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ID PMID Title PublicationDate abstract
24832108 TL1A increased the differentiation of peripheral Th17 in rheumatoid arthritis. 2014 Sep The interaction between TNF-like protein 1A (TL1A) and its receptors, death receptor-3 (DR3) may be involved in the pathogenesis of rheumatoid arthritis (RA) through the regulation of Th17. Our data here showed that TL1A could significantly promote Th17 differentiation and RORc mRNA expression from naive T cells and enhance IL-17A level in cell supernatant in RA patients. Anti-TNF-α treatment had suppressive effects on TL1A-mediated Th17 differentiation and RORc mRNA expression. In addition, The percentage of peripheral CD4+DR3+T cells of RA was significantly higher than that of healthy controls (HC), and this increased percentage of CD4+DR3+T cells was obviously up-regulated when stimulated with anti-CD3 and anti-CD28 antibody in RA patients. However, anti-CD3 and anti-CD28 antibody stimulation did not increase the percentage of CD4+DR3+IL-17A+T cells in RA patients. These results suggested that TL1A could promote Th17 differentiation in RA via the activation of RORc, and this effect may be mediated by the binding of TL1A with DR3.
22906768 Emerging role of interleukin-22 in autoimmune diseases. 2013 Feb Interleukin-22 (IL-22) is an IL-10 family cytokine member that was recently discovered to be mainly produced by Th17 cells. Previous studies have indicated the importance of IL-22 in host defense against Gram-negative bacterial organisms (in gut and lung). Recently, there is emerging evidence that IL-22 is involved in the development and pathogenesis of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), Sjögren's syndrome (SS) and psoriasis. Therapeutics targeting IL-22 therefore may have promise for treating various autoimmune diseases. In this review, we discuss the recent progression of the involvement of IL-22 in the development and pathogenesis of autoimmune diseases, as well as its clinical implications and therapeutic potential.
23172753 The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in h 2013 Jul BACKGROUND: In rheumatoid arthritis (RA), neutrophil granulocytes fuel inflammation and damage tissue in the joint by releasing cytotoxic agents, antimicrobial peptides, proteases and other inflammatory mediators. The human cathelicidin LL-37 has recently been implicated in the development of systemic lupus erythematosus and psoriasis. OBJECTIVE: To elucidate if antimicrobial peptides (AMPs) contribute to the pathogenesis of arthritis. METHODS: Expression of LL-37 was determined in synovial membranes from patients with arthritis and control subjects. Expression of the rat cathelicidin rCRAMP and defensins was characterised in joints, blood and secondary lymphoid organs during pristane-induced arthritis (PIA) in rats and in a transfer model of PIA induced by CD4 T cells. Serum samples of rats with arthritis were tested for IgG and IgM autoantibodies against rCRAMP by immunoblot and for interferon (IFNα) by ELISA. RESULTS: Cathelicidins are strongly upregulated in RA synovial membranes and in joints from rats with arthritis as compared with healthy joints. Expression was most prominent in neutrophil granulocytes and macrophages/osteoclasts. Cathelicidin expression is also upregulated in the blood and spleen of pristane-injected rats, with strongest expression detected in activated CD62L- cells coexpressing granulocyte and monocyte markers. Pristane injection caused accumulation of low-density granulocytes in the blood. After pristane injection, the increased expression of rCRAMP coincided with higher levels of cell death, raised levels of interferon (IFN)α and development of autoantibodies. CONCLUSIONS: Our results show strong upregulation of cathelicidins and β-defensins coinciding with pathological events of arthritis. Higher expression and release of AMPs might contribute to development and/or maintenance of disease by systemic or local mechanisms.
