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ID PMID Title PublicationDate abstract
17040892 UK consultant rheumatologists' access to biological agents and views on the BSR Biologics 2006 Nov OBJECTIVES: The British Society for Rheumatology Biologics Register (BSRBR) is a prospective cohort study to determine the efficacy and toxicity of biological agents in rheumatoid arthritis (RA) patients compared with RA controls. Entry of patients to the register is a condition of use of anti-tumour necrosis factor (anti-TNF) therapy in the UK, but little is known of clinicians' views of its usefulness. Data from the register suggest uneven provision of anti-TNF-alpha therapy. METHODS: A questionnaire was sent on behalf of the BSRBR to all UK consultant rheumatologists concerning provision and use of anti-TNF-alpha therapy and their experience of working with the BSRBR. RESULTS: Response rate was 49.5% representing 252 consultants. Fourty-six per cent had some limitation of access to anti-TNF-alpha drugs, usually a financial cap (70%), even for RA patients meeting National Institute for Health and Clinical Excellence (NICE) criteria. Sixty-seven per cent could prescribe for ankylosing spondylitis (AS) or psoriatic arthritis (PsA) in some circumstances but only 25 and 35%, respectively, could prescribe according to BSR guidance. More than 50% found the workload involved in submitting data to the registry at least difficult, but most had favourable impressions of the BSRBR and thought similar registries desirable or essential for PsA, AS and rituximab. CONCLUSIONS: Access to anti-TNF therapy for patients with inflammatory arthritis is variable in the UK, even for RA where it is NICE-approved. Access is more limited for conditions where NICE has not yet issued guidance. The BSRBR generates a significant workload for rheumatology staff but is generally well-regarded.
17564772 Laser-mediated microdissection for analysis of gene expression in synovial tissue. 2007 In experimental rheumatology, transcriptomics is one of the most important methods for investigating the pathogenesis of diseases. The biological material of most studies on rheumatoid arthritis has been bulk rheumatoid synovial tissues, but they are not suitable because they consist of several kinds of cells or structures. Laser-mediated microdissection (LMM) is a useful tool for isolating particular cells from tissue specimen to assess the functions of each cell. The LMM system employs a combination of a microscope and a laser-beam generator to cut out target areas on cryosections. Tissue compartments or even a single viable cell can be isolated using a non-focused laser beam without direct contact to avoid contamination, and this process is called laser pressure catapulting. An ultraviolet-A laser enables target cells to be procured without any influence on the surrounding. This technique has already been used in several studies in rheumatology, and its validity has been confirmed. Combined with other new techniques such as real-time quantitative polymerase chain reaction or microarray analysis, LMM is becoming more important in the analysis of gene expression in rheumatology.
17362051 Risk: benefit profile of etanercept in elderly patients with rheumatoid arthritis, ankylos 2007 Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are commonly thought of as inflammatory diseases that affect younger individuals. Although the initial presentation of these diseases is commonly in a patient's twenties or thirties, they usually persist for the duration of the patient's life. In addition, up to one-third of patients with RA have disease onset after 60 years of age. Older patients with any of these three diseases are more likely to have more severe disease with significant functional decline. They are also more likely to have co-morbid diseases and use concomitant medications than patients who are younger. In patients with RA, AS or PsA, the introduction of anti-tumour necrosis factor (TNF)-alpha therapies such as etanercept, infliximab and adalimumab has had a significant impact in ameliorating the signs and symptoms of disease, improving patient function and inhibiting radiographic progression. Anti-TNFalpha therapies now have well recognised safety profiles that have been demonstrated in the usual clinical trial populations for these diseases, but such populations under-represent patients > or =65 years of age. This review explores the information currently available regarding patients aged > or =65 years treated with anti-TNFalpha therapies for RA, AS or PsA, focusing on etanercept in RA because of a lack of data for other therapies and conditions. The analyses conducted show that there is similar efficacy in the treatment of RA in patients <65 years old and those > or =65 years of age. Although there are some differences in the adverse events noted in these two age groups, it appears as though treatment of patients > or =65 years of age, compared with age-matched controls, is not dissimilar to treatment of patients <65 years of age compared with their age-matched controls. Only by understanding the risks and benefits of therapy in the older age group can a true risk : benefit profile for etanercept, and ultimately other anti-TNFalpha therapies, be determined by the practising physician and the patient.
