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ID PMID Title PublicationDate abstract
23925554 Safety of joint and soft tissue injections in patients on warfarin anticoagulation. 2013 Dec Performance of joint and soft tissue injections in patients receiving anticoagulation is subject to different protocols, some of which suggest continuing treatment within the therapeutic range, while others recommend stopping the treatment prior to procedures. The aim of this study was to evaluate the safety of two approaches to the management of patients prescribed warfarin requiring joint or soft tissue injection. A systematic literature review on this subject was undertaken. Our departmental protocol was changed from one where anticoagulation treatment was temporarily stopped prior to joint/soft tissue injection to one where treatment was continued in the context of a therapeutic international normalised ratio (INR) level within 24 h of the procedure. In patients in whom warfarin was withheld, 32 procedures were performed in 18 patients (13 rheumatoid arthritis, 11 osteoarthritis, 5 spondyloarthritis and 1 each of adhesive capsulitis, rotator cuff tendinopathy and trochanteric bursitis). Of these, 30 were joint injections and 2 were soft tissue injections. In patients who continued warfarin, 32 procedures were performed in 21 patients (11 rheumatoid arthritis, 7 osteoarthritis, 6 crystal arthritis, 4 rotator cuff tendinopathy, 2 spondyloarthritis and 1 each of adhesive capsulitis and carpal tunnel syndrome). Of these, 27 were joint injections and 5 were soft tissue injections. There were no clinical hemarthroses or complications in either group. Joint and soft tissue injections appear to be safe in patients receiving warfarin anticoagulation with an INR <3. Continuation of anticoagulants reduces staff workload and patient inconvenience with no evidence of increased risk of complications.
24297380 Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecho 2015 Feb OBJECTIVES: Studies in rheumatoid arthritis (RA), osteoarthritis (OA) and mice with arthritis demonstrated tyrosine hydroxylase-positive (TH(+)) cells in arthritic synovium and parallel loss of sympathetic nerve fibres. The exact function of TH(+) cells and mode of TH induction are not known. METHODS: Synovial cells of RA/OA were isolated and cultured under normoxic/hypoxic conditions with/without stimulating enzyme cofactors of TH and inhibitors of TH. We studied TH expression and release of cytokines/catecholamines. In vivo function was tested by cell therapy with TH(+) neuronal precursor cells (TH(+) neuronal cells) in DBA/1 mice with collagen type II-induced arthritis (CIA). RESULTS: Compared with normoxic conditions, hypoxia increased TH protein expression and catecholamine synthesis and decreased release of tumour necrosis factor (TNF) in OA/RA synovial cells. This inhibitory effect on TNF was reversed by TH inhibition with α-methyl-para-tyrosine (αMPT), which was particularly evident under hypoxic conditions. Incubation with specific TH cofactors (tetrahydrobiopterin and Fe(2+)) increased hypoxia-induced inhibition of TNF, which was also reversed by αMPT. To address a possible clinical role of TH(+) cells, murine TH(+) neuronal cells were generated from mesenchymal stem cells. TH(+) neuronal cells exhibited a typical catecholaminergic phenotype. Adoptive transfer of TH(+) neuronal cells markedly reduced CIA in mice, and 6-hydroxydopamine, which depletes TH(+) cells, reversed this effect. CONCLUSIONS: The anti-inflammatory effect of TH(+) neuronal cells on experimental arthritis has been presented for the first time. In RA/OA, TH(+) synovial cells have TH-dependent anti-inflammatory capacities, which are augmented under hypoxia. Using generated TH(+) neuronal cells might open new avenues for cell-based therapy.
24014115 Activin A: a potential therapeutic target for characterizing and stopping joint pain early 2014 Feb It is common for rheumatoid arthritis patients to suffer from persistent joint pain for decades during their lifetime. Activin A, a member of the transforming growth factor β superfamily, which plays a role in the very early phase of inflammatory processes, can also induce pain behaviors. In view of the contribution of synovial inflammation to the progression of rheumatoid arthritis, here we present the hypothesis that activin A may be a potential therapeutic target, serving as a marker for joint pain in which inflammatory processes are involved and as a target for early intervention.