25246639 Profound reduction in hospital admissions and musculoskeletal surgical procedures for rheu 2015 Apr OBJECTIVES: The aims of this study were to audit the annual national incidence of inpatient days and musculoskeletal surgical procedures (MSKSPs) for RA patients and to establish concurrent changes in clinical rheumatology practice from 1995 to 2010. METHODS: Hospital inpatient enquiry systems were evaluated for 57 hospitals from 1995 to 2010. National annual TNF inhibitor (TNFi) and MTX prescriptions were analysed. Trends were analysed by logistic regression and correlations by Spearman's rho. RESULTS: Fifty-four thousand eight hundred and six RA inpatient records were reviewed from 1995 to 2010 [70% female, mean age 66 years (s.d. 16)]. RA inpatient days decreased from 53 671 in 1995 to 29 000 in 2010 (r(2) = 0.8, P < 0.0001). Inpatient MSKSPs for RA patients decreased from a peak of 370 in 1996 to 188 in 2010 (r(2) = 0.7, P < 0.0001). Knee and hip replacements for the general population annually increased over the past 15 years, yet there was a significant decrease in the annual ratio of hip arthroplasties and knee arthroplasties for RA patients compared with those done for the general population from 1995 to 2010 (r(2) = 0.6, P < 0.001 and r(2) = 0.8, P < 0.01, respectively). Annual national TNFi prescriptions increased from 2389 units in 2000 to 116 747 in 2010. Concurrently MTX prescriptions increased nationally from 3300 in 2001 to 9600 in 2010. During the same period there was an increase in rheumatologists from 15 to 40 and in orthopaedic surgeons from 64 to 88. CONCLUSION: Elective MSKSPs for RA patients have almost halved over the past 15 years, despite an increase in hip and knee arthroplasties for the general population, along with an almost halving of inpatient days for RA patients.
23723317 Evaluation of low-dose rituximab for the retreatment of patients with active rheumatoid ar 2014 Aug BACKGROUND: The licensed dose of rituximab in rheumatoid arthritis (RA) is two doses of 1000 mg given 2 weeks apart. A lower dose has never been specifically studied in patients with an inadequate response to anti-tumour necrosis factor (TNF) agents. OBJECTIVE: To compare the efficacy and safety of rituximab repeat treatment with two doses (1000 mg×1 and 1000 mg×2) following initial treatment with 1000 mg×2. METHODS: We set up an open-label, prospective, multicentre, non-inferiority study comprising a non-controlled period (24 weeks) followed by a randomised controlled period (weeks 24-104) in patients with RA and an inadequate response to anti-TNF agents. All patients received one course of rituximab (1000 mg×2) with methotrexate. At week 24, patients achieving a EULAR response (moderate or good) were randomised to rituximab retreatment at 1000 mg×1 (Arm A) or 1000 mg×2 (Arm B). The primary objective measure was disease activity in 28 joints C-reactive protein (DAS28-CRP) area under the curve (AUC) over 104 weeks with a non-inferiority margin defined by 20% (444) of the mean DAS28-CRP AUC (mean±SD 2218±967) of the reference data. RESULTS: The intent-to-treat and per-protocol (PP) populations comprised 143 (A/B: 70/73) and 100 (A/B: 51/49) patients, respectively. The adjusted mean difference in DAS28-CRP AUC (PP) was 51.4 (95% CI -131.2 to 234), demonstrating non-inferiority between arms A and B. The overall rituximab safety profile was similar with both retreatment regimens. CONCLUSIONS: Following a clinical response to a first course of rituximab in RA at the licensed dose of 1000 mg×2, retreatment with rituximab at 1000 mg×1 results in efficacy outcomes that are non-inferior to those achieved with retreatment at 1000 mg×2. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT01126541.
