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Aim: Mood disorders are a serious issue for patients with rheumatoid arthritis (RA) because poor mental health can exacerbate the disease course. This study aimed to identify the effect of proinflammatory cytokines on the mood of patients with RA. Methods: This study was conducted at a rheumatology clinic in Northern Taiwan. In total, 113 patients with RA and 42 healthy controls were assessed for anxiety and depression symptoms using Hospital Anxiety and Depression Scale (HADS). RA was assessed using the Disease Activity Score of 28 joints (DAS28). Serum proinflammatory cytokine levels, including interleukin (IL)‐1β, IL‐6, IL‐17 and tumor necrosis factor alpha (TNF‐α) were measured and compared between different patient groups according to disease activity and pain level. Results: Serum IL‐1β, IL‐6, IL‐17 and TNF‐α levels were significantly higher in patients with RA than in healthy controls, as were the mean anxiety and depression subscale scores. In patients with RA who had different disease activities, pain severity correlated with both anxiety and depression symptoms. When HADS scores were analyzed according to pain levels, age was correlated with depression in the severe pain group. In the mild pain group, patients with higher IL‐6 or higher IL‐17 had a higher risk of depression. There was no correlation between mood symptoms and cytokine levels in healthy controls. Conclusion: Elevated serum IL‐6 and IL‐17 levels in patients with RA induce arthritis and cause mood symptoms, especially depression symptoms. [ABSTRACT FROM AUTHOR]

Objectives. The aims of this study were to investigate the expression of amphiregulin (AREG) and TNF-α-converting enzyme (TACE) in fibroblast-like synoviocytes from humans with RA (FLS-RA) when stimulated with proinflammatory cytokines and to explore whether AREG plays a role in RA.Methods. The effects of cytokines on the expression of AREG and TACE in FLS-RA were measured by quantitative RT-PCR and western blotting. Blockade of IL-1β-mediated pathways was used to verify the involvement of intracellular signal pathways in the induction of AREG and TACE. TAPI-1 and TACE short hairpin RNA (shRNA) infection were used to identify the role of TACE in IL-1β-induced AREG secretion and shedding. AREG-induced production of MMP-1 and cadherin-11 in FLS-RA were measured by ELISA or western blotting. The effect of AREG on FLS-RA invasion was examined using a Transwell invasion assay.Results. IL-1β, but not other tested cytokines, increased the expressions of AREG mRNA and protein in a dose-responsive and time-dependent manner in FLS-RA. IL-1β induced AREG expression via p38 MAPK, NF-κB, JNK and ERK1/2 signalling pathways and induced TACE expression via PI3K, p38MAPK and NF-κB signalling pathways in FLS-RA. TACE mediated AREG secretion and shedding. EGFR (ErbB1) and Her-2 (ErbB2) were expressed in FLS-RA, and AREG increased MMP-1 and cadherin-11 expression in FLS-RA. AREG promoted the FLS-RA invasion ability.Conclusion. AREG and TACE expression were up-regulated by IL-1β and their activations on FLS-RA lead to the matrix degradation by inducing MMP-1 and cadherin-11 production. TACE activity is necessary for IL-1β-induced AREG release. Our results demonstrate that IL-1β-induced AREG release may be involved in the pathogenesis of RA. [ABSTRACT FROM PUBLISHER]

Objective. Decoy receptor 3 (DCR3) has been known to modulate immune functions of monocyte or macrophage. In the present study, we investigated the mechanism and the effect of DCR3 on RANK ligand (RANKL)-induced osteoclastogenesis.Methods. We treated cells with DCR3 in RANKL-induced osteoclastogenesis to monitor osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining. Osteoclast activity was assessed by pit formation assay. The mechanism of inhibition was studied by biochemical analysis such as RT–PCR and immunoblotting. In addition, cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis and apoptosis signalling were evaluated by immunoblotting and using flow cytometry.Results. DCR3 inhibited RANKL-induced TRAP+ multinucleated cells and inhibited RANKL-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1) nuclear translocation in RAW264.7 cells. Also, DCR3 significantly inhibited the bone-resorbing activity of mature osteoclasts. Moreover, DCR3 enhanced RANKL-induced cell apoptosis and enhanced RANKL-induced Fas ligand expression. The mechanisms were mediated via the intrinsic cytochrome c and activated caspase 9 apoptosis pathway.Conclusion. We postulated that the inhibitory activity of DCR3 on osteoclastogenesis occurs via down-regulation of RANKL-induced NFATc1 expression and induction of cell apoptosis. Our results postulated DCR3 as a possible new remedy against inflammatory bone destruction. [ABSTRACT FROM PUBLISHER]

