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ID PMID Title PublicationDate abstract
24005900 Baicalein inhibits interleukin-1β-induced proliferation of human rheumatoid arthritis fib 2014 Feb Baicalein shows anti-inflammatory effects in human rheumatoid arthritis fibroblast-like synoviocytes (RAFLS). Considering its anti-proliferatory effects on various cancer cells, we investigated the effects of baicalein on interleukin-1 beta (IL-1β)-induced proliferation of human RAFLS. Cell proliferation was examined by (3)H-thymidine incorporation assay. Western blot analysis was performed to assess the phosphorylation of extracellular regulating kinase (ERK), p38, and c-Jun N-terminal kinase, and nuclear translocation of nuclear factor kappa B (NF-κB) subunit p65. Notably, baicalein significantly suppressed IL-1β-mediated RAFLS proliferation (P < 0.05), along with reduced ERK1/2 and p38 phosphorylation. The IL-1β-induced p65 nuclear translocation and NF-κB DNA binding activity was significantly decreased by baicalein. Additionally, the inhibitory effects of baicalein on IL-1β-induced proliferation of RAFLS were dose-dependently reversed by the addition of recombinant macrophage migration inhibitory factory (MIF). Our results indicate that baicalein inhibits IL-1β-induced RAFLS proliferation, which involves suppression of NF-κB transcriptional activity and MIF-mediated signaling.
23474125 Antibodies to citrullinated peptides and risk of coronary heart disease. 2013 May OBJECTIVE: Increased cardiovascular risk has been associated with high levels of serum antibodies to citrullinated proteins (ACPA) in patients with rheumatoid arthritis (RA). Citrullination is part of many chronic inflammatory processes and we therefore investigated whether ACPA might be associated with coronary artery disease, in the absence of RA. METHODS: To maximize the potential predictive value of this retrospective study we included sera from a cohort of 3052 healthy male individuals, subsequently followed for the development of coronary artery disease, and documented for other disease risk factors. With each case event (myocardial infarction; n = 144), 2 matched controls were assigned. RESULTS: We found 10.4% of cases were ACPA positive compared to 3.8% of controls (odds ratio (95% CI) = 3.26 (1.36-7.80), p = 0.008), remaining significant after adjustment for classical risk factors including smoking and CRP (4.23 (1.22-14.61) p = 0.02). CONCLUSION: The genesis and fine specificity of ACPA in patients with atherosclerosis, in the absence of Rheumatoid arthritis, may prove worthy of further investigation.
25240611 Dysregulated mature IL-1β production in familial Mediterranean fever. 2015 Apr OBJECTIVE: The aim of this study was to analyse the role of circulating cleaved IL-1β in patients with FMF. METHODS: We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1β was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1β antibody. RESULTS: Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1β (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1β were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1β (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. CONCLUSION: The cleaved form of IL-1β is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1β-mediated inflammatory disorders.
25253538 Sulfasalazine and its metabolites inhibit platelet function in patients with inflammatory 2016 Feb The purpose of this study is to assess the effect of sulfasalazine and its metabolites on platelet function in patients with inflammatory arthritis (IA). One hundred thirty-five consecutive patients with an established diagnosis of IA were screened. Those with a history of cardiovascular disease (CVD), taking anti-platelet agents or non-steroidal anti-inflammatory drugs (NSAIDs) were excluded. A total of 32 patients were investigated, 15 taking sulfasalazine and 17 taking other disease-modifying anti-rheumatic drugs (DMARDs) and no sulfasalazine. These two cohorts were compared to 15 patients with stable CVD on long-term aspirin. The effect of sulfasalazine and its metabolites on arachidonic acid (AA)-induced platelet aggregation was also tested in vitro in samples from healthy donors (n = 18). Demographics, CVD risk factors and disease activity indices were similar in the sulfasalazine and other DMARD groups. AA-induced platelet aggregation was significantly inhibited in the sulfasalazine group (9 ± 7 %) and comparable to that in the aspirin group (10 ± 6 %). In contrast, there was no effect on AA-induced platelet aggregation in the other DMARDs group (77 ± 12 %) (p < 0.001). Furthermore, sulfasalazine therapy had no effect on platelet aggregation in response to multiple other agonists. Sulfasalazine and its metabolites (5-aminosalicylic acid and sulfapyridine) exerted an additive and dose-dependent inhibitory effect on AA-induced platelet aggregation in vitro (p < 0.001). The inhibition of AA-induced platelet aggregation by sulfasalazine is comparable to that achieved by aspirin and is dependent on both sulfasalazine and its metabolites. This represents a potential mechanism that may contribute to the known cardioprotective effect of sulfasalazine in patients with IA.
