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ID PMID Title PublicationDate abstract
23228682 [The distal airways in systemic disease]. 2012 Dec The association of inflammatory involvement of the distal airways or bronchiolitis and systemic diseases is essentially observed in Sjögren's syndrome, rheumatoid arthritis and chronic inflammatory bowel disease. Bronchiolitis may be mainly cellular in nature, often involving lympho-monocytic cells, and sometimes associated with lymphoid follicles, as in Sjögren's syndrome. It may also, particularly in rheumatoid arthritis, be constrictive, with peribronchiolar fibrosis. This type is associated with a worse prognosis, with possible progression to chronic respiratory insufficiency. The diagnosis of bronchiolitis should be suspected in any atypical form of asthma, or recurrent "bronchitis", and it is essential to look for extrarespiratory symptoms and auto-antibodies to establish the diagnose of systemic disease. The CT appearances coupled with the evaluation of pulmonary function parameters usually lead to the diagnosis. In severe and/or rapidly progressive cases treatment-combining corticosteroids with immunosuppressive drugs may be prescribed, but often with disappointing results. In these cases, lung transplantation should be considered in young patients.
23251512 Grape-seed proanthocyanidin extract as suppressors of bone destruction in inflammatory aut 2012 Chronic autoimmune inflammation, which is commonly observed in rheumatoid arthritis (RA), disrupts the delicate balance between bone resorption and formation causing thedestruction of the bone and joints. We undertook this study to verify the effects of natural grape-seed proanthocyanidin extract (GSPE), an antioxidant, on chronic inflammation and bone destruction. GSPE administration ameliorated the arthritic symptoms of collagen-induced arthritis (CIA), which are representative of cartilage and bone destruction. GSPE treatment reduced the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and osteoclast activity and increased differentiation of mature osteoblasts. Receptor activator of NFκB ligand expression in fibroblasts from RA patients was abrogated with GSPE treatment. GSPE blocked human peripheral blood mononuclear cell-derived osteoclastogenesis and acted as an antioxidant. GSPE improved the arthritic manifestations of CIA mice by simultaneously suppressing osteoclast differentiation and promoting osteoblast differentiation. Our results suggest that GSPE may be beneficial for the treatment of inflammation-associated bone destruction.
22709461 Quantiferon-TB Gold in tube assay for the screening of tuberculosis before and during trea 2012 Jun 18 INTRODUCTION: The usefulness of interferon-gamma (IFN-γ) release assays for tuberculosis screening before tumor necrosis factor-alpha (TNF-α) antagonists and for monitoring during treatment is a contraversial issue. The aims of this study were to determine whether TNF-α antagonists affect the results of the Quantiferon-TB Gold in-tube assay (QTF); to assess how QTF performs in comparison with the tuberculin skin test (TST) in rheumatoid arthritis (RA) patients who are about to start treatment with TNF-α antagonists, RA patients who are not candidates for treatment with TNF-α antagonists, rheumatology patients with confirmed current or past tuberculosis infection, and healthy controls, and to determine the specificity of the QTF test to differentiate leprosy patients, another group of patients infected with mycobacteria. METHODS: The 38 RA patients who were prescribed TNF-α antagonists, 40 RA patients who were not considered for TNF-α antagonist use, 30 rheumatology patients with a history or new diagnosis of tuberculosis, 23 leprosy patients, and 41 healthy controls were studied. QTF and TST were done on the same day, and both were repeated after a mean of 3.6 ± 0.2 months in patients who used TNF-α antagonists. RESULTS: Treatment with TNF-α antagonists did not cause a significant change in the QTF or TST positivity rate (34% versus 42%; P = 0.64; and 24% versus 37%; P = 0.22). Patients with leprosy had a trend for a higher mean IFN-γ level (7.3 ± 8.0) and QTF positivity (61%) than did the other groups; however, the difference was not significant (P = 0.09 and P = 0.43). CONCLUSIONS: Treatment with TNF-α antagonists does not seem to affect the QTF test to an appreciable degree. The higher IFN-γ levels in leprosy patients deserves further attention.
