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Active RA (active + ra)
Selected AbstractsLatest news and product developmentsPRESCRIBER, Issue 22 2007Article first published online: 28 DEC 200 Glitazones: benefits outweigh the risks Following a review of the safety of rosiglitazone and pioglitazone, the European Medicines Agency (EMEA) has concluded that their benefits outweigh their risks in the approved indications. The review was prompted by reports of an increased risk of fractures in women and, in patients taking rosiglitazone, ischaemic heart disease. The EMEA concluded that prescribing information for rosiglitazone should now include a warning that, in patients with ischaemic heart disease, it should only be used after careful evaluation of each patient's individual risk, and the combination of rosiglitazone and insulin should only be used in exceptional cases and under close supervision. No change was considered necessary to the prescribing information for pioglitazone. Modern dressings no better? A systematic review has found only weak evidence that modern dressings are better than saline gauze or paraffin gauze for healing acute and chronic wounds (Arch Dermatol 2007;143: 1297-304). The analysis, which included 99 studies, found that only hydrocolloids were demonstrably better than older dressings for healing chronic wounds, and alginates were superior to other modern dressings for debriding necrotic wounds. There was no evidence that modern dressings offered superior overall performance to the older alternatives. Hospital inflation twice primary care level The cost of drugs prescribed in secondary care but dispensed in the community increased by 6.4 per cent in 2006 - twice the rate of inflation in primary care - according to the latest statistics on hospital prescribing in England. The increase follows a reduction in costs in 2005 after the introduction of the new PPRS scheme. Data from The Information Centre (www.ic.nhs.uk) show that hospital medicines make up about 24 per cent of the NHS drugs budget. Secondary care has a consistently better record than primary care in prescribing lower-cost alternatives within therapeutic categories, eg simvastatin and pravastatin among the statins, omeprazole and lansoprazole among PPIs, and ACE inhibitors among drugs acting on the renin angiotensin system. The most expensive drug prescribed by hospital specialists and dispensed in the community is interferon beta. MHRA limits the use of fibrates The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that fibrates should now be reserved for the treatment of isolated severe hypertriglyceridaemia. They should be considered for hypercholesterolaemia only when a statin or other treatment is contraindicated or not tolerated. In the latest Drug Safety Update, the MHRA says there is insufficient evidence of long-term benefits from fibrates, and first-line use is no longer justified because the evidence for the benefits of statins is robust. The MHRA also warns that some breastfeeding infants have increased susceptibility to the adverse effects of codeine taken by their mother, and that St John's wort may affect the hepatic metabolism of any anticonvulsant. Annual zoledronic acid infusion cuts mortality after hip fracture Once-yearly infusion of zoledronic acid (Aclasta) after hip fracture reduces deaths over a two-year period by 28 per cent compared with placebo, US investigators say (N Engl J Med 2007;357:1799-809). The HORIZON Recurrent Fracture Trial randomised 2127 men and women (mean age 75) within 90 days of surgery for hip fracture to zoledronic acid 5mg yearly or placebo. Mortality over 1.9 years of follow-up was 9.6 per cent with zoledronic acid and 13.3 per cent with placebo. Zoledronic acid also significantly reduced the rate of any new clinical fractures (by 35 per cent) and new clinical vertebral fractures(by 45 per cent),but the lower rate of hip fracture (2.0 vs 3.5 per cent with placebo) was not statistically significant. Rivastigmine patch for mild to moderate AD Rivastigmine (Exelon) is now available as a transdermal patch for the treatment of mild to moderate Alzheimer's disease. Applied once daily, the patch delivers 9.5mg per 24 hours and, says manufacturer Novartis, is associated with a lower incidence of nausea and vomiting than a comparable oral dose. The patch is available in two strengths: 4.6mg per 24hr is equivalent to oral doses of 3 or 6mg per day, and the 9.5mg per 24hr patch is equivalent to 9 or 12mg per day orally. The recommended dose of the patch is 9.5mg per day; both strengths cost £83.84 for 30 patches. Women more aspirin resistant than men? The cardioprotective effect of low-dose aspirin may be lower in women than men, say Canadian investigators (BMC Medicine 2007;5:29 doi: 10.1186/1741-70155-29). Their meta-analysis of 23 randomised trials involving a total of 113 494 participants found that aspirin significantly reduced the risk of nonfatal but not fatal myocardial infarction (MI). About one-quarter of the variation in its effects on nonfatal MI was accounted for by the sex mix of the trial population. Separating the results by sex showed the reduction in risk with aspirin use was statistically significant in men (relative risk, RR, 0.62) but not in women (RR 0.87). Look after physical health of mentally ill GPs and other primary care workers should take more responsibility for the physical health of their mentally ill patients, say advocacy groups. Mind and Body: Preventing and Improving Physical Health Problems in Patients With Schizophrenia points out