24433504 Construction of an anti-IL-1β scfv and TNFRI fusion protein and its therapeutic effect on 2014 IL-1β and TNF-α play key roles in the inflammatory response. Their abnormal expression may cause the occurrence of various diseases, such as RA. Recently, medicines of target TNF-α and IL-1β have become popular in the clinical practice. Although these biological agents can get mostly good results, they are not effective in all patients. The reason for this result may be that these biological agents could not fully inhibit a variety of inflammatory cytokines in the inflammatory response. In the present study, a fusion protein gene which encoded human interleukin-1β scfv and soluble TNF receptor I (sTNFRI) was cloned. A number of in vitro assays demonstrated that anti-IL-1β scfv/TNFRI simultaneously bound to both targets. The bioactivity assay showed that the fusion protein could inhibit both the cytotoxicity of hTNF-α on L929 cells and hIL-1β-induced proliferation of L929 cells, indicating that the fusion protein has the ability to neutralize both hTNF-α and hIL-1β. In this study, we established the chicken type II collagen-induced rheumatoid arthritis model in Kunming mice, and evaluated the pharmacological effect of the fusion protein in vivo. Model mice were randomly divided into 8 groups (n=8): CIA model control group, DEX treatment group (1 mg/kg), intraperitoneal treatment group (highdose: 5 mg/kg; medium-dose: 2 mg/kg; low-dose: 0.8 mg/kg), subcutaneous treatment group (high-dose: 5 mg/kg; medium- dose: 2 mg/kg; low-dose: 0.8 mg/kg), and healthy mice as control. The control group received the same volume of saline. The mice were administrated once every 2 days. Arthritis index, anti-CII antibody titers, cytokine levels, histopathological changes were examined. The results showed that anti-IL-1β scfv/TNFRI fusion protein could reduce the degree of joint swelling, inflammatory cell infiltration, synovial cell proliferation and the level of CII antibody in the sera. The Real-time PCR analysis showed that anti-IL-1β scfv/TNFRI had the ability to reduce the expression of IL-1β, TNF-α, IL-17A, MMP-3, IL-6 and improve the expression of IL-10 in a dose-dependent manner, suggesting that the fusion protein is the mediator for IL-1β and TNF-α involved in the RA process. Compared with DEX positive medicine control, anti-IL-1β scfv/TNFRI appeared more beneficial in treatment of CIA mice. The therapeutic effect of the anti-IL-1β scfv/TNFRI at 5mg/kg was significantly better than that of DEX treatment. So the anti-IL-1β scfv/TNFRI can become a candidate for treatment of RA.
25349443 Is serum procalcitonin measurement a useful addition to a rheumatologist's repertoire? A r 2015 Feb Early differentiation between infection and aseptic inflammation is difficult and is a challenge often faced in the rheumatology practice. Procalcitonin (PCT) is a biomarker that is preferentially induced in patients with bacterial infections, and a growing body of evidence supports its use for improving diagnosis of bacterial infections and guiding antibiotic therapy. In this article, we review the evidence for the use of PCT measurement in rheumatology practice. Several studies have examined the use of PCT to assist in the differentiation between septic and non-septic arthritis in patients with an inflamed joint and found it to be a sensitive and specific marker of infection. A number of studies in patients with diverse inflammatory rheumatic diseases have provided useful information regarding the usefulness of PCT in these patients. In summary, PCT when used in the appropriate clinical setting can be a useful adjunct to currently available laboratory infection markers, though further studies are warranted. Furthermore, PCT results should be interpreted in parallel with the clinical assessment.
24943990 Citrullination of epithelial neutrophil-activating peptide 78/CXCL5 results in conversion 2014 Oct OBJECTIVE: To examine whether the citrullinated chemokines epithelial neutrophil-activating peptide 78 (ENA-78)/CXCL5, macrophage inflammatory protein 1α/CCL3, and monocyte chemotactic protein 1/CCL2 are detected in the biologic fluid of patients with rheumatoid arthritis (RA), and if so, to determine the biologic activities of these chemokines. METHODS: Recombinant human chemokines were citrullinated by peptidylarginine deiminase. Enzyme-linked immunosorbent assays were performed to measure the concentrations of citrullinated chemokines in sera from patients with rheumatoid arthritis (RA) and normal individuals and in synovial fluid from patients with RA, patients with osteoarthritis (OA), and patients with other inflammatory rheumatic diseases. The correlation between the citrullinated chemokine levels and clinical data was analyzed. Monocyte and neutrophil chemotaxis assays were performed, and native (noncitrullinated) or citrullinated ENA-78/CXCL5 was injected into mouse knees to evaluate the biologic activities of these chemokines. RESULTS: The concentration of citrullinated ENA-78/CXCL5 was significantly higher in RA sera and SF than in normal sera and in SF from patients with other rheumatic diseases including OA. In RA SF, a strong correlation between the amount of citrullinated ENA-78/CXCL5 and the C-reactive protein level or the erythrocyte sedimentation rate was observed. Citrullinated ENA-78/CXCL5 induced monocyte chemotaxis via CXCR1 and CXCR2, while noncitrullinated ENA-78/CXCL5 did not. In a mouse model of inflammatory arthritis, citrullinated ENA-78/CXCL5 induced more severe inflammation and recruited more monocytes than did noncitrullinated ENA-78/CXCL5. CONCLUSION: Citrullinated ENA-78/CXCL5 is highly correlated with RA disease activity and, unlike noncitrullinated ENA-78/CXCL5, recruits monocytes. These results indicate that citrullinated ENA-78/CXCL5 may exert previously unrecognized inflammatory properties in RA by recruiting monocytes to inflamed joint tissue.