18975348 Antiinflammatory effect of Rho kinase blockade via inhibition of NF-kappaB activation in r 2008 Nov OBJECTIVE: There is increasing evidence that the RhoA signaling pathway may play a critical role in the inflammatory response. This study was undertaken to examine the effects of RhoA and its downstream effector Rho kinase (ROK) in synovial inflammation in rheumatoid arthritis (RA). METHODS: RhoA activity was assessed by pull-down assay. Fasudil and Y27632, both specific inhibitors of ROK, were used to examine the role of ROK in inflammatory responses in vivo and in vitro. Nuclear translocation of NF-kappaB was measured by confocal fluorescence microscopy, and DNA binding activity was assessed with a sensitive multiwell colorimetric assay. Enzyme-linked immunosorbent assay was used to detect cytokine production. RESULTS: Increased activation of RhoA was found in inflamed synovial membrane cells isolated from patients with RA and from rats with collagen-induced arthritis (CIA). Intraperitoneal administration of fasudil in rats with CIA significantly reduced synovial inflammation and ROK activity. In vitro, treatment with fasudil or Y27632 decreased production of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and IL-6 by synovial membrane cells, peripheral blood mononuclear cells, and fibroblast-like synoviocytes from patients with active RA. Inhibition of ROK by specific inhibitors or ROK small interfering RNA suppressed lipopolysaccharide- or TNFalpha-induced NF-kappaB nuclear translocation, DNA binding activity, luciferase reporter gene expression, and IkappaBalpha degradation. CONCLUSION: The results of this study provide new evidence that blockade of ROK inhibits activation of NF-kappaB and production of proinflammatory cytokines, suggesting a critical role of ROK in the synovial inflammation of RA. Specific inhibition of ROK may be a novel therapeutic approach in RA.
17392575 The evaluation of the role of beta-hydroxy fatty acids on chronic inflammation and insulin 2006 Beta-hydroxy fatty acids are a major component of lipid A moiety of lipopolysaccharide. We aimed to investigate the role of free beta-hydroxy fatty acids on inflammation, as well as to evaluate their effects on cytokine release from human blood cells, and whether they exist in plasma of patients with chronic inflammatory diseases with/without insulin resistance. Peripheral venous blood was incubated with beta-hydroxy lauric and beta-hydroxy myristic acids (each 100 ng, 1 microg, 10 microg/mL) up to 24 hours. Cytokines were measured from culture media and plasma. Free fatty acids and biochemical parameters were also measured from patients' plasma. Only beta-hydroxy lauric acid significantly stimulated interleukin-6 production at 10 microg/mL compared to control (533.9 +/- 218.1 versus 438.3 +/- 219.6 pg/mL, P < .05). However, free beta-hydroxy lauric and myristic acids were not found in patients' plasma. Therefore, free beta-hydroxy lauric and myristic acids do not seem to have a role on sterile inflammation in chronic inflammatory diseases associated with insulin resistance.