25545293 Increased expression of human leucocyte antigen class I free heavy chains on monocytes of 2015 Feb Human leucocyte antigen (HLA)-B27 expression is correlated with spondyloarthritis (SpA), but its role in disease pathogenesis remains unclear. The aim of the study was to determine whether HLA-B27 free heavy chain (FHC) contributes to SpA pathogenesis. Flow cytometry was used to analyse the FHC expression on CD3+ and CD14+ cells in the peripheral blood (PB) and synovial fluid (SF) from SpA patients, healthy controls, and rheumatoid arthritis (RA) patients. Human monocytic U937 cell lines stably expressing enhanced green fluorescence protein (EGFP)/HLA-B27, EGFP/HLA-A2 or EGFP alone were created to further investigate the relation between HLA-B27 and FHC expression. The relative FHC level on CD14+ PB cells was significantly higher in SpA patients than in controls, but lower than on the SF cells of SpA patients. No significant correlation was found for relative FHC expression with HLA-B27 or β2-microglobulin expression. HLA-B27-transfected U937 cells expressed higher FHC levels than either EGFP/HLA-A2- or EGFP-transfected cells. HLA class I FHC expression was significantly increased on monocytes of SpA patients and HLA-B27-transfected cells, implying that FHC, perhaps mostly derived from HLA-B27, plays an important role in SpA pathogenesis.
24314260 FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis. 2013 INTRODUCTION: The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients. METHODS: The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab. RESULTS: Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy. CONCLUSIONS: The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
24884566 Single nucleotide polymorphisms in TNFAIP3 were associated with the risks of rheumatoid ar 2014 May 15 BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive inflammation in synovial joints. It is well known that genetic and environmental risk factors and their interaction contribute to RA pathogenesis. This study aimed to investigate the association between the critical polymorphisms in the tumor necrosis factor α (TNFα)-induced protein 3(TNFAIP3) gene and the risk of RA in a large northern Chinese Han population. METHODS: A case-control study of 1280 RA patients and 1280 matched healthy controls was conducted. RESULTS: This study showed that carriers of the rs2230926 TG genotype or rs10499194 CT genotype had an increased risk for RA compared with those carrying the wild genotype (rs2230926: OR = 1.48, 95% CI = 1.17-1.86, p = 0.001; rs10499194: OR = 2.00, 95% CI = 1.46-2.74, p < 0.001). The combined rs2230926TG/GG or rs10499194 CT/TT were associated with an increased risk of RA (ORs were 1.50 and 2.01, 95% CIs were 1.19-1.88 and 1.47-2.74, respectively, both p < 0.001). There was not significant association between rs13207033 polymorphism and RA risk. Subset analysis stratified to gender showed that the increased risks were significant among the genotypes TG, TG/GG of rs2230926 and CT, CT/TT of rs10499194 and the corresponding ORs were 1.42 (95%  CI = 1.10-1.83, p = 0.006), 1.44(95% CI = 1.12-1.85, p = 0.004), 1.52(95% CI = 1.05-2.20, p = 0.026) and 1.52(95% CI = 1.06-2.19, p = 0.023) in the female population. Stratified analyses by age found that rs2230926(TG, TG/GG) and rs10499194(CT, CT/TT) polymorphisms were associated with RA risks in population ≤53 years old and among >53 years old only rs10499194(CT, TT, CT/TT) polymorphism had significant results. The interaction analysis suggested that individuals with both risk genotypes of the two SNPs have a higher elevated risk of RA than those with only one of them (ORs were 3.44 compared to 1.74 and 1.35). The haplotype results showed that individuals with the rs2230926G-rs13207033G-rs10499194C haplotype were associated with increased risks of RA (OR = 1.37, 95% CI = 1.08-1.74, p = 0.010). CONCLUSIONS: Rs10499194 and rs2230926 polymorphisms in the TNFAIP3 gene region may be susceptibility factors for rheumatoid arthritis in the northern Chinese Han population.