25426976 IgG antibodies to cyclic citrullinated peptides exhibit profiles specific in terms of IgG 2014 The Fc-glycan profile of IgG1 anti-citrullinated peptide antibodies (ACPA) in rheumatoid arthritis (RA) patients has recently been reported to be different from non-ACPA IgG1, a phenomenon which likely plays a role in RA pathogenesis. Herein we investigate the Fc-glycosylation pattern of all ACPA-IgG isotypes and simultaneously investigate in detail the IgG protein-chain sequence repertoire. IgG from serum or plasma (S/P, n = 14) and synovial fluid (SF, n = 4) from 18 ACPA-positive RA-patients was enriched using Protein G columns followed by ACPA-purification on cyclic citrullinated peptide-2 (CCP2)-coupled columns. Paired ACPA (anti-CCP2 eluted IgG) and IgG flow through (FT) fractions were analyzed by LC-MS/MS-proteomics. IgG peptides, isotypes and corresponding Fc-glycopeptides were quantified and interrogated using uni- and multivariate statistics. The Fc-glycans from the IgG4 peptide EEQFNSTYR was validated using protein A column purification. Relative to FT-IgG4, the ACPA-IgG4 Fc-glycan-profile contained lower amounts (p = 0.002) of the agalacto and asialylated core-fucosylated biantennary form (FA2) and higher content (p = 0.001) of sialylated glycans. Novel differences in the Fc-glycan-profile of ACPA-IgG1 compared to FT-IgG1 were observed in the distribution of bisected forms (n = 5, p = 0.0001, decrease) and mono-antennnary forms (n = 3, p = 0.02, increase). Our study also confirmed higher abundance of FA2 (p = 0.002) and lower abundance of afucosylated forms (n = 4, p = 0.001) in ACPA-IgG1 relative to FT-IgG1 as well as lower content of IgG2 (p = 0.0000001) and elevated content of IgG4 (p = 0.004) in ACPA compared to FT. One λ-variable peptide sequence was significantly increased in ACPA (p = 0.0001). In conclusion, the Fc-glycan profile of both ACPA-IgG1 and ACPA-IgG4 are distinct. Given that IgG1 and IgG4 have different Fc-receptor and complement binding affinities, this phenomenon likely affects ACPA effector- and immune-regulatory functions in an IgG isotype-specific manner. These findings further highlight the importance of antibody characterization in relation to functional in vivo and in vitro studies.
23483363 A population pharmacokinetic model for low-dose methotrexate and its polyglutamated metabo 2013 Jun BACKGROUND: Measurement of intracellular concentrations of methotrexate (MTX) and its polyglutamated metabolites (MTXGlu(2-5)) in red blood cells (RBCs) has been suggested as a potential means of monitoring low-dose MTX treatment of rheumatoid arthritis (RA). However, a possible correlation between RBC MTX and MTXGlu2-5 concentrations and clinical outcomes of MTX treatment in RA is debated. A better understanding of the dose-concentration-time relationship of MTX and MTXGlu(2-5) in RBCs by population pharmacokinetic modelling is desirable and will facilitate assessing a potential RBC concentration-effect relationship in the future. AIM: The purpose of this analysis was to describe the pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Secondary objectives included investigation of deglutamation reactions and the loss of MTX and MTXGlu(2-5) from the RBC. METHODS: A model was developed using NONMEM(®) version 7.2 based on RBC data obtained from 48 patients with RA receiving once-weekly low-dose MTX treatment. This model was linked to a fixed two-compartment model that was used to describe the pharmacokinetics of MTX in the plasma. A series of five compartments were used to describe the intracellular pharmacokinetics of MTX and MTXGlu(2-5) in RBCs. Biologically plausible covariates were tested for a significant effect on MTX plasma clearance and the intracellular volume of distribution of all MTX species in RBCs ([Formula: see text]). The developed model was used to test hypotheses related to the enzymatic deglutamation of MTXGlu(2-5) and potential loss of MTXGlu(2-5) from RBCs. RESULTS: The final RBC pharmacokinetic model required the intracellular volumes of distribution for the parent and metabolites to be set to the value estimated for the parent drug MTX alone, and the rate constants describing the polyglutamation steps were fixed at literature values. Significant covariates included effect of body surface area-adjusted estimated glomerular filtration rate on renal plasma clearance and effect of allometrically scaled total body weight with a fixed exponent of 0.75 on non-renal plasma clearance of MTX. The only significant covariate with an effect on [Formula: see text] was mean corpuscular volume (MCV). The model supported single deglutamation steps and a single mechanism of MTX and MTXGlu(2-5) loss from RBCs. CONCLUSIONS: The developed model enabled acceptable description of the intracellular kinetics of MTX and MTXGlu(2-5) in RBCs. In the future it can form the basis of a full pharmacokinetic-pharmacodynamic model to assess the time-RBC concentration-effect relationship of low-dose MTX treatment in RA.