18780536 Temporomandibular joint pressure pain threshold is systemically modulated in rheumatoid ar 2008 Summer AIMS: To investigate the relative importance of systemic and local inflammatory mediators (serotonin: 5-HT; tumor necrosis factor: TNF; soluble interleukin-1 receptor II: IL-1sRII) in the modulation of temporomandibular joint (TMJ) pressure pain threshold in patients with seropositive or seronegative rheumatoid arthritis (RA) and to investigate to what extent TMJ pressure pain threshold is related to other TMJ pain parameters. METHODS: Sixty patients with seropositive RA for rheumatoid factor and 74 patients with seronegative RA involving the TMJ were investigated regarding synovial fluid and plasma levels of IL-1sRII, 5-HT, and TNF as well as erythrocyte sedimentation rate, C-reactive protein, thrombocyte particle count, and rheumatoid factor in blood. TMJ resting pain, movement pain, tenderness, and palpebral pain reflex to digital palpation and TMJ pressure pain threshold were examined. RESULTS: Statistical analyses indicated that TMJ pressure pain threshold was only correlated to systemic factors. TMJ movement pain was in turn mainly correlated to systemic mediators in the seropositive patients but to local mediators in the seronegative patients where synovial fluid IL-1sRII was positively correlated to TMJ pain on mouth opening. Seropositive patients had higher systemic inflammatory activity but lower TMJ movement pain intensities than seronegative patients. CONCLUSION: The results indicate that TMJ pressure pain threshold is modulated by systemic rather than local inflammatory mediators and suggest that it is unrelated or only weakly related to other TMJ pain entities in RA patients. A rheumatoid factor-dependent systemic modulation, in combination with local factors, seems to account for TMJ pain in RA patients.
18607581 Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of 2008 Nov OBJECTIVE: Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R-->3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response. METHODS: A genotyping approach was used to determine the studied polymorphisms in 213 RA patients. RESULTS: We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P = 0.039, OR = 3.574, 95% CI = 1.065-11.993 and P = 0.032, OR = 7.801, 95% CI = 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P = 0.027, OR = 0.170, 95% CI = 0.035-0.820). CONCLUSION: Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.
18590608 Abatacept in biologic-naïve patients and TNF inadequate responders: clinical data in focu 2008 Aug BACKGROUND: Advances in the understanding of rheumatoid arthritis (RA) immunopathogenesis support the hypothesis for a 'window of opportunity' for therapeutic intervention in RA and the need for rapid and effective treatment strategies, with the ultimate goal of alleviating symptoms and halting progressive joint damage. Biologic therapies targeting pro-inflammatory cytokines have significantly improved the outlook for patients with RA; however, some patients still experience inadequate treatment responses. Recently, therapeutic agents targeting alternative pathways have been developed. One such therapy--abatacept--targets T-cell activation and is approved in the United States for treatment of moderate-to-severe RA and juvenile idiopathic arthritis. OBJECTIVE: To overview the efficacy and safety of abatacept in the treatment of adult patients with active RA and an inadequate response to methotrexate (MTX) or tumor necrosis factor (TNF) antagonists. SEARCH METHODOLOGY: A comprehensive literature search was performed using the National Library of Medicine (MEDLINE), EMBASE and BIOSIS databases (restricted to articles in the English language posted between January 2000 and February 2007). The search terms 'CTLA-4Ig', 'abatacept' and 'ORENCIA' were used, and data from randomized clinical trials were summarized. RESULTS: Abatacept provided clinically meaningful improvements in the signs and symptoms of RA in both MTX and TNF antagonist inadequate responders in Phase II and III studies. Health-related quality of life was also improved with abatacept, which demonstrated an acceptable safety and tolerability profile in both patient populations. Additionally, when assessed in patients with an inadequate response to MTX, abatacept inhibited structural damage progression. CONCLUSION: Although longer-term data are required and differing study designs preclude direct comparisons with other RA therapies, results of clinical trials to date suggest that abatacept has an acceptable safety profile and is an effective treatment option for patients with RA, whether treating biologic-naïve patients or those who have already had an inadequate response to TNF antagonists.
16536638 Long-term experience with etanercept in the treatment of rheumatoid arthritis in elderly a 2006 BACKGROUND: The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA). METHODS: This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0. RESULTS: Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials. CONCLUSION: Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.
