of patients suffering from rheumato 2007 Feb PURPOSE: Besides the use of conventional x-rays in the diagnostic work-up of initial changes in patients suffering from rheumatoid arthritis (RA), 3-phase bone scintigraphy (3P-Sz) is as well established as magnetic resonance imaging (MRI). The aim of this study was to compare the diagnostic value of ultrasound of the hands with proven methods such as conventional x-rays, low-field MRI and 3P-Sz. METHODS: A total of 30 patients were studied using a 1 day protocol with ultrasound, 3P-Sz, MRI and x-ray of the hands. Images were visually assessed by two blinded nuclear medicine physicians and radiologists and classified as RA typical and non-RA typical changes. All methods were compared to the summarized findings interpreted by a rheumatologist after 2 years. RESULTS: Of the 30 patients, 19 presented with clinical symptoms of initial changes due to rheumatoid arthritis. Ultrasound revealed 14/19 patients with the correct diagnosis. Conventional x-rays indicated 11/19 patients, while 3P-Sz (100%) and low-field MRI (95%) showed high sensitivity. It was possible to differentiate between inflammation and inconspicuous findings. CONCLUSIONS: An experienced examiner can use ultrasound effectively for the initial diagnosis of RA. Based on its low cost, ultrasound is a valid alternative to conventional x-rays.
17565371 In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer. 2007 Jun 13 Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, gammadelta and CD8(+) alphabeta T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4(+)CD28(-)NKG2D(+) T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4(+)CD28(-)NKG2D(+) and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8(+), but not that of CD4(+) T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes.
16886578 [Genetics in rheumatoid arthritis (RA)]. 2006 Apr Rheumatoid arthritis (RA) is a chronic autoimmune disease. Genetic and environmental factors are implicated in the pathogenesis of RA. In this study we describe numerous genetic phenomena that may be implicated in the etiopathogenesis of RA i.e. antigens of major histocompatibility complex, genetic linkage analysis results of whole genome scan and polymorphism of several genes coding receptors, adhesion molecules and cytokines. Genetic background plays an important role in this disorder and is connected with multiple genes.
17425804 Receptor for advanced glycation end products Glycine 82 Serine polymorphism and risk of ca 2007 Patients with rheumatoid arthritis (RA) are at risk of excess mortality, predominantly owing to cardiovascular (CV) events. The receptor for advanced glycation end products (RAGE) has been implicated in the perpetuation of the chronic inflammatory response in vascular disease. A Gly82-->Ser polymorphism in the RAGE gene, which is associated with enhanced RAGE signaling, is present more frequently in patients with RA than the general population. To investigate whether RAGE Gly82-->Ser polymorphism is associated with CV events in RA, we examined CV events, CV risk factors, features of RA and RAGE Gly82-->Ser polymorphism in 232 patients with RA attending a tertiary referral hospital. CV events, the duration and severity of RA, and risk factors for CV disease were determined using patient questionnaires, chart review, laboratory analysis and radiographs. DNA was typed for HLA-DRB1 genes and RAGE Gly82-->Ser polymorphism. The RAGE Ser82 allele, which is in linkage disequilibrium with the RA susceptibility allele HLA-DRB1*0401, was carried by 20% of patients. More than 20% of the cohort had suffered a vascular event; a shorter duration of RA, but not the RAGE genotype, was significantly associated with CV events. However, a history of statin use was protective. Thus, the RAGE Ser82 allele, associated with enhanced RAGE signaling, does not predispose to CV events in RA. However, treatment of hyperlipidemia with statins reduces the probability of a CV event.
18245109 Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis 2008 Dec OBJECTIVES: In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is frequently applied in clinical practice. Individual adjustment of infliximab treatment based on actual disease activity, instead of subjective clinical judgement, could prevent possible unwarranted dose escalation. METHODS: The infliximab dose of all patients with RA treated at our centre was decreased from 5 mg/kg to 3 mg/kg, leaving dosing intervals unaltered. Subsequently patients were followed for at least three infusions. At every visit, 28-joint Disease Activity Score (DAS28), infliximab serum trough levels and anti-infliximab antibody levels were assessed. Inversed European League Against Rheumatism (EULAR) criteria (flare criteria) were used as the endpoint. RESULTS: A total of 18 patients were included in the study. Mean (SD) DAS28 scores before dose reduction and after first and second low dose were 3.2 (1.2), 3.2 (1.8) and 3.3 (1.2), respectively (values not significant). One patient (6%, 95% CI 0% to 17%) developed a persistent flare that subsided after increasing infliximab doses and one patient stopped infliximab because of a lupus-like reaction. In all other patients (n=16) lowering infliximab resulted in unaltered disease activity. Infliximab levels showed that most patients had either low- (<1 mg/litre) or high (>5 mg/litre) serum trough levels. Anti-infliximab antibodies were detected in four patients. CONCLUSION: Infliximab dosages of 5 mg/kg can be lowered in the majority of patients with RA using DAS28-guided dose titration without increase of disease activity. Lowering the dose of infliximab should be considered in every patient receiving higher doses infliximab.
18448865 Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic dise 2008 Aug A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy X-ray densitometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-alpha and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1beta, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-alpha and IL-1beta mRNA most significantly induce paw edema, whereas IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.