24941177 Tofacitinib versus methotrexate in rheumatoid arthritis. 2014 Jun 19 BACKGROUND: Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate. METHODS: We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician). RESULTS: Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels. CONCLUSIONS: In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).
23526386 Understanding human diseases with high-throughput quantitative measurement and analysis of 2013 Mar Microarray and deep sequencing technologies have provided unprecedented opportunities for mapping genome mutations, RNA transcripts, transcription factor binding, and histone modifications at high resolution at the genome-wide level. This has revolutionized the way in which transcriptomes, regulatory networks and epigenetic regulations have been studied and large amounts of heterogeneous data have been generated. Although efforts are being made to integrate these datasets unbiasedly and efficiently, how best to do this still remains a challenge. Here we review major impacts of high-throughput genome-wide data generation, their relevance to human diseases, and various bioinformatics approaches for data integration. Finally, we provide a case study on inflammatory diseases.
24196391 Increased expression of Siglec-1 on peripheral blood monocytes and its role in mononuclear 2014 Feb OBJECTIVES: Elevated expression of Siglec-1 on circulating monocytes has been reported in some inflammatory and autoimmune diseases, but its expression and role in RA has not been elucidated. The aims of this study were to determine the expression of Siglec-1 in peripheral blood and to explore its role in mononuclear cell reactivity to autoantigen in RA. METHODS: Siglec-1 protein and mRNA levels in 42 RA patients, 39 OA patients, 28 SLE patients and 42 normal controls were determined by flow cytometry and quantitative RT-PCR, respectively. In addition, 10 patients with active RA received DMARDs for 12 weeks and the frequencies of Siglec-1-positive cells and the 28-joint DAS (DAS28) were assessed before and after therapy. Furthermore, TNF-α, IFN-γ and type II collagen were used to up-regulate Siglec-1. Peripheral blood mononuclear cells (PBMCs) from different groups were stimulated with mitogens or antigens and cell proliferation and cytokine production were determined. RESULTS: The protein and mRNA levels of Siglec-1 on PBMCs and monocytes in RA patients were significantly higher than those in OA patients and healthy controls. Moreover, the expression of Siglec-1 protein on PBMCs was positively correlated with DAS28, ESR, high-sensitivity CRP and IgM-RF, but not with anti-CCP antibody. Interestingly, Siglec-1 expression was decreased in parallel with the decrease in the DAS28 after 12 weeks of anti-rheumatic treatment. Furthermore, TNF-α, IFN-γ and type II collagen can up-regulate Siglec-1 in PBMCs. Elevated PBMC proliferation and proinflammatory cytokine production to collagen stimulation in RA patients decreased when Siglec-1 was inhibited by anti-Siglec-1 antibodies. CONCLUSION: Elevated Siglec-1 expression in PBMCs and monocytes can potentially serve as a biomarker for monitoring disease activity in RA. Siglec-1 may also play a proinflammatory role in stimulating lymphocyte proliferation and activation in RA.
24878183 Liposomal corticosteroids for the treatment of inflammatory disorders and cancer. 2014 Sep 28 Glucocorticoids (GC) are known for their potent immunosuppressive and anti-inflammatory properties. As a consequence, they have been extensively used for the treatment of many different diseases. Prolonged and/or high-dose GC therapy, however, generally comes with severe side effects, resulting not only from their very diverse mechanism(s) of action, but also from their relatively poor biodistribution. Drug delivery systems, and in particular liposomes, have been extensively used to enhance the biodistribution and the target site accumulation of GC, and to thereby improve the balance between their efficacy and their toxicity. Many different types of liposomes have been employed, and both local and systemic treatments have been evaluated. We here summarize the progress made in the use of liposomal GC formulations for the treatment of asthma, rheumatoid arthritis, multiple sclerosis and cancer, and we show that the targeted delivery of GC to pathological sites holds significant clinical potential.
