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ID PMID Title PublicationDate abstract
16936264 JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosi 2006 Sep Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-alpha stimulation. Here, we show that JAB1 is a critical regulator of the TNF-alpha-mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-alpha-induced apoptosis response, reduction of nuclear factor-kappaB activity, delayed degradation of IkappaB-alpha, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF-alpha to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-alpha stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-alpha can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-kappaB and JNK in RA FLSs.
18474811 Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in 2008 May 20 BACKGROUND: Interleukin-1 increases nitrooxidative stress. We investigated the effects of a human recombinant interleukin-1a receptor antagonist (anakinra) on nitrooxidative stress and vascular and left ventricular function. METHODS AND RESULTS: In an acute, double-blind trial, 23 patients with rheumatoid arthritis were randomized to receive a single injection of anakinra (150 mg s.c.) or placebo and, after 48 hours, the alternative treatment. At baseline and 3 hours after the injection, we assessed (1) coronary flow reserve, aortic distensibility, systolic and diastolic (Em) velocity of the mitral annulus, and E to Em ratio (E/Em) using echocardiography; (2) flow-mediated, endothelium-dependent dilation of the brachial artery; and (3) malondialdehyde, nitrotyrosine, interleukin-6, endothelin-1, and C-reactive protein. In a chronic, nonrandomized trial, 23 patients received anakinra and 19 received prednisolone for 30 days, after which all indices were reassessed. Compared with baseline, there was a greater reduction in malondialdehyde, nitrotyrosine, interleukin-6, and endothelin-1 and a greater increase in flow-mediated dilation, coronary flow reserve, aortic distensibility, systolic velocity of mitral annulus, and E/Em after anakinra than after placebo (malondialdehyde -25% versus 9%; nitrotyrosine -38% versus -11%; interleukin-6 -29% versus 0.9%; endothelin-1 -36% versus -11%; flow-mediated dilation 45% versus -9%; coronary flow reserve 29% versus 4%; and aortic distensibility 45% versus 2%; P<0.05 for all comparisons). After 30 days of treatment, the improvement in biomarkers and in vascular and left ventricular function was greater in the anakinra group than in the prednisolone group (P<0.05). CONCLUSIONS: Interleukin-1 inhibition improves vascular and left ventricular function and is associated with reduction of nitrooxidative stress and endothelin.
18785314 Genetic and expression analysis of CASP7 gene in a European Caucasian population with rheu 2008 Oct OBJECTIVE: To study the possible role of the caspase 7 (CASP7) gene in susceptibility to rheumatoid arthritis (RA) in a European Caucasian population. METHODS: CASP7 rs2227309 single nucleotide polymorphism (SNP) was genotyped in 197 French RA trio families and in 252 European RA families available for replication using Taqman allelic discrimination assay. Relative quantification of caspase 7 isoforms alpha and beta mRNA expression was performed from whole blood in 25 unrelated patients with RA and in 15 healthy controls by real-time quantitative reverse transcription-polymerase chain reaction. The genetic analyses for association and linkage were performed using the comparison of allelic frequencies, the transmission disequilibrium test, and the genotype relative risk. RESULTS: We observed, in the first sample, a significant association of rs2227309-AA genotype with RA [p=0.03, odds ratio (OR) 2.11 (95% CI 1.0-4.6)]. The second sample did not show any significant association of the AA genotype with RA [p=0.6, OR 0.87 (95% CI 0.4-1.8)]. When the 2 samples were combined, no significant association of the AA genotype [p=0.3, OR 1.32 (95% CI 0.8-2.2)] was observed. CASP7 isoforms alpha and beta mRNA were expressed in patients with RA at lower level than in healthy controls (-89%, p=0.003 and -47%, p=0.01; respectively). CONCLUSION: CASP7 rs2227309 SNP was not associated with RA in a European Caucasian population. Nevertheless, CASP7 isoforms alpha and beta could have an involvement in the apoptosis process in RA.