18424069 Cyclosporin A inhibits the production of IL-17 by memory Th17 cells from healthy individua 2008 Jun Recent evidence from several studies indicated that IL-17-producing Th17 cells can represent the key effector cells in the induction and development of autoimmune disorders. Cyclosporine A (CsA) is a commonly used immunosuppressant to treat lots of autoimmune diseases including rheumatoid arthritis (RA). Here, we demonstrated that PBMCs and purified CD4(+) T cells from healthy individuals and patients with RA could be induced to produce large amounts of IL-17 after stimulation with anti-CD3 plus anti-CD28 mAbs. Phenotypic analysis indicated that the majority of IL-17-producing cells were Th17 cells with memory phenotype. The addition of CsA into cell cultures significantly inhibited the IL-17 production by Th17 cells at protein and at mRNA levels. Compared to the PBMCs from normal individuals, PBMCs from the patients with RA produced higher levels of IL-17 that was also significantly inhibited by CsA both at protein and at mRNA levels. The mechanism might be the effect of CsA on the T cells activation because the expression of CD69 and CD25 molecules on T cells was markedly reduced in the presence of CsA. Taken together, these results demonstrated that CsA suppressed the IL-17 production and inhibited the Th17 cells differentiation from both healthy individuals and patients with RA.
18414967 Clinical impact of switching from infliximab to etanercept in patients with rheumatoid art 2008 Jul We assessed the disease activity in patients with rheumatoid arthritis (RA) after switching from infliximab to etanercept according to the reason of infliximab discontinuation. At Helsinki University Central Hospital during the period 1999 to 2003, 49 patients with RA were switched from infliximab to etanercept. The reasons for infliximab discontinuation were: 42% for failure to respond by >American College of Rheumatology 50% criteria; 12% for adverse events; 46% responded to infliximab and were switched for non-medical reasons. Clinical outcome after the switch was compared between the groups according to the reason of infliximab discontinuation. Disease activity was measured with the 28-joint count Disease Activity Score (DAS28). In patients in the non-medical reasons group, the disease activity was suppressed effectively both during infliximab and etanercept. Furthermore, the one-year drug survival of etanercept in this group was the highest of 77% (95% confidence interval (CI), 62 to 97) among the three groups. In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. The 1-year drug survival of etanercept was 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. For RA patients who discontinued taking infliximab because of non-medical reasons experienced similar treatment efficacy during both biological agents. The treatment with etanercept provided sufficient disease control also for patients with infliximab failure or adverse event. Therefore, etanercept can be suggested when infliximab has failed or discontinued for other reasons.
16736520 Comparison of the response to infliximab or etanercept monotherapy with the response to co 2006 Jun OBJECTIVE: To compare outcome at 6 months in unselected "real-world" patients with rheumatoid arthritis treated with etanercept or infliximab as either monotherapy, cotherapy with methotrexate (MTX), or cotherapy with another disease-modifying antirheumatic drug (DMARD). METHODS: A total of 2,711 subjects starting treatment with their first biologic agent (1,453 infliximab and 1,258 etanercept) were followed up for 6 months. Outcome was assessed using the European League Against Rheumatism (EULAR) response criteria. Ordinal regression was used to model the response in the MTX and other DMARD cotherapy groups relative to the monotherapy group separately for the 2 anti-tumor necrosis factor alpha agents, after adjusting for baseline differences. RESULTS: Etanercept-treated patients had an increased likelihood of achieving a higher EULAR response category with cotherapy with MTX (odds ratio [OR] 2.0, 95% confidence interval [95% CI] 1.5-2.7) and with another DMARD (OR 1.2, 95% CI 0.9-1.6) as compared with monotherapy. For infliximab-treated patients, the likelihoods were 1.4 (95% CI 0.9-2.0) for MTX and 1.3 (95% CI 0.8-2.1) for other DMARDs versus monotherapy. Cotherapy with MTX or another DMARD produced significantly higher rates of remission with etanercept (12% and 11%, respectively) as compared with etanercept monotherapy (5%). Infliximab-treated patients showed similar remission rates in the MTX and other DMARD cotherapy groups (8% and 5%, respectively) as in the monotherapy group (7%). CONCLUSION: In this study of real-world patients, the use of MTX and, to a lesser extent, other DMARDs as cotherapy with etanercept was associated with a higher likelihood of response. Although the infliximab guidelines suggest that MTX be used as cotherapy, in clinical practice, both monotherapy and cotherapy with DMARDs other than MTX are used. These data suggest that either of the latter strategies may be useful in patients who are intolerant to MTX.