21840621 Anti-TNF therapy in patients with rheumatoid arthritis decreases Th1 and Th17 cell populat 2011 Dec The aim of this work was to study the effect of anti-TNF treatment on CD4+ Th1, Th17 and regulatory T cells (Tregs), together with CD8+ T cells and NK cells from rheumatoid arthritis (RA) patients. For this purpose, 18 RA patients received adalimumab during 16weeks and their peripheral blood lymphocytes were assessed by flow cytometry at the beginning and at the end of the study. We found that the proportion of Th17 cells was directly correlated with Th1 cells, but inversely correlated with IFN-γ-producing NK cells. A decrease was observed in Th1, Th17 cells and IFN-γ-producing CD8+ T cells by anti-TNF therapy. Conversely, the proportion of Tregs increased, as did the percentage of IFN-γ-producing NK cells. We postulate that a rise in IFN-γ production due to recovery of NK cells' function, together with expanded Tregs, contribute to decrease the Th17 response in anti-TNF-treated RA patients.
22900704 Hydrogen peroxide as an immunological transmitter regulating autoreactive T cells. 2013 Apr 20 SIGNIFICANCE: An unexpected finding, revealed by positional cloning of genetic polymorphisms controlling models for rheumatoid arthritis, exposed a new function of Ncf1 and NADPH oxidase (NOX) 2 controlled oxidative burst. RECENT ADVANCES: A decreased capacity to produce ROS due to a natural polymorphism was found to be the major factor leading to more severe arthritis and increased T cell-dependent autoimmunity. CRITICAL ISSUES: In the vein of this finding, we here review a possible new role of ROS in regulating inflammatory cell and autoreactive T cell activity. It is postulated that peroxide is an immunologic transmitter secreted by antigen-presenting cells that downregulate the responses by autoreactive T cells. FUTURE DIRECTIONS: This may operate at different levels of T cell selection and activation: during negative selection in the thymus, priming of T cells in draining lymph nodes, and while interacting with macrophages in peripheral target tissues.
21542789 Non-major histocompatibility complex rheumatoid arthritis susceptibility genes. 2011 Recent results from genetic and treatment studies have shed new light on chronic inflammatory and autoimmune diseases such as rheumatoid arthritis (RA). In particular, genome-wide association studies (GWAS) have provided supportive evidence that RA is a disease with a strong genetic background. Interestingly, a series of candidate genes have been identified outside of the classical major histocompatibility (MHC) locus, which had long been regarded as the major contributor to the pathogenesis of this disease. Among these genes, PTPN22 plays an outstanding role. CD40, STAT4, PRM1, and TNFAIP3 also seem to be of relevance. Interestingly, there is a significant overlap between RA susceptibility genes and those of other autoimmune diseases such as systemic lupus erythematosus (SLE) and type 1 diabetes, which suggests common pathogenic mechanisms. Genetic analyses may not only provide new insights into the pathogenesis of RA, but may also open new avenues for therapeutic approaches, because overactive immune-signaling pathways might specifically be addressed by biologic therapies. However, the predictive value of many of the recent findings of large-scale genetic analyses in identifying new genetic polymorphisms remains low. We describe the current knowledge about the role of non-MHC genes in the pathogenesis of rheumatoid arthritis.
22275240 Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis. 2012 Jul OBJECTIVE: To examine the effect of hypoxia on Notch-1 signaling pathway components and angiogenesis in inflammatory arthritis. METHODS: The expression and regulation of Notch-1, its ligand delta-like protein 4 (DLL-4) and downstream signaling components (hairy-related transcription factor 1 [HRT-1], HRT-2), and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions (1-3%) were assessed in synovial tissue specimens from patients with inflammatory arthritis and controls and in human dermal microvascular endothelial cells (HDMECs) by immunohistology, dual immunofluorescence staining (Notch-1/factor VIII), Western blotting, and real-time polymerase chain reaction. In vivo synovial tissue oxygen levels (tissue PO2) were measured under direct visualization at arthroscopy. HDMEC activation under hypoxic conditions in the presence of Notch-1 small interfering RNA (siRNA), the γ-secretase inhibitor DAPT, or dimethyloxalylglycine (DMOG) was assessed by Matrigel tube formation assay, migration assay, invasion assay, and matrix metalloproteinase 2 (MMP-2)/MMP-9 zymography. RESULTS: Expression of Notch-1, its ligand DLL-4, and HRT-1 was demonstrated in synovial tissue, with the strongest expression localized to perivascular/vascular regions. Localization of Notch-1 to synovial endothelium was confirmed by dual immunofluorescence staining. Notch-1 intracellular domain (NICD) expression was significantly higher in synovial tissue from patients with tissue PO2 of <20 mm Hg (<3% O2) than in those with tissue PO2 of >20 mm Hg (>3% O2). Exposure of HDMECs to 3% hypoxia induced HIF-1α and NICD protein expression and DLL-4, HRT-1, and HRT-2 messenger RNA expression. DMOG directly induced NICD expression, while Notch-1 siRNA inhibited hypoxia-induced HIF-1α expression, suggesting that Notch-1/HIF-1α signaling is bidirectional. Finally, 3% hypoxia-induced angiogenesis, endothelial cell migration, endothelial cell invasion, and proMMP-2 and proMMP-9 activities were inhibited by Notch-1 siRNA and/or the γ-secretase inhibitor DAPT. CONCLUSION: Our findings indicate that Notch-1 is expressed in synovial tissue and that increased NICD expression is associated with low in vivo tissue PO2. Furthermore, Notch-1/HIF-1α interactions mediate hypoxia-induced angiogenesis and invasion in inflammatory arthritis.