23954923 High rate of disease remission in moderate rheumatoid arthritis on etanercept therapy: dat 2014 Jan The aim of this study was to evaluate the clinical outcomes of etanercept in rheumatoid arthritis (RA) patients with moderate or severe disease activity. We analyzed data from the Italian biologics register Gruppo Italiano Studio Early Arthritides (GISEA) to investigate the rate of disease remission and functional improvement, based on the 28-Joint Disease Activity Score (DAS28) and the (Health Assessment Questionnaire (HAQ) score in RA patients with moderate or severe disease activity beginning etanercept therapy. Disease was defined as severe (H-RA) with DAS28 ≥5.1 and moderate (M-RA) with DAS28 ≥3.2 to 5.1 at baseline. Patients were considered in remission if DAS28 was ≤2.6, and HAQ ≤0.5 defined normal function. We enrolled 953 RA patients, 320 with M-RA and 633 H-RA. Age and disease duration were similar in the two cohorts, but H-RA patients had significantly more comorbidities (p < 0.01) and took significantly more disease-modifying antirheumatic drugs (p < 0.001) than M-RA patients. After 1 year, the percentage of patients achieving disease remission and normal function (DAS28 ≤2.6 plus HAQ ≤0.5) was higher in M-RA (21.4 %) than in H-RA patients (14.8 %, p = 0.007), regardless of the disease duration. Additionally, female gender (p = 0.006) and H-RA class (p = 0.002) negatively predicted disease remission at 1 year. However, the drug survival rate did not differ between the two subsets. This study confirms that etanercept was effective in the treatment of active RA, but best response, in terms of disease remission and normal function ability, was greater and easier to attain in M-RA patients. These findings may aid clinicians to choose the best strategy to treat RA.
24033110 Morphologic features of binucleated lymphocytes to assess the diagnosis of persistent B-ce 2014 Jul The observation of binucleated lymphocytes (BNLs) on a peripheral blood smear is essential to the diagnosis of persistent polyclonal B-cell lymphocytosis (PPBL). Only a few case reports have mentioned their presence in other contexts, mainly mature B-cell neoplasms such as chronic lymphocytic leukemia or reactive circumstances such as multiple sclerosis undergoing natalizumab treatment. We sought to investigate whether any particular morphologic features of BNL were more specific to PPBL than other diseases. We reviewed peripheral blood smears of a series of patients affected by PPBL or harboring BNLs whatever the diagnosis. We found that BNLs in PPBL were heterogeneous, but mostly medium-sized with a moderately abundant basophilic cytoplasm, sometimes vacuolated. The chromatin was mature in an asymmetrically bilobed nucleus showing one to two nucleoli. Though mainly observed in patients with PPBL, all these criteria remained non-specific. Conversely, the presence of either monocytoid or hyperbasophilic cells had clinical value to confirm PPBL. We conclude that a substantial percentage of BNLs possessing the morphologic features described and observed in a context of monocytoid and/or hyperbasophilic lymphocytes is predictive of the diagnosis of PPBL.
24876675 ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation. 2014 ADAMTS-12 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which were known to play important roles in various biological and pathological processes, such as development, angiogenesis, inflammation, cancer, arthritis, and atherosclerosis. In this review, we briefly summarize the structural organization of ADAMTS-12; concentrate on the emerging role of ADAMTS-12 in several pathophysiological conditions, including intervertebral disc degeneration, tumorigenesis and angioinhibitory effects, pediatric stroke, gonad differentiation, trophoblast invasion, and genetic linkage to schizophrenia and asthma, with special focus on its role in arthritis and inflammation; and end with the perspective research of ADAMTS-12 and its potential as a promising diagnostic and therapeutic target in various kinds of diseases and conditions.