24643522 The metastasis-associated protein S100A4 promotes the inflammatory response of mononuclear 2014 Aug OBJECTIVES: S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12. The production of IL-1β, IL-6 and TNF-α was measured by ELISA. Receptor for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4) signalling were examined. For signalling pathway blocking studies, inhibitors of myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-κB) and the mitogen activated protein (MAP) kinases p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) were used. MAP kinase activation was evaluated by western blotting. RESULTS: Stimulation of PBMCs with S100A4 significantly up-regulated IL-1β, IL-6 and TNF-α production compared with unstimulated cells (P < 0.001). Importantly, the production of these cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12; however, it was less pronounced compared with S100A9. Furthermore, enhanced production of proinflammatory cytokines in S100A4-stimulated PMBCs was at least partly mediated via TLR4, but not RAGEs, and by activation of the transcription factor NF-κB and the MAP kinases p38 and ERK1/2. CONCLUSION: This is the first study to demonstrate that S100A4 can induce an inflammatory response mediated by TLR4 and by the activation of NF-κB and the kinases p38 and ERK1/2 in mononuclear cells from patients with RA. Therefore S100A4 may be a potential therapeutic target for immune-mediated diseases.
23417288 Micro-RNAs in inflammatory diseases and as a link between inflammation and cancer. 2013 Apr OBJECTIVE: The objective of this review is to examine the role of miRNA in various inflammatory diseases and in inflammatory diseases progressing to cancer. INTRODUCTION: MicroRNAs are small, conserved, non-coding RNA molecules which are present in most of the eukaryotes. miRNA have been reported to play a major role in the physiological control of gene expression and in the pathogenesis of various diseases. They regulate the gene expression mainly at the post-transcriptional level. miRNA expression profile is reported to be altered in various inflammatory diseases and subsequently affects the expression of genes, which is important in disease pathogenesis. METHODS: A Pubmed database search was performed for studies related to miRNA studies in inflammatory disease, cancer and in inflammatory diseases progressing to cancer. CONCLUSION: The evidence shows very important role of miRNA in inflammatory diseases. Few miRNAs involved in common inflammatory process and suggest miRNA as a link between inflammation and cancer. Future research should be directed to use miRNA therapeutically to target common inflammatory pathway and to develop miRNA as biomarker to detect development of cancer at early stages.
24012043 Comparative cancer risk associated with methotrexate, other non-biologic and biologic dise 2014 Feb OBJECTIVE: There is little information comparing the potential risk of cancer across conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Methotrexate has not been the focus of most contemporary pharmacoepidemiologic studies of cancer. METHODS: We conducted a comparative effectiveness study with cancer as the outcome. A large observational cohort of RA was followed up from 2001 to 2010. Reports of any cancer prompted a confirmation process that included adjudication of the primary cancer records. We used a propensity score (PS) with relevant covariates and cohort trimming to improve the balance between DMARD cohorts. Cox proportional hazard regression models were constructed to estimate the risk of cancer with various DMARDs, all compared with methotrexate. RESULTS: We identified 6806 DMARD courses for analysis (1566 methotrexate; 904 nbDMARDs; 3761 TNF antagonists; 408 abatacept; and 167 rituximab). Non-biologic DMARDs (HR 0.17, 95% CI 0.05-0.65) and TNF antagonists (HR 0.29, 95% CI 0.05-0.65) were associated with a reduced adjusted risk of cancer compared with methotrexate. Abatacept (HR 1.55, 95% CI 0.40-5.97) and rituximab (HR 0.42, 95% CI 0.07-2.60) were similar in risk of cancer with methotrexate. These results were robust to sensitivity analyses. After controlling for DMARD exposures, risk factors for cancer included male gender, age, and alcohol consumption. CONCLUSIONS: Cancer risk was elevated for methotrexate users compared with nbDMARDs and TNF antagonists.
25677586 Anti-tumor necrosis factor patent expiration and the risks of biocopies in clinical practi 2014 Dec 6 Biosimilars that were not compared in clinical trials with the compound innovator are not true biosimilars (biocopies) and are associated with risks that the clinical rheumatologist should be aware of before generalized use. This article comments on various aspects surrounding the use of such biocopies in clinical rheumatology.