17332973 Isoniazid intervention for latent tuberculosis among 86 patients with rheumatologic diseas 2007 Nov In this study, we investigated the safety and toxicity of isoniazid (INH) intervention therapy to the patients with latent tuberculosis who were given tumor necrosis factor alpha (TNFalpha) for the treatment of their rheumatologic diseases. In this prospective clinical study, we enrolled 86 patients receiving anti-TNFalpha therapy for their rheumatologic diseases between April 2005 and September 2006. Of all the subjects, 45 had rheumatoid arthritis, 36 had ankylosing spondylitis, and 5 had psoriatic arthritis. In addition to anti-TNFalpha therapy, 60 of the 86 patients were given INH intervention for revealed latent tuberculosis. INH at a dosage of 300 mg daily was given for 9 months. Hepatotoxicity due to the INH therapy was considered when the serum alanine aminotransferase (ALT) and/or aspartate aminotransaminase (AST) levels showed at least threefold increase with respect to their baseline serum levels. Serum ALT and AST levels were measured by enzymatic colorimetric method in fasting peripheral blood samples at 0 (baseline), 1, 2, 3, 6, and 9 months. Of 86 patients, 47 (54.7%) were women (mean age+/-SD, 44.1 +/- 10.9 years) and 39 (45.3%) were men (38.8 +/- 10.1 years). Except five patients (8.3%), liver toxicity due to the INH therapy was not encountered among the patients, and after temporarily discontinuing the INH therapy of these five subjects, serum transaminase levels returned to the normal ranges. No hepatotoxicity was observed in the non-INH group. However, there was no statistical significance between INH-treated and non-INH-treated group (p = 0.317). In addition, none of the 86 patients developed active tuberculosis infection during the treatment period. In conclusion, for those patients who were assigned to the TNFalpha treatment for their rheumatologic disorders and carrying risk for latent tuberculosis, INH intervention therapy was found to be safe and efficacious.
18044347 [Immunopathology of Lyme arthritis]. 2007 Aug Lyme borreliosis (Lyme disease) is the most prevalent tick-borne disease caused by spirochaetes of the Borrelia species complex. Arthritis is one of the common manifestations of B. burgdorferi infection. The pathomechanism of articular changes in Lyme arthritis has not yet been elucidated. Histopathological studies of synovia and immunological changes are similar to rheumatoid arthritis. In the early stage of inflammation B. burgdorferi interact with polynuclear granulocytes and epithelial cells, triggering production of reactive oxygen species, lipid peroxidation products and other inflammatory mediators. The imbalance between anabolic and catabolic processes in inflamed joints results in the progressive destruction of articular cartilage and disintegration of extracellular matrix. Molecular mimicry between OspA (outer surface protein A) and adhesion molecule LFA-1alpha seems to be responsible for chronic arthritis.
18362100 Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent i 2008 May OBJECTIVES: Dose-dependant gastrointestinal and cardiovascular side-effects limit the use of NSAIDs in the management of RA. The n-3 essential fatty acids (EFAs) have previously demonstrated some anti-inflammatory and NSAID-sparing properties. The objective of this study was to determine whether cod liver oil supplementation helps reduce daily NSAID requirement of patients with RA. METHODS: Dual-centre, double-blind placebo-controlled randomized study of 9 months' duration. Ninety-seven patients with RA were randomized to take either 10 g of cod liver oil containing 2.2 g of n-3 EFAs or air-filled identical placebo capsules. Documentation of NSAID daily requirement, clinical and laboratory parameters of RA disease activity and safety checks were done at 0, 4, 12, 24 and 36 weeks. At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake. Relative reduction of daily NSAID requirement by >30% after 9 months was the primary outcome measure. RESULTS: Fifty-eight patients (60%) completed the study. Out of 49 patients 19 (39%) in the cod liver oil group and out of 48 patients 5 (10%) in the placebo group were able to reduce their daily NSAID requirement by >30% (P = 0.002, chi-squared test). No differences between the groups were observed in the clinical parameters of RA disease activity or in the side-effects observed. CONCLUSIONS: This study suggests that cod liver oil supplements containing n-3 fatty acids can be used as NSAID-sparing agents in RA patients.