23499975 Nanomolar to sub-picomolar affinity measurements of antibody-antigen interactions and prot 2013 Jun 15 Although several techniques exist for the measurement of high-affinity interactions, it is still challenging to determine dissociation constants around or even below 1pM. During the analysis of several human-derived monoclonal antibodies to adalimumab, we found a clone with a very high affinity that could not be measured using conventional surface plasmon resonance assays. We developed a straightforward and robust method to measure affinities in the nanomolar to sub-picomolar range. The assay is based on separation of bound and free fluorescently labeled antigen using size exclusion chromatography and quantification by in-line fluorescence detection. We describe optimal conditions and procedures that result in a very sensitive assay that can be used to reliably determine ultra-high affinities. Using the method described in this article, a dissociation constant of 0.78pM could be determined for the anti-adalimumab antibody.
24064519 Comparison of sagittal subluxation in two different three-component total ankle replacemen 2013 Dec BACKGROUND: Malalignment following total ankle arthroplasty (TAA) has been reported in 4% to 45% of patients. However, all reports to date have been related to coronal deformity. This study compared sagittal malalignment between the Mobility and Hintegra total ankle systems and assessed the positional stability of the implant components over time. METHODS: The study included 50 cases each of total ankle replacement arthroplasty with the Hintegra and Mobility total ankle systems performed between May 2008 and June 2010. The Mobility group included 24 men and 25 women, and the mean age was 60.3 years (range, 50.7-70.0 years). The Hintegra group included 25 men and 25 women, and the mean age was 59.8 years (range, 50.8-68.7 years). The 2 groups did not differ in terms of gender (P = .76) or age (P = .77). Three independent observers with different levels of training evaluated the radiographs and performed the measurements independently. Each observer evaluated the radiographs twice at a 6-week interval to determine the intraobserver reliability, and the anteroposterior offset ratio was evaluated. RESULTS: The anteroposterior offset ratio intra- and interobserver reliabilities all showed good or excellent levels of agreement in the Hintegra total ankle system and the Mobility total ankle system. With respect to the stability of sagittal translation of the talus, the Mobility system (0.08 ± 0.07 immediately, 0.0 ± 0.07 at 6 weeks postoperatively, and 0.01 ± 0.07 at 1 year postoperatively) was better than the Hintegra system (0.20 ± 0.08 immediately, 0.18 ± 0.11 at 6 weeks postoperatively, and 0.15 ± 0.10 at 1 year postoperatively) (P < .0001). CONCLUSIONS: The Mobility system had less sagittal malalignment of the talus than the Hintegra system. Consequently, when treating ankles in patients with osteoarthritis using the Hintegra system, one must pay careful attention to sagittal malalignment during surgery. LEVEL OF EVIDENCE: Level III, retrospective comparative series.
23815433 Activated γδ T cells inhibit osteoclast differentiation and resorptive activity in vitro 2013 Nov Extensive evidence suggests that the immune system exerts powerful effects on bone cells, particularly in chronic disease pathologies such as rheumatoid arthritis (RA). The chronic inflammatory state in RA, particularly the excessive production of T cell-derived proinflammatory cytokines such as tumour necrosis factor (TNF)-α and interleukin (IL)-17, triggers bone erosions through the increased stimulation of osteoclast formation and activity. While evidence supports a role for IL-17 and TNF-α secreted by conventional CD4⁺ T cells in RA, recent evidence in animal models of RA have implicated γδ T cells as a major producer of pathogenic IL-17. However, the capacity of γδ T cells to influence osteoclast formation and activity in humans has not yet been investigated widely. To address this issue we investigated the effects of γδ T cells on osteoclast differentiation and resorptive activity. We have demonstrated that anti-CD3/CD28-stimulated γδ T cells or CD4⁺ T cells inhibit human osteoclast formation and resorptive activity in vitro. Furthermore, we assessed cytokine production by CD3/CD28-stimulated γδ T cells and observed a lack of IL-17 production, with activated γδ T cells producing abundant interferon (IFN)-γ. The neutralization of IFN-γ markedly restored the formation of osteoclasts from precursor cells and the resorptive activity of mature osteoclasts, suggesting that IFN-γ is the major factor responsible for the inhibitory role of activated γδ T cells on osteoclastogenesis and resorptive activity of mature osteoclasts. Our work therefore provides new insights on the interactions between γδ T cells and osteoclasts in humans.