22980164 Asthma and proinflammatory conditions: a population-based retrospective matched cohort stu 2012 Oct OBJECTIVE: To determine the association between asthma and proinflammatory conditions. PARTICIPANTS AND METHODS: This population-based retrospective matched cohort study enrolled all asthmatic patients among Rochester, Minnesota, residents between January 1, 1964, and December 31, 1983. For each asthmatic patient, 2 age-and sex-matched nonasthmatic individuals were drawn from the same population. The asthmatic and nonasthmatic cohorts were followed forward in the Rochester Epidemiology Project diagnostic index for inflammatory bowel disease (IBD), rheumatoid arthritis (RA), diabetes mellitus (DM), and coronary heart disease (CHD) as outcome events. Data were fitted to Cox proportional hazards models. RESULTS: We identified 2392 asthmatic patients and 4784 nonasthmatic controls. Of the asthmatic patients, 1356 (57%) were male, and mean age at asthma onset was 15.1 years. Incidence rates of IBD, RA, DM, and CHD in nonasthmatic controls were 32.8, 175.9, 132.0, and 389.7 per 100,000 person-years, respectively; those for asthmatic patients were 41.4, 227.9, 282.6, and 563.7 per 100,000 person-years, respectively. Asthma was associated with increased risks of DM (hazard ratio, 2.11; 95% confidence interval, 1.43-3.13; P<.001) and CHD (hazard ratio, 1.47; 95% confidence interval, 1.05-2.06; P=.02) but not with increased risks of IBD or RA. CONCLUSION: Although asthma is a helper T cell type 2-predominant condition, it may increase the risks of helper T cell type 1-polarized proinflammatory conditions, such as CHD and DM. Physicians who care for asthmatic patients need to address these unrecognized risks in asthmatic patients.
21724705 Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active 2011 Sep OBJECTIVE: To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047. METHODS: In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index. RESULTS: Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels. CONCLUSION: CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.
23025928 Characterization of nitrotyrosine as a biomarker for arthritis and joint injury. 2013 Jan OBJECTIVES: To characterize the utility of nitrotyrosine (NT) as a biomarker for arthritis and joint injury. DESIGN: Synovial fluid, plasma, and urine from patients diagnosed with osteoarthritis (OA), rheumatoid arthritis (RA), anterior cruciate ligament (ACL) injury, meniscus injury and pseudogout, and knee-healthy volunteers were analyzed for concentrations of NT, nitrate and nitrite (NO(x)), matrix metalloproteinase (MMP)-3, MMP-1, MMP-9, more than 40 chemokines and cytokines. RESULTS: In OA, plasma and synovial fluid NT were increased versus healthy volunteers. Synovial fluid to plasma NT ratios were elevated in OA patients. Synovial fluid from patients with ACL and meniscus injury and pseudogout had increased levels of NT (P < 0.001). In these samples, NT levels significantly correlated with ARGS-aggrecan neoepitope generated by aggrecanase cleavage of aggrecan (P ≤ 0.001), cross-linked C-telopeptides of type II collagen (P < 0.001), MMP-1 (P = 0.008), and MMP-3 (P ≤ 0.001). In RA, plasma NT decreased following 6 months of anti-tumor necrosis factor (TNF) treatment. For every 1.1% change in log(10) NT, there was a 1.0% change in the log(10) disease activity scores (DAS28-3 CRP). Both predicted and observed DAS28-3 CRP showed a robust linear relationship with NT. RA plasma NT positively correlated with CRP, MMP-3 and interferon γ-induced protein 10. CONCLUSIONS: NT may serve as a useful biomarker for arthritis and joint injury. In RA, NT is highly correlated with several biomarkers and clinical correlates of disease activity and responds to anti-TNF therapy.