25299270 Ethyl acetate fraction from Angelica sinensis inhibits IL-1β-induced rheumatoid synovial 2014 Sep 5 BACKGROUND: The root of Angelica sinensis (AS), also known as "Dang-gui," was a popular herbal medicine widely used in the treatment of gynecological diseases in China, Korea, and Japan for a long time. This study aimed to determine the effects of ethyl acetate fraction from Angelica sinensis (EAAS) on the interleukin-1β (IL-1β)-induced proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), and production of matrix metalloproteinases (MMPs), cyclooxygenase (COX) 2, and prostaglandin E2 (PGE2), involved in articular bone and cartilage destruction, by RASFs. RESULTS: RASF proliferation was evaluated with cholecystokinin octapeptide (CCK-8) reagent in the presence of IL-1β with/without EAAS. Expression of MMPs, tissue inhibitor of metalloproteinases-1 (TIMP-1), COXs, PGE2, and intracellular mitogen-activated protein kinase (MAPK) signaling molecules, including p-ERK, p-p38, p-JNK, and NF-κB, were examined using immunoblotting or semi-quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. EAAS inhibited IL-1β-induced RASF proliferation; MMP-1, MMP-3, and COX-2 mRNA and protein expressions; and PGE2 production. EAAS also inhibits the phosphorylation of ERK-1/2, p38, and JNK, and activation of NF-κB by IL-1β. CONCLUSION: EAAS might be a new therapeutic modality for rheumatoid arthritis management.
24918924 Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associ 2014 OBJECTIVE: To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA). METHODS: Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag). RESULTS: In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P<0.05 for all) and inhibited Ox-PAPC-induced mRNA expression of IL-8 (P<0.05) and IL-6, albeit not to a statistically significant level (p = 0.07). In contrast, eritoran did not affect FFA-induced mRNA expression of IL-6 (P>0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all). CONCLUSIONS: TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.
23908446 Safety and effectiveness of 6 months' etanercept monotherapy and combination therapy in Ja 2013 Oct OBJECTIVE: To assess real-world safety, tolerability, and effectiveness of etanercept monotherapy, etanercept plus methotrexate (MTX), or etanercept plus other disease-modifying antirheumatic drugs (DMARD) in Japanese patients with active rheumatoid arthritis (RA) despite previous treatment with DMARD. METHODS: In this 24-week, all-cases postmarketing surveillance study, adverse events (AE) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was assessed every 4 weeks using the 28-joint Disease Activity Score and the European League Against Rheumatism response criteria. RESULTS: Of 13,861 patients (81% women) in the analysis, 3616, 2506, and 7739, respectively, were classified into etanercept monotherapy (ETN-mono), etanercept plus DMARD other than MTX (ETN + DMARD), and etanercept plus MTX (ETN + MTX) groups. Rates of AE and serious AE (SAE) in the ETN + MTX group were lower than in other groups. Risk of SAE or serious infections was not significantly increased with higher versus lower MTX doses at baseline or with concomitant use of salazosulfapyridine or bucillamine in ETN + DMARD versus ETN-mono groups. A greater likelihood of achieving clinical remission was seen with ETN + MTX versus ETN-mono (OR 1.36; 95% CI, 1.16-1.60; p < 0.001). Higher MTX dose at baseline was associated with a higher remission rate (> 8 mg vs 0 to ≤ 4 mg, OR 1.47, 95% CI 1.07-2.00, p = 0.016; 6 to ≤ 8 mg vs 0 to ≤ 4 mg, OR 1.27, 95% CI 1.01-1.60, p = 0.038). CONCLUSION: Combination therapies with etanercept plus MTX or other DMARD were reasonably well tolerated, and ETN + MTX at higher doses was more effective than ETN-mono in Japanese patients with RA.