25103892 DRB1*0402 may influence arthritis by promoting naive CD4+ T-cell differentiation in to reg 2014 Nov HLA-DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), while HLA-DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4+ T-cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen-specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4+ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN-γ. *0401 Tg mice harbor memory CD4+ T cells that differentiate into IL-17(+) cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg-cell numbers in *0401 Tg mice, causes immune dysregulation.
25445409 Anti-nuclear antibody detection in cryoprecipitates: distinctive patterns in hepatitis C v 2015 Jan BACKGROUND: Anti-nuclear antibodies are immunoglobulins directed against nuclear antigens. They are associated with many autoimmune disorders, but are frequently found in patients infected with hepatitis C virus, possibly indicating an underlying common origin. Likewise, mixed cryoglobulinemia often accompanies autoimmune diseases and hepatitis C infection. AIM: To compare anti-nuclear antibodies and immunoglobulin content of cryoprecipitates from hepatitis C virus-positive patients in order to assess their predictive value in the onset of hepatitis C virus-driven extrahepatic disorders. METHODS: Serum from 40 hepatitis C virus-positive patients and 50 controls with rheumatoid arthritis was processed for cryoglobulin detection: all subjects presented with Type III mixed cryoglobulinemia. Immunoglobulin content and immunoglobulin subclasses of cryoprecipitates were assessed by immunofixation and tested by ELISA for rheumatoid factor. Cryoprecipitates were also analysed for anti-nuclear antibodies by indirect immuno-fluorescence to identify specific patterns typical of each condition. RESULTS: Anti-nuclear antibody patterns differed significantly; 26 infected subjects (65%) were IgG3 positive: of these, 25 were also anti-nuclear antibody-positive (96.1%). CONCLUSIONS: IgG3 are autoreactive clones unrelated to viral recognition and possibly involved in autoimmune disorders. Altogether, these results may represent useful diagnostic device for early detection of hepatitis C virus-induced autoimmune diseases.
26058345 Cardiovascular morbidity and associated risk factors in Spanish patients with chronic infl 2015 Jun OBJECTIVE: To establish the cardiovascular (CV) morbidity and associated risk factors for CV disease (CVD) in Spanish patients with chronic inflammatory rheumatic diseases (CIRD) and unexposed individuals attending rheumatology clinics. METHODS: Analysis of data from the baseline visit of a 10-year prospective study [CARdiovascular in rheuMAtology (CARMA) project] that includes a cohort of patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and another cohort of matched individuals without CIRD attending outpatient rheumatology clinics from 67 hospitals in Spain. Prevalence of CV morbidity, CV risk factors, and systematic coronary risk evaluation (SCORE) assessment were analyzed. RESULTS: A total of 2234 patients (775 RA, 738 AS, and 721 PsA) and 677 unexposed subjects were included. Patients had low disease activity at the time of recruitment. PsA patients had more commonly classic CV risk factors and metabolic syndrome features than did the remaining individuals. The prevalence of CVD was higher in RA (10.5%) than in AS (7.6%), PsA (7.2%), and unexposed individuals (6.4%). A multivariate analysis adjusted for the presence of classic CV risk factors and disease duration revealed a positive trend for CVD in RA (OR = 1.58; 95% CI: 0.90-2.76; p = 0.10) and AS (OR = 1.77; 95% CI: 0.96-3.27; p = 0.07). Disease duration in all CIRD groups and functional capacity (HAQ) in RA were associated with an increased risk of CVD (OR = 2.15; 95% CI: 1.29-3.56; p = 0.003). Most patients had a moderate CV risk according to the SCORE charts. CONCLUSIONS: Despite recent advances in the management of CIRD, incidence of CVD remains increased in Spanish subjects with CIRD attending outpatient rheumatology clinics.