that the mental health needs of patients with schizophrenia are met in secondary care, but their physical health needs should be met in primary care. In particular, the metabolic effects of antipsychotics may lead to obesity, diabetes and cardiovascular disease, and weight gain in particular is a frequent reason for nonadherence to treatment. The Mind and Body Manifesto was developed by SANE, The Mental Health Nurses Association, The National Obesity Forum and The Disability Rights Commission and sponsored by Bristol-Myers Squibb Pharmaceuticals Limited and Otsuka Pharmaceuticals (UK) Ltd. Copies are available from elizabeth.green@ ogilvyhealthworld.com. Health eCard costs Some costs quoted in our article on the Health eCard (The Health eCard: the way ahead for medical records?,5 October issue, pages 28-9) have been revised: the card and initial download will cost patients £39.50, and GPs will be entitled to charge patients £10 per annum for subsequent downloads. NICE appraisals of cytokine inhibitors in RA NICE has endorsed the use of the anti-TNF agents adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), normally in conjunction with methotrexate, for the treatment of active RA when methotrexate and another DMARD have failed (also see New from NICE below). NICE has provisionally concluded, subject to consultation, that abatacept (Orencia) should not be recommended for the treatment of RA. Boots and BMJ launch health advice site www.askbootshealth.com is a new website providing information about health and medicines for the public produced by Boots using information provided by the BMJ Publishing Group. The website covers many of the topics already available from NHSDirect, with perhaps more information about available treatments. Diabetes care shows small improvement The third National Diabetes Audit in England and Wales has found that more people with diabetes were achieving the targets set by NICE for cholesterol levels, glycaemic control and blood pressure in 2005/06 - but younger patients were doing less well. Overall, the HbA1C target of ,7.5 per cent was achieved in 60 per cent of people with diabetes compared with 58 per cent in 2004/05. However, HbA1C was >9.5 per cent in 30 per cent of children and young people, of whom 9 per cent experienced at least one episode of ketoacidosis. More topics for NICE New topics referred to NICE include clinical guidelines on ovarian cancer, coeliac disease and stable angina, public health guidance on preventing cardiovascular disease, and technology appraisals on insulin detemir (Levemir) for type 1 diabetes, several treatments for cancer and hepatic and haematological disorders, and biological therapies for juvenile arthritis. New from NICE NICE appraisal on anti-TNFs for RA Since NICE published its first appraisal of agents acting against tumour necrosis factor-alpha (anti-TNFs) for the treatment of RA in 2002, the product licences for etanercept (Enbrel) and infliximab (Remicade) have changed and a new agent, adalimumab (Humira), has been introduced. The anti-TNFs act in different ways. Infliximab is a chimeric monoclonal antibody that binds to TNF-alpha, neutralising its activity. Etanercept, a recombinant human TNF-alpha receptor fusion protein, and adalimumab, a human-sequence antibody, both bind to TNF-alpha and block its interaction with cell surface receptors. Adalimumab also modulates some biological responses induced or regulated by TNF-alpha. These agents are recommended for adults with severe active RA (defined as a disease activity score - DAS28 - greater than 5.1) who have already tried two disease-modifying drugs, including methotrexate (if not contraindicated). Prior treatment should have been of at least six months' duration, including two months at the standard dose (unless limited by toxicity). Anti-TNFs should normally be prescribed with methotrexate; when this is not appropriate, etanercept and adalimumab may be prescribed as monotherapy. Treatment with an anti-TNF should be continued beyond six months only if there is an adequate response (defined as an improvement in DAS28 of at least 1.2). Data from the British Rheumatology Society Biologics register show that, after six months, 67 per cent of patients met NICE criteria for an adequate response; this declined to 55 per cent at 18 months. The basic annual cost of treatment is £9295 for adalimumab 40mg on alternate weeks or etanercept 25mg twice weekly; infliximab costs £3777 for a loading dose, then £7553-£8812 depending on dose. Assuming no progression of disability, the incremental costs per QALY (compared with sequential DMARDs) were £30 200 for adalimumab, £24 600 for etanercept and £39 400 for infliximab. There are no direct comparative trials of the anti-TNFs, and their clinical trial findings are not directly comparable. Unless other factors determine treatment choice, NICE therefore recommends the least expensive. If the first anti-TNF is withdrawn within six months due to an adverse event, a second may be tried. [source] Rituximab: first monoclonal antibody for severe, active RAPRESCRIBER, Issue 12 2007Article first published online: 4 OCT 200 Rituximab (MabThera) is a monoclonal antibody that exerts a novel anti-inflammatory action in rheumatoid arthritis via B-cell depletion. In our New products review Michael Guida presents the clinical data relating to its efficacy and adverse effects, and Dr Michael Plant comments on its place in therapy. Copyright © 2007 Wiley Interface Ltd [source] Role of Th17 cells in human autoimmune arthritisARTHRITIS & RHEUMATISM, Issue 