Background/purpose: Antibodies against type II collagen (anti-CII) are arthritogenic and central to the initiation of the disease. An animal model of collagen type II-specific monoclonal antibody-induced arthritis (CAIA) has been used for the evaluation of various therapeutic effects in rheumatoid arthritis (RA). We aimed to measure the expression of matrix metalloproteinase (MMP)-9 (gelatinase B), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in the acute and chronic stages of the CAIA model for application as a therapeutic marker.Methods: A commercially available antibody cocktail containing four monoclonal anti-type II collagen antibodies were injected into 6 to 8-week-old male BALB/c mice (n=20) and 50 microL lipopolysaccharide was injected 3 days later. The clinical manifestations of RA were recorded and scored at 10 days (acute stage) and 21 days (chronic stage). Then the mice were sacrificed for histologic analysis of the inflamed footpad and gene expression of IL-1beta, TNF-alpha and MMP-9 by ELISA and quantitative polymerase chain reaction amplification.Results: Marked inflammation was found in the limb joints of mice at 10 days. Both IL-1beta and MMP-9 expression played a central role in the inflammatory reaction in the acute stage. The expression level of MMP-9 mRNA remained high in the chronic stage of CAIA, but that of IL-1beta mRNA was unexpectedly negligible; the serum level of TNF-alpha in CAIA was undetectable in the acute stage. The expression level of TNF-alpha mRNA was also lower than IL-1beta and MMP-9 in the acute inflammatory stage.Conclusion: The CAIA model is a fast and highly replicable model of RA. MMP-9 and IL-1beta were highly expressed in the acute stage of CAIA. It is suggested the MMP-9 mRNA level is a suitable marker for both acute and chronic stage, whereas IL-1beta is a marker only for the acute stage of the CAIA murine model. [ABSTRACT FROM AUTHOR]

1 Plant alkaloid tetrandrine (Tet), purified from Chinese herb Han-Fang Chi, is a potent immunomodulator used to treat rheumatic disorders, silicosis and hypertension in mainland China. 2 We previously demonstrated that Tet effectively suppresses cytokine production and proliferation of CD28-costimulaied T cells. In the present study, we investigated the possible involvement of nuclear factor kappa B (NF-κB) transcription factors, critical in CD28 costimulation, in Tet-mediated immunosuppression in human peripheral blood T cells. 3 We showed that Tel inhibited NF-κB DNA-binding activities induced by various stimuli, including CD28 costimulation. At equal molar concentrations, Tet was as strong as methotrexate in suppressing CD28-costimulated NF-κB activities. Since Tet itself did not affect NF-κB binding lo its corresponding DNA sequence, the results suggested that Tet might regulate NF-κB upstream signaling molecules. 4 Further studies demonstrated that Tet could prevent the degradation of IκBα and inhibit nuclear translocation of p65 by blocking IκBα kinases α and β activities. In addition, the activation of mitogen-activated protein kinases such as c-jun N-terminal kinase, p38 and extracellular signalregulated kinase and activator protein-1 DNA-binding activity were all downregulated by Tet. Transfection assays performed in purified human peripheral blood T cells also confirmed the inhibition of NF-κB transcriptional activity by Tet. 5 When four Tel analogues were readily compared, dauricine appeared to preserve the most potent inhibition on CD28-coslimulaled but not on H2O2-induced NF-κB DNA-binding activities. 6 Our results provide the molecular basis of immunomodulation of Tet for being a potential diseasemodifying antirheumalic drug in the therapy of autoimmune disorders like rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

To characterize the pharmacokinetic (PK) profile of interleukin-1 receptor antagonist (IL-1ra) after a single injection, and to assess the safety and tolerability of IL-1ra, a total of 15 adult Chinese subjects with rheumatoid arthritis (RA) were enrolled into this study. Study medication was administered on day 1. Blood samples for PK testing were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, and 48 h postdose. Adverse events data was collected and monitored throughout the study. Plasma IL-1ra concentrations were measured by enzyme-linked immunosorbent assay. Individual IL-1ra PK parameters were estimated by noncompartmental analysis. After subcutaneous (s.c.) injection of 1 mg/kg IL-1ra, the Tmax was reached at 2–6 h postdose. The mean (S.D.) of Cmax was 687 ng/ml (197 ng/ml). Plasma concentration subsequently declined with a mean (S.D.) of T1/2 value of 3.76 h (1 h). The mean (S.D.) of plasma clearance after administration value was 150 ml/min (52.1 ml/min). No deleterious effects, serious adverse events, or withdrawals due to adverse events occurred during this study. The PK parameters for Chinese subjects with RA were comparable to those for non-Chinese subjects with RA. IL-1ra was well tolerated during this study, and no significant safety concerns were identified after administration. [Copyright &y& Elsevier]