25351972 Predictors of treatment initiation with tumor necrosis factor-α inhibitors in patients wi 2014 Nov BACKGROUND: Introduction of biologic disease-modifying antirheumatic drugs (DMARDs) has revolutionized treatment in patients with rheumatoid arthritis (RA). However, due to substantially higher costs of biologics compared with nonbiologics, patients with less insurance generosity may have difficulty affording these agents, which may lead to potential access disparities. OBJECTIVE: To identify factors affecting treatment initiation with tumor necrosis factor (TNF)-α inhibitor biologics in patients with RA. METHODS: Health insurance claims data derived from Truven's MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits (2007-2010) were used to conduct a retrospective cohort study. Two separate cohorts of RA patients were identified: (1) monotherapy nonbiologic DMARD users and (2) combination therapy nonbiologic DMARD users. The primary outcome was TNF-α inhibitor initiation 12 months following an index inpatient or outpatient RA visit during 2008-2009. Predictors were measured 12 months pre-index and grouped into predisposing, enabling, or need factors based on Andersen's Behavior Model. Predisposing variables included age, sex, and geographic location; enabling variables included insurance-related factors such as capitation, payer type, and insurance generosity, which was defined using cost-sharing information from prescriptions filled by the patients in the previous year; and need variables included disease-related factors such as severity of RA, use of pain control medications, and presence of other comorbidities. Hierarchical logistic regression models were used to derive estimates of the impact of individual predictors. RESULTS: Initiation of TNF-α inhibitors was observed in 10.31% of the monotherapy nonbiologic DMARD users (1,922 of 18,641) and 13.09% of combination nonbiologic DMARD users (983 of 7,508). Among monotherapy nonbiologic DMARD users, initiation with TNF-α inhibitors was associated with the predisposing factors of age (OR = 0.98, 95% CI = 0.97-0.98 for each year increase) and geographic region (Midwest vs. South OR = 0.83, 95% CI = 0.73-0.93; Northeast vs. South OR = 0.77, 95% CI = 0.64-0.92; and West vs. South OR = 0.86, 95% CI = 0.74-0.99); enabling factors of visit to rheumatologists (1 visit vs. no visit OR = 1.22, 95% CI = 1.01-1.46), health insurance type (commercial vs. Medicare supplemental OR = 0.79, 95% CI = 0.66-0.95), and drug benefit generosity (above average vs. poor OR = 1.16, 95% CI = 1.01-1.34 and most generous vs. poor OR = 1.21, 95% CI = 1.05-1.40); and need factors of RA severity (OR = 1.19, 95% CI = 1.14-1.23 for each unit increase in a claims-based RA severity index [CIRAS]), pre-index pain reliever use (steroids OR = 1.81, 95% CI = 1.62-2.02; nonselective nonsteroidal anti-inflammatory drugs [NSAID] OR = 1.17, 95% CI = 1.05-1.31; COX-2 inhibitors OR = 1.22, 95% CI = 1.05-1.41), and comorbidities (OR = 0.94, 95% CI = 0.90-0.99 for each unit increase in a comorbidity index). Treatment initiation with TNF-α inhibitors among patients with combination therapy nonbiologic DMARDs use at baseline was associated with age (OR = 0.98, 95% CI = 0.97-0.99 for each year increase) and region (Midwest vs. South OR = 0.81, 95% CI = 0.68-0.96). Stronger associations with some of the need factors were observed (CIRAS OR = 1.28, 95% CI = 1.21-1.35 for each unit increase, steroids use OR = 2.05, 95% CI = 1.73-2.42, and nonselective NSAID use OR = 1.36, 95% CI = 1.17-1.58) in these patients compared with the monotherapy nonbiologic DMARD users. However, unlike the monotherapy DMARD user group, the enabling factors of health insurance type and drug benefit generosity were not found to be associated with TNF-α inhibitor initiation among nonbiologic DMARD combination therapy users. CONCLUSIONS: Potential disparities in the initiation of TNF-α inhibitors among RA patients on monotherapy DMARDs at baseline were noted among older patients, patients in certain geographic region of the United States, and patients with less generous prescription drug benefits. Although future research should examine the impact of these disparities on health outcomes, payers should be aware of the potential for undertreatment among these groups of RA patients when making formulary decisions.