10 2010Jan Leipe Objective To delineate the role of Th17 cells in the pathogenesis of autoimmune arthritides. Methods Th17 cells were analyzed in well-defined homogeneous cohorts of patients with the prototypical autoimmune arthritides rheumatoid arthritis (RA) and psoriatic arthritis (PsA), grouped according to patients who had very early active RA (n = 36; mean disease duration 2.8 months, Disease Activity Score in 28 joints 5.0) and those who had very early active PsA (n = 20; mean disease duration 2.3 months), none of whom had received treatment with glucocorticoids or disease-modifying antirheumatic drugs, as well as patients with established RA (n = 21; mean disease duration 68 months) who were considered either responders or nonresponders to therapy. Groups of healthy individuals and patients with osteoarthritis (a noninflammatory arthritis) were used as control cohorts. Expression of T lineage,specific transcription factors (RORC, T-bet, GATA-3, and FoxP3) and the response of CD4 T cells to Th17 cell,inducing conditions were analyzed in vitro. Results The frequencies of Th17 cells and levels of interleukin-17 strongly correlated with systemic disease activity at both the onset and the progression of RA or PsA. The values were reduced to control levels in patients with treatment-controlled disease activity. Th17 cells were enriched in the joints, and increased frequencies of synovial Th17 cells expressed CCR4 and CCR6, indicative of selective migration of Th17 cells to the joints. The intrinsically elevated expression of RORC, accompanied by biased Th17 cell development, and the resistance of Th17 cells to a natural cytokine antagonist in patients with RA and patients with PsA were suggestive of the underlying molecular mechanisms of uncontrolled Th17 activity in these patients. Conclusion Th17 cells play an important role in inflammation in human autoimmune arthritides, both at the onset and in established disease. [source] Glucocorticoid-induced leucine zipper is an endogenous antiinflammatory mediator in arthritisARTHRITIS & RHEUMATISM, Issue 9 2010Elaine Beaulieu Objective Glucocorticoid-induced leucine zipper (GILZ) is a glucocorticoid-induced protein, the reported molecular interactions of which suggest that it functions to inhibit inflammation. However, the role of endogenous GILZ in the regulation of inflammation in vivo has not been established. This study was undertaken to examine the expression and function of GILZ in vivo in collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis (RA), and in RA synoviocytes. Methods GILZ expression was detected in mouse and human synovium by immunohistochemistry and in cultured cells by real-time polymerase chain reaction and permeabilization flow cytometry. GILZ function was assessed in vivo by small interfering RNA (siRNA) silencing using cationic liposome,encapsulated GILZ or control nontargeting siRNA and was assessed in vitro using transient overexpression. Results GILZ was readily detectable in the synovium of mice with CIA and was up-regulated by therapeutic doses of glucocorticoids. Depleting GILZ expression in vivo increased the clinical and histologic severity of CIA and increased synovial expression of tumor necrosis factor and interleukin-1 (IL-1), without affecting the levels of circulating cytokines or anticollagen antibodies. GILZ was highly expressed in the synovium of patients with active RA and in cultured RA synovial fibroblasts, and GILZ overexpression in synovial fibroblasts inhibited IL-6 and IL-8 release. Conclusion Our findings indicate that GILZ functions as an endogenous inhibitor of chronic inflammation via effects on cytokine expression and suggest that local modulation of GILZ expression could be a beneficial therapeutic strategy. [source] Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: Results of a randomized, double-blind, placebo-controlled, phase I/II study,ARTHRITIS & RHEUMATISM, Issue 8 2010Mikkel Østergaard Objective To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to ,1 disease-modifying antirheumatic drug. Methods This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. Results AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. Conclusion Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA. [source] The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritisARTHRITIS & RHEUMATISM, Issue 7 2010Amalia P. Raptopoulou Objective T cells play a major role in the pathogenesis of rheumatoid arthritis (RA). The programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway is involved in peripheral tolerance through inhibition of T cells at the level of synovial tissue. The aim of this study was to examine the role of PD-1/PDL-1 in the regulation of human and murine RA. Methods In synovial tissue and synovial fluid (SF) mononuclear cells from patients with RA, expression of PD-1/PDL-1 was examined by immunohistochemistry and flow cytometry, while PD-1 function was assessed in RA peripheral blood (PB) T cells after stimulation of the cells with anti-CD3 and PDL-1.Fc to crosslink PD-1. Collagen-induced arthritis (CIA) was induced in PD-1,/, C57BL/6 mice, and recombinant PDL-1.Fc was injected intraperitoneally to activate PD-1 in vivo. Results RA synovium and RA SF were enriched with PD-1+ T cells (mean ± SEM 24 ± 5% versus 4 ± 1% in osteoarthritis samples; P = 0.003) and enriched with PDL-1+ monocyte/macrophages. PD-1 crosslinking inhibited both T cell proliferation and production of interferon-, (IFN,) in RA patients; PB T cells incubated with RA SF, as well as SF T cells from patients