22704914 Catastrophic health expenses and impoverishment of households of patients with rheumatoid 2012 Jul BACKGROUND: The cost of certain diseases may lead to catastrophic expenses and impoverishment of households without full financial support by the state and other organizations. OBJECTIVE: To determine the socioeconomic impact of the rheumatoid arthritis (RA) cost in the context of catastrophic expenses and impoverishment. PATIENTS AND METHODS: This is a cohort-nested cross-sectional multicenter study on the cost of RA in Mexican households with partial, full, or private health care coverage. Catastrophic expenses referred to health expenses totaling >30% of the total household income. Impoverishment defined those households that could not afford the Mexican basic food basket (BFB). RESULTS: We included 262 patients with a mean monthly household income (US dollars) of $376 (0–18,890.63). In all, 50.8%, 35.5%, and 13.7% of the patients had partial, full, or private health care coverage, respectively. RA annual cost was $ 5534.8 per patient (65% direct cost, 35% indirect). RA cost caused catastrophic expenses in 46.9% of households, which in the logistic regression analysis were significantly associated with the type of health care coverage (OR 2.7, 95%CI 1.6–4.7) and disease duration (OR 1.024, 95%CI 1.002–1.046). Impoverishment occurred in 66.8% of households and was associated with catastrophic expenses (OR 3.6, 95%CI 1.04–14.1), high health assessment questionnaire scores (OR 4.84 95%CI 1.01–23.3), and low socioeconomic level (OR 4.66, 95%CI 1.37–15.87). CONCLUSION: The cost of RA in Mexican households, particularly those lacking full health coverage leads to catastrophic expenses and impoverishment. These findings could be the same in countries with fragmented health care systems.
22203320 Adult coeliac disease in Ireland: a case series. 2012 Jun BACKGROUND: The clinical spectrum of adult coeliac disease (ACD) is varied with limited Irish data. AIMS AND OBJECTIVES: The aim of this study was to analyse the presenting symptoms, associated conditions and complications in a consecutive series of patients with ACD. METHODS: Data were obtained from database on patients with ACD between 1988 and 2004. RESULTS: One hundred and six patients (69F:37M, mean age: 46, range: 23-95 years) were included. The modes of presentation were diarrhoea in 44 patients (45%), weight loss in 41 (42%), anaemia in 37 (38%), abdominal pain in 15 (15%), fatigue in 8 (8%), hypocalcaemia in 4 (4%) and steatorrhoea in 4 (4%). Associated conditions included thyroid disorders in 7 patients (7%), bipolar affective disorder in 4 (4%), major depression in 3 (3%), rheumatoid disease in 3 (3%), inflammatory bowel disease in 4 (4%) and type I diabetes mellitus in 2 (2%). Malignancy emerged as a major complication in 15 patients (15%) CONCLUSION: The presenting features of ACD are diverse and associated with high risk of malignancy.
21496228 Increased plasma levels of the soluble Mer tyrosine kinase receptor in systemic lupus eryt 2011 Apr 15 INTRODUCTION: Mer and Tyro3 are receptor tyrosine kinases important for the phagocytosis of apoptotic cells. Together with Axl, they constitute the TAM receptor family. These receptors can be shed from the cell membrane and their soluble extracellular regions can be found in plasma. The objective of this study was to elucidate whether the plasma levels of soluble Mer (sMer) and Tyro3 (sTyro3) were increased in systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), or critical limb ischemia (CLI). METHODS: ELISA kits were used to test plasma concentrations in controls and in patients with SLE, RA or CLI. RESULTS: Increased levels of, in particular, sMer and, to some extent, sTyro3, were found in patients with SLE or RA, but not in patients with CLI. Patients with SLE demonstrated the highest sMer levels and there was a strong correlation to higher SLE disease activity score (SLEDAI). In contrast, in patients with RA, the sMer levels did not correlate with the disease activity score (DAS). In SLE, sMer levels were particularly high in those with lupus nephritis, patients who also had decreased C1q levels and increased titers of anti-DNA antibodies. After therapy, the plasma concentrations of sMer decreased in parallel to the decrease in SLEDAI score. CONCLUSIONS: The plasma concentrations of sMer and sTyro3 were significantly increased in patients with active SLE and RA, suggesting the TAM receptor shedding was affected by these autoimmune diseases. In particular, sMer was increased in SLE, the plasma levels of sMer reflecting disease activity.