24626307 The use of Mycobacterium tuberculosis HspX and GlcB proteins to identify latent tuberculos 2014 Feb Rheumatoid arthritis (RA) is an autoimmune disease characterised by the destruction of articular cartilage and bone damage. The chronic treatment of RA patients causes a higher susceptibility to infectious diseases such as tuberculosis (TB); one-third of the world's population is latently infected (LTBI) with Mycobacterium tuberculosis (Mtb). The tuberculin skin test is used to identify individuals LTBI, but many studies have shown that this test is not suitable for RA patients. The goal of this work was to test the specific cellular immune responses to the Mtb malate synthase (GlcB) and heat shock protein X (HspX) antigens of RA patients and to correlate those responses with LTBI status. The T-helper (Th)1, Th17 and Treg-specific immune responses to the GlcB and HspX Mtb antigens were analysed in RA patients candidates for tumour necrosis factor-α blocker treatment. Our results demonstrated that LTBI RA patients had Th1-specific immune responses to GlcB and HspX. Patients were followed up over two years and 14.3% developed active TB. After the development of active TB, RA patients had increased numbers of Th17 and Treg cells, similar to TB patients. These results demonstrate that a GlcB and HspX antigen assay can be used as a diagnostic test to identify LTBI RA patients.
24840205 A systematic critical appraisal of non-pharmacological management of rheumatoid arthritis 2014 Clinical practice guidelines (CPGs) have been developed to summarize evidence about the management of rheumatoid arthritis (RA) and facilitate the uptake of evidence-based knowledge by consumers, health professionals, health administrators and policy makers. The objectives of this review was to assess the quality of CPGS on non-pharmacological management of RA with a standardized and validated instrument--the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool and summarize the key recommendations from these CPGs. Scientific literature databases from 2001 to 2013 were systematically searched and a total of 13 CPGs for RA was identified. Only a minority of AGREE II domains were effectively addressed by the CPGS. Scope and purpose was effectively addressed in 10 out of 13 CPGs, stakeholder involvement in 11 CPGs, rigor of development in 6 CPGs, clarity/presentation in 9 CPGs, editorial independence in 1 CPGs, and applicability in none of the CPGs. The overall quality of the included CPGs according to the 7-point AGREE II scoring system was 4.8 ± 1.04. Patient education/self-management, aerobic, dynamic and stretching exercises were the commonly recommended for the non-pharmacological management of RA by the high-quality CPGs. The general clinical management recommendations tended to be similar among high-quality CPGs. Non-pharmacological management interventions were superficially addressed in more than half of the selected CPGs. CPGs creators should use the AGREE II criteria when developing guidelines. Innovative and effective methods of CPGs implementation to users are needed to ultimately enhance the quality of life of arthritic individuals. In addition, it was difficult to establish between strongly recommended, recommended and weakly recommended, as there is no consensus between the strength of the recommendations between the appraised CPGs.
23238979 Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid 2013 Jan OBJECTIVES: To quantify the risk of cancer and compare it with that for the general population in a modern cohort of UK patients with RA and to identify risk factors for cancer among this cohort. METHODS: The study population comprised biologic-naïve RA subjects receiving non-biologic disease-modifying therapy recruited to the British Society for Rheumatology Biologics Register from 2002 to 2009. Standardized incidence ratios (SIRs) for cancers were calculated using age- and gender-specific cancer rates in the English population. Poisson regression models adjusted for age and gender using England general population data were used to determine the association of other predictors with incident malignancy. RESULTS: The cohort comprised 3771 individuals with RA contributing 13 315 person-years of follow-up. One hundred and eighty-two cancers were reported: 156 solid and 26 myelo- or lymphoproliferative cancers. The overall SIR was 1.28 (95% CI 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and non-Hodgkin lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were higher compared with the general population and risks of prostate cancer (SIR 0.35, 95% CI 0.11, 0.82) and cancers of the female genital organs (SIR 0.35, 95% CI 0.10, 0.90) were reduced. Within the cohort, cancer risk was more than 2-fold higher in current or ex-smokers than in non-smokers. CONCLUSION: The overall incidence of cancer was increased in this national cohort of subjects with RA. The association of RA with certain cancers needs to be considered when studying the effects of biologic therapy, such as anti-TNF, on cancer risk.