22679301 Induction therapy with a combination of DMARDs is better than methotrexate monotherapy: fi 2013 Jan OBJECTIVE: To determine the most effective induction disease-modifying antirheumatic drug (DMARD) strategy in early rheumatoid arthritis (RA), second to compare one single dose of intramuscular glucocorticoids (GCs) with daily oral GCs during the induction phase. METHODS: The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis (tREACH) were used. Patients were included who had a high probability (>70%) of progressing to persistent arthritis, based on the prediction model of Visser. Patients were randomised into three induction therapy strategies: (A) combination therapy (methotrexate (MTX) + sulfasalazine + hydroxychloroquine) with GCs intramuscularly; (B) combination therapy with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. A total of 281 patients were randomly assigned to strategy (A) (n=91), (B) (n=93) or (C) (n=97). RESULTS: The Disease Activity Score (DAS) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy (0.39 (0.67 to 0.11, 95% CI)). DAS did not differ between the different GC bridging treatments. After 3 months 50% fewer biological agents were prescribed in the combination therapy groups. Although the proportion of patients with medication adjustments differed significantly between the treatment arms, no differences were seen in these adjustments due to adverse events after stratification for drug. CONCLUSION: Triple DMARD induction therapy is better than MTX monotherapy in early RA. Furthermore, no differences were seen in medication adjustments due to adverse events after stratification for drug. Intramuscular and oral GCs are equally effective as bridging treatments and both can be used.
23440041 Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a stron 2013 Mar 11 Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II-driven T cell help, remain unclarified. To address these questions, we have used a single B cell-based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA(+) RA patients, whereas such antibodies were not found in ACPA(-) patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA(+) antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.
25433043 An outsourced health-enhancing physical activity programme for people with rheumatoid arth 2015 Jun OBJECTIVES: The aims of this study were to document adherence to and changes in health-enhancing physical activity (HEPA) levels and self-reported and assessed functioning and to explore aspects of adherence and response during the first year of an outsourced 2-year HEPA programme in people with RA. METHODS: Two-hundred and twenty patients participated in this observational cohort study, which included daily physical activity, twice-weekly circuit training and biweekly support group meetings. Self-reported data included current (past week) and maintained (past 6 months) HEPA levels, sociodemographics and disease-related and psychosocial factors. Tests of aerobic capacity and muscle function were performed and anthropometric data were collected. RESULTS: Eighty-eight per cent of the participants completed 1 year assessments. Self-reported current and maintained HEPA increased. General health perception and a number of other self-reported disease-related and psychosocial factors improved, while exercise self-efficacy declined. Aerobic capacity, timed standing and grip strength improved and waist circumference decreased. The mean number of circuit training sessions performed was 48, the mean number of days with HEPA was 189 and the mean number of support group meetings attended was 9. Better adherence to circuit training improved general health, and better adherence to group meetings improved timed standing. Exercise self-efficacy improved among those adhering more to circuit training or support group meetings. CONCLUSION: The outsourced HEPA programme had high retention and reasonable adherence. A number of health outcomes improved. Relationships between adherence to the programme components and response were not clear-cut and need further attention. TRIAL REGISTRATION: ISRCTN register; http://www.controlled-trials.com. Trial registration number ISRCTN25539102.
24177275 APL-1, an altered peptide ligand derived from human heat-shock protein 60, selectively ind 2013 Dec Rheumatoid arthritis (RA) is a chronic T-cell mediated autoimmune disease that affects primarily the joints. The induction of immune tolerance through antigen-specific therapies for the blockade of pathogenic CD4+ T cells constitutes a current focus of research. In this focus it is attempted to simultaneously activate multiple regulatory mechanisms, such as: apoptosis and regulatory T cells (Tregs). APL-1 is an altered peptide ligand derived from a novel CD4+ T-cell epitope of human heat-shock protein of 60kDa, an autoantigen involved in the pathogenesis of RA. Previously, we have reported that APL-1 induces CD4+ CD25(high)Foxp3+ Tregs in several systems. Here, we investigated the ability of APL-1 in inducing apoptosis in PBMCs from RA patients, who were classified as active or inactive according to their DAS28 score. APL-1 decreased the viability of PBMCs from active but not from inactive patients. DNA fragmentation assays and typical morphological features clearly demonstrated that APL-1 induced apoptosis in these cells. Activated CD4+ CD25+ T cells but not resting CD4+ CD25- T cells were identified as targets of APL-1. Furthermore, CD4+ T-cell responses to APL-1 were found to be dependent on antigen presentation via the HLA-DR molecule. Thus, APL-1 is a regulatory CD4+ T cell epitope which might modulate inflammatory immune responses in PBMCs from RA patients by inducing CD4+ CD25(high)Foxp3+ Tregs and apoptosis in activated CD4+ T cells. These results support further investigation of this candidate drug for the treatment of RA.