with active RA, exhibited reduced PD-1,mediated inhibition of T cell proliferation at suboptimal, but not optimal, concentrations of PDL-1.Fc. PD-1,/, mice demonstrated increased incidence of CIA (73% versus 36% in wild-type mice; P < 0.05) and greater severity of CIA (mean maximum arthritis score 5.0 versus 2.3 in wild-type mice; P = 0.040), and this was associated with enhanced T cell proliferation and increased production of cytokines (IFN, and interleukin-17) in response to type II collagen. PDL-1.Fc treatment ameliorated the severity of CIA and reduced T cell responses. Conclusion The negative costimulatory PD-1/PDL-1 pathway regulates peripheral T cell responses in both human and murine RA. PD-1/PDL-1 in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA. [source] The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulationARTHRITIS & RHEUMATISM, Issue 6 2010Lena Björkman Objective Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. Methods Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. Results Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. Conclusion The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response. [source] Rapid and sustained improvement in bone and cartilage turnover markers with the anti,interleukin-6 receptor inhibitor tocilizumab plus methotrexate in rheumatoid arthritis patients with an inadequate response to methotrexate: Results from a substudy of the multicenter double-blind, placebo-controlled trial of tocilizumab in inadequate responders to methotrexate alone,ARTHRITIS & RHEUMATISM, Issue 1 2010Patrick Garnero Objective To investigate the effects of tocilizumab (TCZ) added to a stable dosage of methotrexate (MTX) on biochemical markers of bone and cartilage metabolism in patients in the multicenter double-blind, placebo-controlled OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders) study who have moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to MTX. Methods Included in this study were 416 of the 623 patients with active RA enrolled in the OPTION study. Patients were randomized to receive TCZ (4 mg/kg or 8 mg/kg) or placebo intravenously every 4 weeks, with MTX continued at the stable prestudy doses (10,25 mg for 20 weeks, with a final followup at week 24). Serum biochemical markers of bone formation (osteocalcin, N-terminal propeptide of type I collagen [PINP]), bone resorption (C-terminal crosslinking telopeptide of type I collagen [CTX-I] and C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases [ICTP]), cartilage metabolism (N-terminal propeptide of type IIA collagen [PIIANP]), collagen helical peptide [HELIX-II]), and matrix metalloproteinase 3 (MMP-3) were measured at baseline and at weeks 4, 16, and 24. Results TCZ induced marked dose-dependent reductions in PIIANP, HELIX-II, and MMP-3 levels at week 4 that were maintained until week 24, an effect associated with increased levels of bone formation markers that were significant as compared with placebo only for PINP and only at 4 weeks (P < 0.01 for both TCZ doses). TCZ induced significant decreases in the bone degradation markers CTX-I and ICTP, providing initial evidence of a beneficial effect on bone turnover. TCZ-treated patients who met the American College of Rheumatology 50% improvement criteria (achieved an ACR50 response) or achieved clinical remission (as determined by a Disease Activity Score in 28 joints <2.6) at week 24 had greater reductions in ICTP, HELIX-II, and MMP-3 levels as compared with ACR50 nonresponders. Conclusion TCZ combined with MTX reduces systemic bone resorption, cartilage turnover, and proteolytic enzyme MMP-3 levels, which provides evidence of a limitation of joint damage and possible beneficial effects on skeletal structure in patients with established moderate-to-severe RA. [source] Novel role of plasmacytoid dendritic cells in humans: Induction of interleukin-10,producing treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapyARTHRITIS & RHEUMATISM, Issue 1 2010Melina Kavousanaki Objective Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting. Methods DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25, T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay. Results Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25, T cells into interleukin-10,secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC,primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner. Conclusion These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation. [source] Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial,ARTHRITIS & RHEUMATISM, Issue 1 2010Clifton O. Bingham III Objective To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab-induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell,dependent antigen), pneumococcal polysaccharide (T cell,independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed-type hypersensitivity (DTH). Methods In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab-treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ,4-fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti-KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2,3 days following placement. Results Responses to tetanus toxoid vaccine (,4-fold rise) were similar in both groups (39.1% of rituximab-treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab-treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab-treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2-fold rise in titer in response to ,1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti-KLH IgG, compared with 93% of patients treated