24814038 Hempseed oil induces reactive oxygen species- and C/EBP homologous protein-mediated apopto 2014 Jul 3 ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal efficacy of hempseed (Cannabis sativa L.), which is rich in polyunsaturated fatty acids, in atopic dermatitis, inflammation, and rheumatoid arthritis (RA) has been suggested for centuries. Hempseed has been used as a treatment for these diseases in Korean and Chinese folk medicine. The aim of the study is to investigate the effects of hempseed oil (HO) on MH7A human RA fibroblast-like synovial cells. MATERIALS AND METHODS: MH7A cells were used to study the anti-rheumatoid effects of hempseed (Cannabis sativa L., cv. Cheungsam/Cannabaceae) oil by investigating cell viability, apoptosis, lipid accumulation, oxidative stress, and endoplasmic reticulum (ER) stress-induced apoptosis. RESULTS: HO treatment reduced the survival rate of MH7A cells and promoted apoptotic cell death in a time- and dose-dependent manner. Both lipid accumulation and the level of intracellular reactive oxygen species (ROS) increased in HO-treated MH7A cells. Co-treatment with the antioxidant Tiron effectively abrogated the cytotoxic effects of HO; the ROS level was reduced, cell viability was recovered, and apoptotic cell death was significantly diminished. Moreover, HO-treated cells exhibited increased expression of the major ER stress markers, glucose-regulated protein 78 and C/EBP homologous protein (CHOP). The siRNA-mediated knockdown of CHOP prevented HO-induced apoptosis. CONCLUSIONS: Our results suggest that HO treatment induced lipid accumulation, ROS production, CHOP expression, and apoptosis in MH7A cells, and that CHOP functions as an anti-rheumatoid factor downstream of HO in MH7A cells.
24708642 Development of a new occupational balance-questionnaire: incorporating the perspectives of 2014 Apr 5 BACKGROUND: Self-reported outcome instruments in health research have become increasingly important over the last decades. Occupational therapy interventions often focus on occupational balance. However, instruments to measure occupational balance are scarce. The aim of the study was therefore to develop a generic self-reported outcome instrument to assess occupational balance based on the experiences of patients and healthy people including an examination of its psychometric properties. METHODS: We conducted a qualitative analysis of the life stories of 90 people with and without chronic autoimmune diseases to identify components of occupational balance. Based on these components, the Occupational Balance-Questionnaire (OB-Quest) was developed. Construct validity and internal consistency of the OB-Quest were examined in quantitative data. We used Rasch analyses to determine overall fit of the items to the Rasch model, person separation index and potential differential item functioning. Dimensionality testing was conducted by the use of t-tests and Cronbach's alpha. RESULTS: The following components emerged from the qualitative analyses: challenging and relaxing activities, activities with acknowledgement by the individual and by the sociocultural context, impact of health condition on activities, involvement in stressful activities and fewer stressing activities, rest and sleep, variety of activities, adaptation of activities according to changed living conditions and activities intended to care for oneself and for others. Based on these, the seven items of the questionnaire (OB-Quest) were developed. 251 people (132 with rheumatoid arthritis, 43 with systematic lupus erythematous and 76 healthy) filled in the OB-Quest. Dimensionality testing indicated multidimensionality of the questionnaire (t = 0.58, and 1.66 after item reduction, non-significant). The item on the component rest and sleep showed differential item functioning (health condition and age). Person separation index was 0.51. Cronbach's alpha changed from 0.38 to 0.57 after deleting two items. CONCLUSIONS: This questionnaire includes new items addressing components of occupational balance meaningful to patients and healthy people which have not been measured so far. The reduction of two items of the OB-Quest showed improved internal consistency. The multidimensionality of the questionnaire indicates the need for a summary of several components into subscales.