23433791 Sagittal alignment of the first metatarsophalangeal joint after arthrodesis for rheumatoid 2013 May The present study assessed the midterm results of reconstruction for rheumatoid forefoot deformity with arthrodesis of the first metatarsophalangeal (MTP) joint, scarf osteotomy, resection arthroplasty of the metatarsal head of the lesser toes, and surgical repair of hammertoe deformity (arthrodesis of the proximal interphalangeal joint). Special focus was placed on the sagittal alignment of the first metatarsophalangeal joint after arthrodesis. We retrospectively evaluated the postoperative clinical outcomes and radiographic findings for 16 consecutive female patients (20 feet) with symptomatic rheumatoid forefoot deformities. The mean duration of follow-up was 7.9 (range 4 to 13) years. All first MTP joints and first metatarsal bones were fused successfully. The mean value of the American Orthopaedic Foot and Ankle Society and Japanese Society for Foot Surgery clinical scores significantly improved overall, except for 2 patients (10%), who complained of first toe pain at the final follow-up visit owing to sagittal misalignment of the fused first MTP joint. Sagittal alignment of the first metatarsal varies greatly because of the rheumatoid midfoot and hindfoot deformities. Therefore, inclination of the first metatarsal should be considered when determining the first MTP joint sagittal fusion angle.
23620212 Transferability of indirect cost of chronic disease: a systematic review and meta-analysis 2013 Jun BACKGROUND: Indirect cost is an important component in economic evaluations. The variation in the magnitude of indirect costs across studies and countries is substantial and affects the transferability of results across jurisdictions. OBJECTIVE: This study explored the factors involved in the variation of reported indirect cost and investigated the feasibility of transferring indirect costs across settings. METHODS: A systematic literature review was conducted to identify studies estimating indirect costs for four selected chronic diseases, namely, asthma (AS), diabetes (DI), rheumatoid arthritis (RA) and schizophrenia (SC). A multiple linear regression analysis was run to identify the factors that potentially explain the variation in reported indirect costs. Parametric (fixed- and random-effect models) and non-parametric (bootstrapping method) meta-analyses were applied to local gross domestic product (GDP)/capita-adjusted indirect costs for each disease. Results from the three different analytical methods were compared to ascertain the robustness of estimation. RESULTS: The systematic literature review identified 77 articles that reported indirect costs of AS (n = 18), DI (n = 20), RA (n = 25) and SC (n = 14) for literature synthesis. Substantial inter- and intra-disease variations among the indirect cost studies were observed with respect to geographic distribution, methodology and magnitude of cost estimation. Regression analysis showed that disease categories and local GDP/capita significantly (p < 0.001) contributed to the variance of indirect cost. The range of intra-disease variation in indirect costs was substantially reduced after adjusting by and expressing values as local GDP/capita. The GDP-adjusted indirect cost in terms of percentage of local GDP/capita of AS was the lowest and that of SC was the highest. Bootstrapping estimation was relatively conservative, with slightly wider confidence intervals (CIs) than the parametric method, with a mean (95 % CI) of 2.12 % (1.4089-2.9332) for AS, 10.65 % (7.215-14.7438) for DI, 21.98 % (17.4360-27.0631) for RA, and 79.19 % (52.4243-117.833) for SC. CONCLUSION: It would be convenient and feasible to construct a universal reference range of indirect cost for a specific disease based on existing data and present this as a percentage of local GDP to assist local decision making in jurisdictions where indirect cost data are not available.
25477056 High-risk pregnancy and the rheumatologist. 2015 Apr Rheumatologists are increasingly involved in the care of young women who, in the age of biologic therapy, are now gaining control of their rheumatic diseases and attempting pregnancy. With careful planning, most women with rheumatic diseases have successful pregnancies. This article focuses specifically on the highest-risk pregnancies and controversial areas. We discuss the women at risk of complications, the types of maternal and fetal complications, the treatments that can be used in pregnancy (and breastfeeding) and longer-term outcomes that could affect the mother. SLE, RA, ANCA-associated vasculitides, large vessel vasculitis (e.g. Takayasu's) and other CTDs (e.g. scleroderma) are among the conditions covered. The evidence and controversies regarding the recommendations for the use of biologics in pregnancy are discussed. The role of the rheumatologist in pregnancy planning and caring for the pregnant and post-partum woman as part of the multidisciplinary team is discussed.