with MTX alone). Conclusion Recall responses to the T cell,dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab-treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell,independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses. [source] Brain involvement in rheumatoid arthritis: A magnetic resonance spectroscopy studyARTHRITIS & RHEUMATISM, Issue 11 2009Bart J. Emmer Objective Tumor necrosis factor , was recently implicated as an important mediator of communication between the peripheral and cerebral immune systems in an animal model of chronic inflammation. The purpose of this study was to examine by proton magnetic resonance spectroscopy (1H-MRS) the influence of inflammation on cerebral metabolism in patients with rheumatoid arthritis (RA). Methods Single-voxel 1H-MRS of the centrum semiovale was performed on 35 RA patients (6 men and 29 women; mean ± SD age 51.8 ± 14.6 years) and 28 healthy age- and sex-matched control subjects (9 men and 19 women; mean ± SD age 50.2 ± 10.4 years). None of the study subjects had any neurologic signs or symptoms. Clinical markers of disease activity were correlated with the 1H-MRS findings. Results Patients with active RA, as reflected by an elevated erythrocyte sedimentation rate (ESR), had a significantly higher ratio of choline to creatine and a significantly lower ratio of N -acetylaspartate to choline than did patients with inactive RA, as reflected by a normal ESR. Moreover, the ratios of choline to creatine and NAA to choline were significantly correlated with the ESR after correction for age, sex, smoking status, handedness, alcohol consumption, medication use, and disease duration. Medication use had no additional effect on these associations. Conclusion Our data show that systemic inflammation in RA is associated with metabolic changes in the brain. [source] Epitope-specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial,ARTHRITIS & RHEUMATISM, Issue 11 2009Eva C. Koffeman Objective Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. Methods One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. Results The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor , and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity. [source] The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: A prospective study,,ARTHRITIS & RHEUMATISM, Issue 11 2009Ruth Klaasen Objective Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment. Methods Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA). Results Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R2 = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R2 = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti,cyclic citrullinated peptide antibody positivity, and synovial TNF, expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA. Conclusion RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment. [source] Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 10 2009Christina Charles-Schoeman Objective To characterize the antiinflammatory function of high-density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL-associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL. Methods We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell-free assay, and proinflammatory HDL was defined by an HDL inflammatory index ,1. Plasma and HDL-associated protein levels of apolipoprotein A-I (Apo A-I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme-linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay. Results Age, disease activity, the presence of erosive disease, non-Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A-I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001). Conclusion Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality. [source] The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: The eleven-year results of the Finnish rheumatoid arthritis combination therapy trialARTHRITIS & RHEUMATISM, Issue 5 2009Vappu Rantalaiho Objective To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD. Methods A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission. Results At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean ± SD HAQ scores were 0.34 ± 0.54 in the combination-DMARD group and 0.38 ± 0.58 in the single-DMARD group (P = 0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P = 0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P = 0.017), respectively. Conclusion Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients. [source] Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studiesARTHRITIS & RHEUMATISM, Issue 3 2009Elizabeth W. Karlson Objective To examine the association of biomarkers of inflammation with preclinical rheumatoid arthritis (RA). Methods A nested case,control study was performed using samples from 2 large, prospectively studied cohorts of women (the Women's Health Study [WHS] and the Nurses' Health Study [NHS]). Blood samples obtained prior to symptom onset in women who later developed RA were selected as incident RA cases, and 3 controls per case were randomly chosen, matched for age, menopausal status, postmenopausal hormone use, and day, time, and fasting status at the time of collection. Plasma was tested for levels of interleukin-6 (IL-6), soluble tumor necrosis factor receptor II (sTNFRII) (as a proxy for TNF,), and high-sensitivity C-reactive protein. Relationships between biomarkers and RA were assessed using conditional logistic regression models, adjusting for age, body mass index, smoking habits, ethnicity, and reproductive factors. Results In 93 incident cases in the NHS and 77 incident