23532053 Matching by propensity score in cohort studies with three treatment groups. 2013 May BACKGROUND: Nonrandomized pharmacoepidemiology generally compares one medication with another. For many conditions, clinicians can benefit from comparing the safety and effectiveness of three or more appropriate treatment options. We sought to compare three treatment groups simultaneously by creating 1:1:1 propensity score-matched cohorts. METHODS: We developed a technique that estimates generalized propensity scores and then creates 1:1:1 matched sets. We compared this methodology with two existing approaches-construction of matched cohorts through a common-referent group and a pairwise match for each possible contrast. In a simulation, we varied unmeasured confounding, presence of treatment effect heterogeneity, and the prevalence of treatments and compared each method's bias, variance, and mean squared error (MSE) of the treatment effect. We applied these techniques to a cohort of rheumatoid arthritis patients treated with nonselective nonsteroidal anti-inflammatory drugs, COX-2 selective inhibitors, or opioids. RESULTS: We performed 1000 simulation runs. In the base case, we observed an average bias of 0.4% (MSE × 100 = 0.2) in the three-way matching approach and an average bias of 0.3% (MSE × 100 = 0.2) with the pairwise technique. The techniques showed differing bias and MSE with increasing treatment effect heterogeneity and decreasing propensity score overlap. With highly unequal exposure prevalences, strong heterogeneity, and low overlap, we observed a bias of 6.5% (MSE × 100 = 10.8) in the three-way approach and 12.5% (MSE × 100 = 12.3) in the pairwise approach. The empirical study displayed better covariate balance using the pairwise approach. Point estimates were substantially similar. CONCLUSIONS: Our matching approach offers an effective way to study the safety and effectiveness of three treatment options. We recommend its use over the pairwise or common-referent approaches.
24351518 Gastrointestinal events in at-risk patients starting non-steroidal anti-inflammatory drugs 2015 Apr OBJECTIVES: Data concerning rates of gastrointestinal (GI) events in non-steroidal anti-inflammatory drug (NSAID) users derive mainly from clinical trials. The EVIDENCE study quantified the incidence of symptomatic uncomplicated and/or complicated GI events in at-risk European patients treated with NSAIDs in real-life practice. METHODS: This non-interventional study assessed 4144 adults with at least one GI risk factor who recently initiated NSAID therapy for osteoarthritis (85%), rheumatoid arthritis (11%), ankylosing spondylitis (3%) or a combination (1%). Patient characteristics and medical history were collected from medical records. GI events (upper and lower) were recorded at in-clinic visits during 6 months' follow-up. RESULTS: Mean time on index NSAID at enrolment was 33 days. The incidence (per 100 person-years) was 18.5 per 100 person-years for uncomplicated GI events and 0.7 per 100 person-years for complicated GI events. Upper GI events were far more common (12%) than lower GI events (1%) during study follow-up (median 182 days (range 61-320)). Other reported rates for cardiovascular, anaemia or non-GI events were much less frequent. A minority (28%) of patients had ongoing proton pump inhibitor use at enrolment, with strong variation by practice and country. CONCLUSIONS: EVIDENCE is the largest prospective study of the real-life management of European patients treated with NSAIDs for rheumatic diseases and at increased GI risk. It shows that GI events from the upper GI tract are far more common than those from the lower GI tract. It also shows adherence to guidelines for gastroprotection is generally low. CLINICALTRIALSGOV IDENTIFIER: NCT01176682.