23086517 A study of baseline prevalence and cumulative incidence of comorbidity and extra-articular 2013 Jan OBJECTIVES: To study the prevalence at diagnosis and cumulative incidence of comorbidity in RA, associations with clinical features and impact on outcome. METHODS: Standard clinical, laboratory and radiological measures of RA, and details of comorbidity and extra-articular features were recorded at baseline and yearly in an inception cohort of 1460 patients with recently diagnosed RA from nine regions in the UK. The General Practice Research Database was used to compare the incidence of common comorbid conditions (International Classification for Disease-10 codes). RESULTS: Baseline prevalence was 31.6% and 8.6% for all comorbidities and extra-articular features, respectively, and 15-year cumulative incidence was 81% and 53%, respectively. Rates of hypertension [standardized incidence ratio (SIR) = 1.61; 95% CI 1.43, 1.79] and ischaemic heart disease (SIR = 1.60; 95% CI 1.35, 1.84) were raised compared with figures for the general population, as was stroke in females (SIR = 1.34; 95% CI 1.02, 1.77) and chronic obstructive pulmonary disorder in males (SIR = 1.63; 95% CI 1.17, 2.26). Comorbidity was associated with risk of both all-cause and cardiovascular mortality (hazard ratio = 1.09; 95% CI 1.02, 1.17) and increased rates of functional decline over 10 years (b = 0.011; 95% CI 0.004, 0.019). Comorbidity was not related to disease activity or structural damage. CONCLUSION: Significant comorbidity was present at the outset of RA, increasing with follow-up, mainly in cardiovascular, non-cardiac vascular and respiratory systems. Specific conditions (e.g. hypertension) occurred more frequently than in the general population. Comorbidity was related to mortality and functional decline, and more intensive therapies may need consideration in these patients. As many co-existent conditions are amenable to preventative/therapeutic measures, comorbidity needs earlier detection and management in order to reduce its impact on outcome in RA.
22401593 Apolipoprotein-defined lipoprotein abnormalities in rheumatoid arthritis patients and thei 2012 May OBJECTIVES: The aim of this study was to explore apolipoprotein-defined lipoproteins for abnormalities when comparing non-rheumatological controls to rheumatoid arthritis (RA) patients. METHODS: Apolipoprotein and lipoprotein profiles were measured on 94 RA patients and 79 controls by immunoturbidimetric procedures, electroimmunoassays, and immunoprecipitation. Differences between means were tested with a two-sided Student t test with Satterthwaite adjustment. p-values were adjusted for multiple comparisons using the Bonferroni procedure. RESULTS: RA patients had significantly higher levels of total cholesterol (TC), triglycerides (TG), and very low density lipoprotein cholesterol (VLDL-C) than controls, but no significant differences in the levels of high density lipoprotein cholesterol (HDL-C) and LDL-C. RA patients had significantly lower levels of apolipoprotein (apo)A-I and lipoprotein (Lp)A-I:A-II, but no difference in levels of LpA-I than normal controls. There was a significant difference in the levels of LpB:C but not in LpB:C:E between RA patients and controls. The main abnormality among apoB lipoproteins was the significantly increased concentration of the LpA-II:B:C:D:E subclass in RA patients in comparison with controls. The high levels of LpA-II:B:C:D:E are also reflected in significantly increased levels of apoC-III, and apoC-III bound to apoB lipoproteins. CONCLUSION: The LpA-II:B:C:D:E subclass has potential as a new marker for cardiovascular disease (CVD) in RA patients.
21084326 Ten years with biologics: to whom do data on effectiveness and safety apply? 2011 Jan OBJECTIVES: During the past decade, the position of biologics in the therapeutic armamentarium, the number of approved indications and the number of available biologics have changed. Available data on (long-term) safety might thus pertain to patient populations not comparable with contemporary patients. The aim of this study was to assess the extent to which contemporary patients who start or switch biologic therapies are comparable with those patients who gave rise to the currently available data on effectiveness and safety. METHODS: We identified all adult patients with RA (n=9612), PsA (n=1417) and other SpA (n=1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. RESULTS: Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite <50% drug retention at 5 years, most patients remained exposed to some biologic. CONCLUSIONS: The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.