Presents several abstracts related to the efficacy and safety of tumor necrosis factor (TNF)-alpha blockers in rheumatoid arthritis. Expression profile analysis by microarray to predict responders to anti-TNF biologics in rheumatoid arthritis; Postmarketing surveillance of etanercept in Australia; Open-label evaluation of the efficacy and safety of etanercept in patients with active rheumatoid arthritis and ankylosing spondylitis.

Abstract: Objective: To investigate the expression of growth differentiation factor-5 (GDF-5) in chondrocytes (HC) and fibroblast-like synoviocytes (FLS) from humans with rheumatoid arthritis (RA) when stimulated with proinflammatory cytokines and to explore whether GDF-5 plays a role in regulating the differentiation of FLS-RA into chondrocytes. Methods: Expression of GDF-5 in synovium and cartilage in RA and osteoarthritis (OA) was assessed by immunohistochemistry. GDF-5 production in FLS-RA and HC-RA was examined through real-time quantitative RT-PCR (Q-PCR) and western blotting. Expressions of GDF-associated receptors on FLS-RA were determined by semiquantitative-PCR, and MTT assay was used to study the effects on FLS-RA proliferation. Effect of GDF-5 and TGF-β3 on in vitro chondrogenic ability of FLS-RA was investigated using pellet-culture system, Q-PCR and histological analysis. Results: Immunohistochemical analysis demonstrated that GDF-5 expression in the synovium and cartilage from joints of RA patients was much lower than that of OA patients. Addition of IL-1β or TNF-α appeared to downregulate the expression of GDF-5 in HC-RA and FLS-RA. Inhibition of GDF-5 expression by IL-1β in RA-FLS was attenuated by pretreatment with MEK1/2 inhibitor. GDF-5-associated receptors were expressed in FLS-RA, but GDF-5 had no effect on FLS-RA proliferation. GDF-5 had a strong chondrogenic-promoting effect on TGF-β3-induced chondrocyte differentiation in FLS-RA. Conclusions: GDF-5 is expressed in FLS-RA and HC-RA, and its expression is strongly downregulated by proinflammatory cytokines. MEK-ERK pathway is a negative regulator of GDF-5 expression in FLS-RA. In FLS-RA, synergy between GDF-5 and TGF-β3 enhances chondrogenesis. Anti-inflammatory drugs combined with GDF-5 might be a new therapeutic treatment for RA. [Copyright &y& Elsevier]

Résumé: L’arthrite septique est une complication rare de l’acupuncture. Nous rapportons l’observation d’un patient atteint de polyarthrite rhumatoïde qui a développé une arthrite septique du genou droit après des séances hebdomadaires d’acupuncture pendant trois semaines consécutives. L’infection a été localisée par une échographie de l’articulation et une IRM, avec une mise en culture du liquide synovial ponctionné dans l’articulation contenant Listeria monocytogenes. Le patient a bien répondu au traitement par antibiotique et a retrouvé la mobilité de l’articulation. Le processus infectieux doit être présent à l’esprit pour un diagnostic et un traitement rapide des infections articulaires associées à l’acupuncture chez les patients atteints de polyarthrite rhumatoïde qui représente un risque infectieux supplémentaire. [Copyright &y& Elsevier]

Abstract: Septic arthritis is a rare complication of acupuncture. We present a patient with rheumatoid arthritis who developed septic arthritis of the right knee after consecutive weekly sessions of acupuncture therapy for 3 weeks. The infection was localized by musculoskeletal sonography and magnetic resonance imaging, with culture of the synovial fluid aspirated from the joint yielding Listeria monocytogenes. The patient responded well to antibiotic treatment and regained joint mobility. A high index of suspicion for an infectious process is required for prompt diagnosis and treatment of acupuncture-induced joint infections in rheumatoid arthritis patients who might have additional risk factors for infection. [Copyright &y& Elsevier]