cases in the WHS, the mean time between blood collection and the onset of RA symptoms was 5.2 years (range 0.3,12 years). Median IL-6 and sTNFRII levels were significantly higher in preclinical RA cases compared with matched controls in the NHS (P = 0.03 and P = 0.003, respectively) though not in the WHS. Pooled analysis of the NHS and WHS cohorts demonstrated significant association of sTNFRII with RA (relative risk 2.0 [95% confidence interval 1.1,3.6], P for trend = 0.004), and a modest association of IL-6 with RA (relative risk 1.4 [95% confidence interval 0.8,2.5], P for trend = 0.06). Conclusion Levels of sTNFRII, a biomarker typically associated with active RA, were elevated up to 12 years prior to the development of RA symptoms and were positively associated with incident RA in these nested case,control studies. Studies with repeated assessments of biomarkers prior to RA development may provide further insight into the timing of biomarker elevation in preclinical RA. [source] Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis,ARTHRITIS & RHEUMATISM, Issue 2 2009Stanley B. Cohen Objective To determine the efficacy and safety of pamapimod (a selective inhibitor of the ,-isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA). Methods Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double-blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs. Results Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300-mg dose appeared to be more toxic than either the 2 lower doses or MTX. Conclusion The present results showed that pamapimod was not as effective as MTX in the treatment of active RA. [source] Treatment of rheumatoid arthritis with a syk kinase inhibitor: A twelve-week, randomized, placebo-controlled trial,ARTHRITIS & RHEUMATISM, Issue 11 2008Michael E. Weinblatt Objective Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fc,-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA). Methods We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Results Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related. Conclusion These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions. [source] Rituximab for rheumatoid arthritis refractory to anti,tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeksARTHRITIS & RHEUMATISM, Issue 9 2006Stanley B. Cohen Objective To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti,tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population. Methods We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy,Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks. Results Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group. Conclusion At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies. [source] The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destructionARTHRITIS & RHEUMATISM, Issue 6 2006P. P. Geusens Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. Methods OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. Results The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P , 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. Conclusion This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio). [source] Followup radiographic data on patients with rheumatoid arthritis who participated in a two-year trial of prednisone therapy or placeboARTHRITIS & RHEUMATISM, Issue 5 2006Johannes W. G. Jacobs Objective In a previous clinical trial of patients with early rheumatoid arthritis (RA), it was determined that patients who received 10 mg of prednisone per day for 2 years had less radiographic joint damage compared with those who received placebo. Our goal was to investigate whether this beneficial effect persisted after the end of the trial. Methods A blinded assessment of radiographic joint damage was performed ,3 years after the end of the original 2-year study. Twenty-four patients from the original prednisone group (60%) and 28 patients from the original placebo group (68%) participated in this followup study. At the end of the original trial, prednisone dosages were tapered down in the prednisone group and stopped, if possible. Patients from the original prednisone group took prednisone during 35% of the followup period (,1 year) at a mean daily dose of ,5 mg. Two patients from the original placebo group started taking prednisone during followup. Radiographs of the hands and feet were scored according to the van der Heijde modification of the Sharp method. Results During 3 additional years of followup, radiographic scores showed significantly less progression in the original prednisone group than in the original placebo group. Radiographic damage in the original prednisone group did not show an accelerated rate of progression during the followup period. Conclusion The inhibition of radiographic joint damage in patients with early active RA treated with 10 mg of prednisone per day for 2 years seems to persist after the end of prednisone therapy. [source] The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: A large, randomized, placebo-controlled trialARTHRITIS & RHEUMATISM, Issue 4 2006Rene Westhovens Objective To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities. Methods Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n = 363), 3 mg/kg infliximab (group 2, n = 360), or 10 mg/kg infliximab (group 3, n = 361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg. Results At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3,3.1, P = 0.995) and 3.1 (95% CI 1.2,7.9, P = 0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis. Conclusion The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22. [source] The