21567378 Identification and functional characterization of T cells reactive to citrullinated viment 2011 Oct OBJECTIVE: Antibodies toward the citrullinated form of the synovial antigen vimentin are specific for rheumatoid arthritis (RA) and are associated with HLA-DRB1*0401. This suggests that T cells specific for peptides derived from citrullinated vimentin presented in the context of HLA-DRB1*0401 may contribute to the etiopathogenesis of RA. The aim of this study was to identify immunodominant epitopes from citrullinated vimentin presented by HLA-DRB1*0401 and to characterize the resulting T cell responses. METHODS: We first predicted an HLA-binding T cell epitope from citrullinated vimentin based on the binding motif of HLA-DRB1*0401 and then confirmed its affinity. A class II major histocompatibility complex (MHC) tetramer loaded with the citrullinated form of vimentin aa 59-78 (cit-vimentin aa 59-78) was constructed and used to screen for specific T cells in HLA-DRB1*0401-transgenic mice, patients with RA, and healthy control subjects. Additionally, the cytokine output following cit-vimentin aa 59-78 challenge was analyzed in patients and healthy control subjects by multicolor flow cytometry and Luminex-based analysis. RESULTS: The citrullinated form of vimentin aa 59-78 bound to HLA-DRB1*0401, but the native form could not. Subsequently, cit-vimentin aa 59-78-specific T cells were detected in immunized mice and in the periphery of both HLA-DR*0401-positive healthy control subjects and HLA-DR*0401-positive patients with RA, using class II MHC tetramers, CD154 up-regulation, and intracellular cytokine measurements. As demonstrated in cell culture supernatants, the production of cytokines (predominantly interferon-γ) in response to cit-vimentin aa 59-78 was significantly higher in patients compared with controls. CONCLUSION: Here, we describe a posttranslational modification of an RA candidate autoantigen toward which HLA-DRB1*0401-restricted T cells can be detected in both patients with RA and healthy controls but for which a proinflammatory response is observed uniquely in patients with RA.
22170453 Relationship between placenta growth factor 1 and vascularization, dehydroepiandrosterone 2012 Jun OBJECTIVE: Proliferating pannus is in many aspects similar to placental tissue. Both fibroblast-rich tissues have high vascularity, and tissue from patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA) demonstrates conversion of androgenic prehormones to downstream estrogens. We undertook this study to investigate similarities between proliferating pannus and placental tissue by focusing on angiogenic placenta growth factor 1 (PlGF-1) in patients with OA and patients with RA. METHODS: We used immunohistochemistry to study the presence of PlGF-1, its synovial distribution, and the PlGF-1-expressing synovial cell type. The relationship between PlGF-1 and conversion of the biologically inactive placental prehormone dehydroepiandrosterone sulfate (DHEAS) to the biologically active dehydroepiandrosterone (DHEA) was investigated in mixed synovial cells. The effects of DHEA on PlGF-1 expression were studied by intracellular fluorescence-activated cell sorting analysis. RESULTS: PlGF-1-positive cells were detected in the lining and sublining areas in patients with RA and patients with OA, and cellular density was similar. Double staining revealed that PlGF-1-positive cells were macrophages. In RA and OA, the density of PlGF-1-positive cells correlated positively with the density of macrophages and the density of type IV collagen-positive vessels. The supernatant concentration of (3) H-DHEA after conversion from (3) H-DHEAS and the density of aromatase-positive cells were positively correlated with the density of PlGF-1-positive cells only in OA. Low DHEA concentrations (≤10(-9) M) had stimulatory effects on PlGF-1 when compared to serum concentrations (10(-8) M to 10(-7) M) in the monocytic cell line THP-1 and in primary mixed synovial cells. CONCLUSION: PlGF-1 functions similarly in inflamed synovium and in the placenta. It is related to vessel formation and, in OA patients, to androgen/estrogen conversion. Evolutionarily conserved functions of PlGF-1 for placental phenomena are obviously also present in synovial inflammation.
22615456 Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARD 2012 Dec OBJECTIVE: To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis). METHODS: Patients-categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) -received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses. RESULTS: Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission. CONCLUSIONS: In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.
22565193 Identifying disease related sub-pathways for analysis of genome-wide association studies. 2012 Jul 15 Most methods for genome-wide association studies (GWAS) focus on discovering a single genetic variant, but the pathogenesis of complex diseases is thought to arise from the joint effect of multiple genetic variants. Information about pathway structure, such as the interactions and distances between gene products within pathways, can help us learn more about the functions and joint effect of genes associated with disease risk. We developed a novel sub-pathway based approach to study the joint effect of multiple genetic variants that are modestly associated with disease. The approach prioritized sub-pathways based on the significance values of single nucleotide polymorphisms (SNPs) and the interactions and distances between gene products within pathways. We applied the method to seven complex diseases. The result showed that our method can efficiently identify statistically significant sub-pathways associated with the pathogenesis of complex diseases. The approach identified sub-pathways that may inform the interpretation of GWAS data.