18457473 Belimumab: anti-BLyS human monoclonal antibody, anti-BLyS monoclonal antibody, BmAb, human 2008 Belimumab is a fully human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS. Belimumab is in phase III trials for the treatment of systemic lupus erythematosus (SLE) and has completed a phase II trial in rheumatoid arthritis (RA); the product may also have potential in the treatment of other autoimmune disorders. In May 2001, Cambridge Antibody Technology (now MedImmune) completed its discovery programme and Human Genome Sciences identified belimumab as a candidate for clinical development. More than 1000 distinct human antibodies specific to BLyS were characterized by the collaboration.B-lymphocyte stimulator is a naturally occurring protein discovered by Human Genome Sciences that stimulates B-lymphocytes to develop into mature B cells. Laboratory studies have indicated that higher than normal levels of B-lymphocyte stimulator may contribute to the pathogenesis of autoimmune diseases, such as SLE and RA. Human Genome Sciences (HGS) and Cambridge Antibody Technology signed a collaborative agreement in August 1999 to study the B-lymphocyte stimulator as a human protein target. HGS is also developing other BLyS products. In March 2000, HGS and Cambridge Antibody Technology expanded their agreement into a 10-year collaboration and product development alliance, providing Human Genome Sciences with the right to use the antibody technology of Cambridge Antibody Technology to fully develop human antibodies for therapeutic and diagnostic purposes. Cambridge Antibody Technology will receive royalty payments on product sales from HGS, as well as the development and milestone payments it has already received. Belimumab will be manufactured in Human Genome Sciences' manufacturing facility, located in Rockville, MD, USA. HGS holds commercial rights to the drug. In July 2005, GlaxoSmithKline (GSK) exercised its co-development and co-promotion option to belimumab. In an agreement made in June 1996, HGS had granted a 50/50 co-development and co-promotion option to GSK for certain therapies that complete phase IIa trials successfully. The companies subsequently entered into a definite worldwide, co-development and commercialization agreement in August 2006, under which HGS will be responsible for conducting phase III trials of the product, with assistance from GSK. The companies will share equally phase III/IV development costs, sales and marketing expenses, and profits. In October 2007, Cambridge Antibody Technology was integrated into MedImmune. Both companies were previously independent subsidiaries of AstraZeneca. MedImmune is now the operationally independent biologics business unit of AstraZeneca. Human Genome Sciences intends to initiate a phase II trial of subcutaneous belimumab by mid-2008. Results from a phase II trial in 449 patients with SLE demonstrated that belimumab improved or stabilized SLE over 2.5 years. The phase II trial was a double-blind, placebo-controlled, multicentre study that evaluated the safety, optimal dosing, and preliminary efficacy of belimumab in patients with active SLE over 52 weeks initially, followed by a continuation phase for a total of 2.5 years. Belimumab has received fast-track designation for the treatment of SLE from the US FDA and has also been selected for inclusion in the agency's continuous Marketing Application Pilot 2 programme.
18369042 [Homocysteine and rheumatic disease]. 2007 Dec In the last decade hyperhomocysteinemia has become an element of great interest as a recognized factor of independent risk for atherotrombosis. Moreover a role has been suggested in some different diseases, like rheumatic ones. Hyperhomocysteinemia could represent a mechanism of amplification of vascular damage in rheumatic disease, therefore it could interact with treatements. Moreover it could contribute to explain the high incidence of cardiovascular events, than they do not find support in traditional risk factors.