18030180 Reporting of adherence to medication in recent randomized controlled trials of 6 chronic d 2007 Oct BACKGROUND: International recommendations such as the CONSORT and International Conference on Harmonisation statements recognize patient adherence to prescribed treatment as an important aspect of a treatment's evaluation, but this issue is little assessed. OBJECTIVES: To evaluate how medication adherence was assessed and reported in recently published randomized controlled trials (RCTs). MATERIAL AND METHODS: All publications of RCTs assessing pharmacological treatments in 6 major chronic diseases published in high-impact-factor journals in 2003 and 2004 were selected from the Medline database. Two investigators analyzed how medication adherence was assessed and reported. RESULTS: A total of 192 publications were analyzed: 71 in HIV infection, 48 diabetes mellitus, 24 rheumatoid arthritis, 23 asthma, 15 hypertension, 7 osteoporosis, and 4 about 2 of these diseases. The assessment of medication adherence was documented in 69 (35.9%) publications, by counting pill intake in half of these. Results of adherence were reported in 64 (33.3%) publications. Adherence was reported as a quantitative measure: Proportion of the treatment prescribed in 27 articles and as a qualitative measure (adherent patient, yes/no) in 41 (in 4 reports both techniques were used). When reported, the median intake of prescribed medication was 93%, and the median proportion of "nonadherent" patients was 6.2%. CONCLUSIONS: There is important variability in the assessment and reporting of medication adherence in published RCTs of pharmacological treatments of selected chronic diseases, for a given disease and across diseases. Standardization is advisable to allow for comparisons among studies.
16247581 Association of systemic and thyroid autoimmune diseases. 2006 Mar OBJECTIVE: There are few large cohort studies available on the association of systemic and thyroid autoimmune diseases. In this study, we wished to determine the association of Hashimoto's thyroiditis (HT) and Graves' disease (GD) with systemic autoimmune diseases. METHODS: One thousand five hundred and seventeen patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), mixed connective tissue disease (MCTD), Sjögren's syndrome (SS) and polymyositis/dermatomyositis (PM/DM) were included in the study. The HT and GD were diagnosed based on thorough clinical evaluation, imaging and fine-needle aspiration cytology (FNAC). The frequency of HT and GD in these diseases was assessed. In addition, 426 patients with HT or GD were assessed and the incidence of SLE, RA, SSc, MCTD, SS and PM/DM among these patients was determined. Prevalence ratios indicating the prevalences of GD or HT among our autoimmune patients in comparison to prevalences of GD or HT in the general population were calculated. RESULTS: Altogether 8.2% of systemic autoimmune patients had either HT or GD. MCTD and SS most frequently overlapped with autoimmune thyroid diseases (24 and 10%, respectively). HT was more common among MCTD, SS and RA patients (21, 7 and 6%, respectively) than GD (2.5, 3 and 1.6%, respectively). The prevalences of HT in SLE, RA, SSc, MCTD, SS and PM/DM were 90-, 160-, 220-, 556-, 176- and 69-fold higher than in the general population, respectively. The prevalences of GD in the same systemic diseases were 68-, 50-, 102-, 76-, 74- and 37-fold higher than in the general population, respectively. Among all thyroid patients, 30% had associated systemic disease. In particular, 51% of HT and only 16% of GD subjects had any of the systemic disorders. MCTD, SS, SLE, RA, SSc and PM/DM were all more common among HT patients (20, 17, 7, 4, 2 and 2%, respectively) than in GD individuals (2, 5, 5, 1, 2 and 1%, respectively). CONCLUSION: Systemic and thyroid autoimmune diseases often overlap with each other. HT and GD may be most common among MCTD, SSc and SS patients. On the other hand, these systemic diseases are often present in HT subjects. Therefore it is clinically important to screen patients with systemic autoimmune diseases for the co-existence of thyroid disorders.
16824715 Immunomodulatory activity of Semecarpus anacardium extract in mononuclear cells of normal 2006 Dec 6 Semecarpus anacardium (SA) Linn. (family Anacardiaceae), is a plant well-known for its medicinal value in Ayurveda. The nut extracts of this plant have been traditionally used as antihelminthic, anti-fungal, anti-carcinogenic and in the treatment of nervous debilities and arthritis. In this study we have evaluated crude ethanolic extract of SA nuts for its anti-inflammatory activities in vitro using peripheral blood and synovial fluid mononuclear cells of healthy individuals and rheumatoid arthritis (RA) patients. SA extract inhibited the spontaneous and LPS induced production of proinflammatory cytokines IL-1beta and IL-12p40 but had no effect on TNF-alpha and IL-6 production, both at protein and mRNA level. The crude extract also suppressed LPS induced nuclear translocation of transcription factors, NF-kappaB and AP-1; the inhibition of NF-kappaB was through the inhibition of IkappaBalpha phosphorylation. The extract also suppressed LPS activated nitric oxide production in mouse macrophage cell line, RAW 264.7. Our results for the first time show that SA extract can inhibit proinflammatory cytokine production and demonstrate its mechanism of action.