24567922 Inter & intra-observer reliability of grading ultrasound videoclips with hand pathology in 2014 Mar AIM: To evaluate the inter- and intraobserver agreement of a group of European rheumatologist ultrasonographers in grading musculoskeletal ultrasound videoclips posted on the Internet by using a non-sophisticated electronic environment. METHODS: Forty short movie clips (less than 30 secs) were made available over the Internet to all participants. Normal and pathological RA hand joints and tendons were included in the movie clips. In the first phase 30 investigators from European countries were invited to evaluate the clips and to interpret/grade them. No instruction session was held prior to the initiation of the study. For synovitis the requested scoring system included 0 to3 grades and for tenosynovitis a binary variable 0/1; separate evaluations were performed for gray scale (GS) and Power Doppler (PD) examinations. In the second phase the responders were asked to grade the same clips in a different order without having access to their first grading scale. Light's k and Cohen's k were used to analyse inter- and intraobserver reliability. RESULTS: Twenty two European rheumatologists agreed to finalise both study phases. Mean Cohen's κ for intraobserver reliability was 0.614/0.689 for tenosynovitis GS/PD and 0.523/0.621 for synovitis GS/PD. Light's k for interobserver reliability was 0.503 for tenosynovitis evaluation and 0.455 for global (synovitis and tenosynovitis) evaluation. Mean global overall agreement was 84.95% (90.2% for global synovitis). CONCLUSIONS: An over-the-net US evaluation and grading has shown moderate to good reliability. The results could be improved if a training session is added at the beginning of the study.
23918037 Long-term safety and efficacy of certolizumab pegol in combination with methotrexate in th 2014 Dec OBJECTIVES: To examine the safety and efficacy of 5-year administration of certolizumab pegol (CZP)+methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Eligible patients from the Rheumatoid Arthritis Prevention of Structural Damage (RAPID)1 randomised controlled trial (RCT) were treated in open-label extension (OLE) with CZP 400 mg every other week (Q2W), reduced to 200 mg Q2W after ≥6 months, +MTX. Combined safety data from RCT and OLE are presented from initiation of CZP treatment to 12 wks post last visit in patients receiving ≥1 dose of CZP (Safety population, N=958). Efficacy data are presented to start of first site closure (wk 256 of CZP treatment: 52 wks in RCT+204 wks in OLE) for all patients randomised to receive CZP (intent-to-treat (ITT) population, N=783) and CZP patients who completed the 52 wk RCT and enrolled into OLE (wk 52 CZP completers, N=508). Disease Activity Score (DAS)28 (Erythrocyte Sedimentation Rate (ESR)), American College of Rheumatology Criteria (ACR) 20/50/70, Health Assessment Questionnaire - Disability Index (HAQ-DI), and patient retention (Kaplan-Meier analysis) were assessed. RESULTS: Overall event rate per 100 patient-years (ER) of adverse events (AEs) was 290.4, most frequently: urinary tract infections (ER=7.9), nasopharyngitis (ER=7.3) and upper respiratory tract infections (ER=7.3). ER of serious AEs was 20.3 (infections=5.9, malignancies=1.2). 21 patients (2.2%) experienced an AE resulting in death (incidence rate=0.6). At wk 256 of treatment, 55.3% of the CZP ITT population were estimated to remain on treatment (68.7% if solely withdrawals due to AE or lack of efficacy were considered). In wk 52 CZP completers and CZP ITT population, DAS28 (ESR) remission rates and improvements from baseline were sustained to wk 256. CONCLUSIONS: CZP+MTX treatment provided a favourable risk-benefit profile over 5 years in patients with active RA. No new safety signals were identified.