LUNDEX, a new index of drug efficacy in clinical practice: Results of a five-year observational study of treatment with infliximab and etanercept among rheumatoid arthritis patients in southern SwedenARTHRITIS & RHEUMATISM, Issue 2 2006Lars Erik Kristensen Objective To describe the use of the LUNDEX, a new index for comparing the long-term efficacy and tolerability of biologic therapies in rheumatoid arthritis (RA) patients treated in clinical practice. Methods Patients (n = 949) with active RA that had not responded to at least 2 disease-modifying antirheumatic drugs (DMARDs) including methotrexate, in whom biologic therapy was being initiated, were included in a structured clinical followup protocol. The protocol included collection of data on diagnosis, disease duration, previous and ongoing DMARD treatment, and dates on which biologic treatment was started and terminated. In addition, data on efficacy measures used for calculating validated response criteria, i.e., the European League Against Rheumatism and American College of Rheumatology response criteria, were collected at fixed time points. Data were prospectively registered from March 1999 through January 2004. The LUNDEX, a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy, was designed to compare the efficacy of the different therapies. Results Etanercept had higher overall LUNDEX values compared with infliximab, mostly because of a lower rate of adherence to therapy with infliximab. The relationship between the drugs was consistent irrespective of the response criteria used. Conclusion The LUNDEX is a valuable tool for evaluating drug efficacy in observational studies. It has the advantage of integrating clinical response as well as adherence to therapy in a composite value. Moreover, the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria. [source] Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: A double-blind trialARTHRITIS & RHEUMATISM, Issue 12 2003David E. Yocum Objective To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA). Methods This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg. Results A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by ,40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in ,90% of patients. Conclusion Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates. [source] Association of interleukin-18 expression with enhanced levels of both interleukin-1, and tumor necrosis factor , in knee synovial tissue of patients with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2003Leo A. B. Joosten Objective To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation. Methods Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor , (TNF,), IL-1,, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained. Results IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1, (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNF, (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17. Conclusion Our results show that expression of IL-18 is associated with that of IL-1, and TNF, and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1, and TNF,. [source] Elucidation of the relationship between synovitis and bone damage: A randomized magnetic resonance imaging study of individual joints in patients with early rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 1 2003Philip G. Conaghan Objective To simultaneously image bone and synovium in the individual joints characteristically involved in early rheumatoid arthritis (RA). Methods Forty patients with early, untreated RA underwent gadolinium-enhanced magnetic resonance imaging (MRI) of the second through fifth metacarpophalangeal joints of the dominant hand at presentation, 3 months, and 12 months. In the first phase (0,3 months), patients were randomized to receive either methotrexate alone (MTX) or MTX and intraarticular corticosteroids (MTX + IAST) into all joints with clinically active RA. The MTX-alone group received no further corticosteroids until the second phase (3,12 months), when both groups received standard therapy. Results In the first phase, MTX + IAST reduced synovitis scores more than MTX alone. There were significantly fewer joints with new erosions on MRI in the former group compared with the latter. During the second phase, the synovitis scores were equivalent and a similar number of joints in each group showed new erosions on MRI. In both phases, there was a close correlation between the degree of synovitis and the number of new erosions, with the area under the curve for MRI synovitis the only significant predictor of bone damage progression. In individual joints, there was a threshold effect on new bone damage related to the level of synovitis; no erosions occurred in joints without synovitis. Conclusion In early RA, synovitis appears to be the primary abnormality, and bone damage occurs in proportion to the level of synovitis but not in its absence. In the treatment of patients with RA, outcome measures and therapies should focus on synovitis. [source] Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: Results of a twenty-four,week, multicenter, randomized, double-blind, placebo-controlled trialARTHRITIS & RHEUMATISM, Issue 3 2002Stanley Cohen Objective To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). Methods Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ,3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. Results A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. Conclusion In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone. [source] | ||||||||||