19109936 Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization ca 2009 Mar BACKGROUND: Antibody-antigen complexes formed by IgG autoantibodies against citrullinated proteins and citrullinated forms of the alpha- and beta-chains of fibrin in rheumatoid synovial tissue play a key role in the pathophysiology of rheumatoid arthritis. METHODS: Recombinant fibrinogen was citrullinated by rabbit skeletal muscle peptidylarginine deiminase so that we could analyze the function of citrullinated fibrinogen. Namely, thrombin-catalyzed fibrin polymerization and fibrinopeptide release, protection against plasmin digestion, and factor XIIIa-catalyzed cross-linking of fibrin or fibrinogen were performed. RESULTS: Strong citrullination of the Aalpha- and Bbeta-chains and weak citrullination of the gamma-chain were detected by an anti-modified citrulline detection kit. Citrullinated fibrinogen did not release FPA or FPB by thrombin catalyzation and no thrombin-stimulated conversion of fibrinogen into fibrin occurred. The citrullination of fibrinogen did not affect the 3 functions of the C-terminal gamma-chain, "a-hole," low affinity Ca binding, and gamma-gamma cross-linking. CONCLUSION: Our functional analyses demonstrated that no thrombin-stimulated conversion of fibrinogen into fibrin occurred, because citrullinated fibrinogen did not release FPA or FPB after thrombin catalyzation. Our results and those of other reports suggest that citrullinated fibrin and fibrinogen are present in the synovium and might both be associated with the pathophysiology of RA.
18223354 Rheumatoid arthritis: beyond tumor necrosis factor-alpha antagonists, B cell depletion, an 2008 Jan Significant advances have been made in the treatment of rheumatoid arthritis (RA). For instance, novel biologic therapeutics capable of blocking tumor necrosis factor-alpha (TNF-alpha) have improved outcomes for RA patients. New therapeutic agents directed at antagonizing two previously untargeted pathways have recently been approved by the U.S. Food and Drug Administration for RA patients who have had inadequate responses to anti-TNF therapy or who have failed to maintain an adequate clinical response. We review the data supporting the use of these agents, rituximab and abatacept.
18178593 Evaluating the adequacy of disease control in patients with rheumatoid arthritis: a RAND a 2008 Feb OBJECTIVES: There is a lack of agreement on assessing disease activity in patients with RA and determining when the RA treatment should be changed or continued. A panel of rheumatologists was convened to develop guidelines to assess adequacy of disease control, focusing on the use of disease-modifying anti-rheumatic drugs. METHODS: The Research and Development/University of California in Los Angeles (RAND/UCLA) Appropriateness Method was used to evaluate disease control adequacy. After a literature review, 108 scenarios were developed to simulate situations most likely to be encountered in clinical practice and rated on a 9-point scale by a 10-member expert panel. RESULTS: Final appropriateness rankings for the scenarios were as follows: 37% 'appropriate', 48% 'inappropriate', and 16% 'neutral'. The panelists felt that patients with disease control in the 'appropriate' range have adequate control with their current therapy, whereas those in the 'inappropriate' range should be considered for a change in therapy. Those in 'neutral' areas should have their therapy reviewed carefully. The panelists recommended that the clinically active joint count should be considered the most important decision factor. In patients with no clinically active joints, regardless of other factors no change in therapy was felt to be warranted. Patients with five or more active joints should be considered inadequately treated, and in patients with one to four active joints other variables must be considered in the decision to change therapy. CONCLUSION: These preliminary guidelines will assist the clinician in determining when a patient's clinical situation warrants therapy escalation and when continuing the current regimen would be appropriate.
17289381 Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing 2007 Apr 15 A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 4b bound to TACE was obtained.
17640718 The enigmatic development of psoriasis and psoriasiform lesions during anti-TNF therapy: a 2008 Feb OBJECTIVES: The paradoxical observation that antitumor necrosis factor (anti-TNF) agents are capable of inducing psoriasis and psoriasiform skin lesions while also being therapy for psoriasis gained substantial support following the description of this condition by several authors. Our aim was to review the literature of this subject. METHODS: A retrospective review of the literature was performed using the Medline database between 2005 and February 2007. RESULTS: Since the first publication by our group in April 2005 to the present, 50 cases of this type of dermatitis have been described. More than half of the cases were associated with the use of infliximab. Different presentations of psoriasis were reported, plaque form being the most prevalent. A number of clinical and immunological observations suggest a cytokine disequilibrium in patients receiving chronic anti-TNF therapy leading to this condition. Treatment for the skin disease includes changing the anti-TNF agent or discontinuing the medication. CONCLUSIONS: The appearance of psoriasis and psoriasiform lesions during chronic anti-TNF therapy is dependent on the presence of known and unknown interrelated factors. Enhanced clinician awareness of this drug complication and further investigation of its mechanisms are warranted.