17516242 Impairment of thioredoxin reductase activity by oxidative stress in human rheumatoid synov 2007 Jun The thioredoxin/thioredoxin reductase system is strongly induced in patients with rheumatoid arthritis (RA). We have investigated the impact on TR activity of doses of superoxide anion generated by the hypoxanthine (HX)/xanthine oxidase (XO) system and by hydrogen peroxide, H(2)O(2), for various times and compared the findings with synoviocytes obtained from osteoarthritis (OA) patients. At baseline, TR activity in RA cells was significantly higher than in OA cells (2.31 +/- 0.65 versus 0.74 +/- 0.43 mUnit/mg protein, p < 0.01). HX/XO and H(2)O(2) in RA cells decreased TR activity, which was found to be unchanged in OA cells. H(2)O(2) and superoxide anion caused a time-dependent accumulation of oxidized TR and induced the formation of carbonyl groups in TR protein in RA cells rather than OA cells, and oxidized the selenocysteine of the active site. The oxidation in TR protein was irreversible in RA cells but not in OA cells. In conclusion, we report that the oxidative aggression generates modifications in the redox status of the active site of the TR and induces an alteration of the Trx/TR system, concomitant with those of the other antioxidant systems that could explain the causes of oxidative stress related to RA disease.
18400836 Frequency and duration of clinical remission in patients with peripheral psoriatic arthrit 2008 Jun OBJECTIVE: To evaluate the frequency and duration of clinical remission in patients with PsA. METHODS: All consecutive new outpatients with peripheral PsA requiring second-line drugs and RA observed between January 2000 and December 2005 were included in a prospective, case-control study. Primary end point was to assess the frequency of remission in peripheral PsA compared with RA. Secondary end points were to compare the duration of clinical remission during treatment and after therapy interruption, ACR 20, 50, 70 response rates and to detect any remission predictor at diagnosis. Treatment regimen was standardized in both groups. From January 2003 to December 2005, therapy was suspended in PsA patients and controls if achieving remission. RESULTS: One or more episodes of remission occurred in 57/236 (24.1%) PsA patients and in 20/268 (7.5%) controls (P < 0.001). The mean duration of remission was of 13 +/- 9.4 months in PsA patients and 4 +/- 3.7 in controls (P > 0.001). Remission episodes were more frequent in PsA patients treated with anti-TNF compared with those receiving traditional DMARDs (P > 0.001), with no differences regarding the duration. After therapy interruption, the remission duration was 12 +/- 2.4 months in PsA and 3 +/- 1.5 in RA (P < 0.001). No remission predictor at diagnosis resulted by multivariate analysis. CONCLUSION: Remission is possible in up to 24% of patients with peripheral PsA. It is significantly more frequent, but not longer, in patients receiving anti-TNF drugs compared with those treated with traditional DMARDs. Patients remain in remission for a long period after therapy interruption, thus suggesting an intermittent therapeutic strategy.
17303203 Inhibitory effects of melittin on the production of lipopolysaccharide-induced matrix meta 2007 May In continuation of our previous study which explored the effect of bee venom (BV) on the global gene expression profiles in lipopolysaccharide (LPS)-treated human chondrosarcoma cells, we investigated herein the effect of melittin, a major component of BV, on the productions of matrix metalloproteinases (MMPs) 1, 3, and 13 in primary cultured human arthritic chondrocytes. Increased generations of MMPs 1, 3, and 13 were observed by MMPs stimulating agents LPS, tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The generations of LPS (1 microg/ml)-induced MMPs 1 and 13 were not decreased by melittin, whereas that of LPS-stimulated MMP 3 was significantly inhibited by melittin. IL-1beta (10ng/ml) and TNF-alpha (10ng/ml)-induced MMPs 1, 3 and 13, however, were not decreased by melittin. Immunoblot analysis revealed that melittin exerted no effect on the LPS-stimulated expression levels of MMPs 1 and 13 but attenuated the LPS-induced MMP 3, which is consistent with the enzyme-linked immunosorbent assay (ELISA) data. Taken together, these findings suggest melittin may exert its anti-arthritic effect, at least in part, by inhibiting LPS-stimulated MMP 3 production in human osteoarthritic chondrocytes.