23934388 Perspectives of the relationship between IL-7 and autoimmune diseases. 2013 Dec Interleukin (IL)-7 is one of the IL-2 family cytokines comprised of IL-2, IL-4, IL-7, IL-9, IL-15, as well as IL-21. IL-7 is mainly secreted by stroma cells in primary lymphoid tissues, playing an essential role in the program of T cell development. Recently, studies have revealed that physiological function exerted by immunocytes can be influenced by aberrant IL-7 signaling, which is common in abnormal autoimmunity regulation. There is also increasing evidence that IL-7 is involved in several autoimmune diseases, such as rheumatoid arthritis, type I diabetes, multiple sclerosis and systemic lupus erythematosus, etc. Targeting components in IL-7 signaling pathways may have potential significance for treating numerous autoimmune diseases. In this review, we therefore summarize our current understandings regarding the relationship between IL-7 and autoimmune diseases so as to render more valuable information on this kind of research.
24664592 Evening primrose oil and celecoxib inhibited pathological angiogenesis, inflammation, and 2014 Oct Rheumatoid arthritis is a chronic inflammatory disease characterized by overproduction of inflammatory mediators along with undermined oxidative defensive mechanisms. Pathological angiogenesis was found to play a critical role in the progression of this disease. The current study was carried out to evaluate the anti-angiogenic, anti-inflammatory, and anti-oxidant effects of evening primrose oil (EPO), rich in gamma linolenic acid (GLA), either alone or in combination with aspirin or celecoxib, on adjuvant-induced arthritis. Arthritis was induced by subcutaneous injection of complete Freund's adjuvant (CFA) in the right hind paw of male albino rats. All treatments were administered orally from day 0 (EPO, 5 g/kg b.w.) or day 4 (celecoxib, 5 mg/kg; aspirin, 150 mg/kg) till day 27 after CFA injection. In the arthritic group, the results revealed significant decrease in the body weight and increase in ankle circumference, plasma angiopoietin-1 (ANG-1) and tumor necrosis factor-alpha (TNF-α) levels. Anti-oxidant status was suppressed as manifested by significant decline in reduced glutathione content along with decreased enzymatic activity of superoxide dismutase and increased lipid peroxidation. Oral administration of EPO exerted normalization of body weight, ANG-1, and TNF-α levels with restoration of activity as shown by reduced malondialdehyde levels. Moreover, histopathological examination demonstrated that EPO significantly reduced the synovial hyperplasia and inflammatory cells invasion in joint tissues, an effect that was enhanced by combination with aspirin or celecoxib. The joint use of GLA-rich natural oils, which possess anti-angiogenic, anti-inflammatory, and anti-oxidant activities, with traditional analgesics represents a promising strategy to restrain the progression of rheumatoid arthritis.
24688026 JAK2-STAT3 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regula 2014 May 1 IL-6-mediated STAT3 signaling is essential for Th17 differentiation and plays a central role in the pathogenesis of rheumatoid arthritis. To investigate the molecular mechanism underlying the antirheumatic effects and T cell regulatory effects of STAT3 inhibition, we studied the effects of the JAK 2 inhibitor AG490 on Th17 cell/regulatory T cell (Treg) balance and osteoclastogenesis. AG490 was administered to mice with collagen-induced arthritis (CIA) via i.p. injection, and its in vivo effects were determined. Differential expression of proinflammatory cytokines, including IL-17A, IL-1β, and IL-6, was analyzed by immunohistochemistry. Levels of phosphorylated STAT3 and STAT5 and differentiation of Th17 cells and Tregs after AG490 treatment in our CIA model were analyzed by immunostaining. In vitro development of Th17 cells and Tregs was analyzed by flow cytometry and real-time PCR. AG490 ameliorated the arthritic phenotype in CIA and increased the proportion of Foxp3(+) Tregs. In contrast, the proportion of IL-17A-producing T cells and levels of inflammatory markers were reduced in AG490-treated mice. Numbers of p-STAT3(+) CD4(+) T cells and p-STAT5(+) CD4(+) T cells were reduced and elevated, respectively, after treatment with AG490. Furthermore, AG490 markedly increased the expression of molecules associated with Treg development (ICOS, programmed cell death protein 1, ICAM-1, and CD103). The development and function of osteoclasts were suppressed by AG490 treatment. Our results suggest that AG490, specifically regulating the JAK2/STAT3 pathway, may be a promising treatment for rheumatoid arthritis.