17075599 Risk and prevention of tuberculosis and other serious opportunistic infections associated 2006 Nov Tumor necrosis factor (TNF) is a proinflammatory cytokine that has a key role in the pathogenesis of a variety of autoimmune diseases-including rheumatoid arthritis-and is an important constituent of the human immune response to infection. At present, three anti-TNF agents are approved (in the US and elsewhere) to treat selected autoimmune diseases: infliximab, etanercept, and adalimumab. These biologic agents have been associated with a variety of serious and 'routine' opportunistic infections; however, differences exist in the mechanisms of action of these agents that might confer variation in their associated risks of infection. From a public-health standpoint, the development of active tuberculosis in some patients who receive anti-TNF therapy is a matter of serious concern. Tuberculosis in such patients frequently presents as extrapulmonary or disseminated disease, and clinicians should be vigilant for tuberculosis in any patient taking anti-TNF therapy who develops fever, weight loss, or cough. To prevent the reactivation of latent tuberculosis infection during anti-TNF therapy, clinicians should screen all patients for tuberculosis, and begin treatment if latent infection is found, before anti-TNF therapy is initiated. Specific tuberculosis screening and treatment strategies vary between geographical regions and are reviewed in this document. The screening strategies employed in Europe and North America have reduced the occurrence of anti-TNF-associated tuberculosis and are clearly to be recommended, but the role of screening in the prevention of other opportunistic (e.g. fungal) infections is far less certain.
18727628 Expansion of a unique macrophage subset in rheumatoid arthritis synovial lining layer. 2008 Oct The Z39Ig protein (complement receptor for C3b and iC3b) is expressed on resident tissue macrophages in various tissues. This study was undertaken to examine the distribution of Z39Ig+cells and their phenotypic features in rheumatoid arthritis (RA) synovium, in comparison with those of osteoarthritis (OA) and psoriatic arthritis (PsA) synovium. Monoclonal anti-Z39Ig antibody was produced by immunizing Z39Ig transfected murine pre B cells and used for the identification of Z39Ig+cells. Z39Ig+cells were further stained with antibodies to macrophages, fibroblast-like synoviocytes, complement receptors and dendritic cells by using the double immunostaining method in normal, RA, OA and PsA synovium. RA synovial mononuclear cells were double-stained using anti-Z39Ig and anti-CD11c antibodies and sorted into Z39Ig+CD11c+cells and Z39Ig+CD11c-cells. These cell populations were then analysed by electron microscopy. The expression of the Z39Ig protein was limited to intimal macrophages in normal, RA, OA and PsA synovium. The numbers of Z39Ig+CD11c+cells and the ratios of Z39Ig+CD11c+cells to Z39Ig+cells were increased in the synovial lining layer of RA as compared with those of OA and PsA. The ultrastructural analysis of Z39Ig+CD11c+cells showed the character of macrophages with many secondary lysosomes and swelling of mitochondria. Z39Ig+ cells appeared to be useful for identification of resident tissue macrophages in normal synovium and the corresponding macrophages in the synovial lining layer of inflammatory arthritis. Expansion of Z39Ig+CD11c+cells was characteristic of RA synovial lining layer.
18250111 EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a 2009 Jan OBJECTIVES: To develop evidence-based recommendations for the diagnosis of hand osteoarthritis (OA). METHODS: The multidisciplinary guideline development group, representing 15 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched for systematically. Whenever possible, the sensitivity, specificity and likelihood ratio (LR) were calculated; relative risk and odds ratios were estimated for risk factors for hand OA. Quality of evidence was categorised using the European League Against Rheumatism (EULAR) hierarchy, and strength of recommendation was assessed by the EULAR visual analogue scale. RESULTS: Diagnostic topics included clinical manifestations, radiographic features, subgroups, differential diagnosis, laboratory tests, risk factors and comorbidities. The sensitivity, specificity and LR varied between tests depending upon the cut-off level, gold standard and controls. Overall, no single test could be used to define hand OA on its own (LR <10) but a composite of the tests greatly increased the chance of the diagnosis. The probability of a subject having hand OA was 20% when Heberden nodes alone were present, but this increased to 88% when in addition the subject was over 40 years old, had a family history of nodes and had joint space narrowing in any finger joint. CONCLUSION: Ten key recommendations for diagnosis of hand OA were developed using research evidence and expert consensus. Diagnosis of hand OA should be based on assessment of a composite of features.
17963167 Cysteine and serine proteases of synovial tissue in rheumatoid arthritis and osteoarthriti 2007 Sep OBJECTIVE: To compare the activities of cathepsin B (EC 3.4.22.1) and L (EC 3.4.22.15), calpain (EC 3.4.22.17), and dipeptidyl peptidase (EC 3.4.14.5 or DPP IV or CD26) in synovial membrane from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and post-traumatic joint injury (PT). METHODS: Forty RA patients were divided into two groups on the basis of surgical procedure: the RAs group comprised 18 patients requiring surgical synovectomy; the RAr group comprised 22 patients requiring a total joint replacement or arthrodesis. A third group (the OA group) comprised 19 OA patients while six patients with post-traumatic joint injury were included in the fourth group (the PT group). Cathepsin and calpain activity was assessed using a Cobas Fara II centrifugal analyser. DPP IV activity was determined kinetically using a fluorogenic substrate. RESULTS: RAs patients were significantly younger than RAr patients, and the mean duration of RA was shorter in the RAs group than in the RAr group. Cathepsin and calpain activity in synovial membrane was higher in RA and OA patients than in the control group, but no statistical difference was observed between RA and OA. However, cathepsin, calpain, and DPP IV synovial activity was significantly higher in the RAs group than in either the OA or the PT group. CONCLUSION: Our results show that proteinase activity tends to be higher in joints with early synovitis in RA, and suggest that these enzymes are not all involved at the same stage of the disease.
18341834 [Efficacy and security of tumor necrosis factor antagonists in the treatment of rheumatoid 2008 Feb 16 In the last decade, tumor necrosis factor (TNF) antagonists had supposed an important therapeutic advance in the treatment of patients with rheumatoid arthritis (RA) in both early and established RA. Three agents currently available--infliximab, etanercept, and adalimumab--have been designed to modify the biologic effects of TNF. Infliximab and adalimumab are monoclonal antibodies, whereas etanercept is a soluble protein, with different pharmacokinetic and pharmacodynamic properties, conditioning some possible adverse effects. Although comparative studies are not available, the 3 drugs have demonstrated efficacy and security, with a better quality of life of patients with RA. Infliximab, etanercept and adalimumab have been proved alone and in combination with methotrexate, with a better therapeutic, clinical, radiological and functional response in the group under combined therapy. Both clinical trials and post-market experience have demonstrated the security of these drugs, minimizing the risks with an adequate selection of patients.
18403881 Angina bullosa hemorrhagica of the soft palate: a clinical study of 16 cases. 2008 Mar Angina bullosa hemorrhagica (ABH) is an oral mucosal blood blister that develops without blood dyscrasia or vesiculobullous disorder. Although a minor mucosal trauma has been suggested as a triggering factor for ABH, its etiopathogenesis, especially the causative role of systemic conditions, is largely unknown. We investigated the presence or absence of local factors as well as systemic background disease in 16 patients with ABH arising in the soft palate. All the lesions were solitary, and 75% of them (n = 12) appeared during the ingestion of hard or crispy food. With regard to underlying systemic conditions, hypertension was the most common (n = 6), and asthma, insomnia, diabetes mellitus, rheumatoid arthritis, gastrointestinal disorder and hyperuricemia were also recorded (n = 1 each). Five patients had no significant background disease. There were no recalcitrant or recurrent cases. In conclusion, the present study has revealed that scratching of the oral mucosa during eating plays an important role in the formation of ABH. Hypertension appears to be the most frequent background condition, but its pathogenic relationship with ABH remains speculative, as hypertension is fairly common in adults.
18405470 Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, cel 2008 Apr OBJECTIVES: To review the clinical effectiveness and cost-effectiveness of cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis (OA) and rheumatoid arthritis (RA). DATA SOURCES: Electronic databases were searched up to November 2003. Industry submissions to the National Institute for Health and Clinical Excellence (NICE) in 2003 were also reviewed. REVIEW METHODS: Systematic reviews of randomised controlled trials (RCTs) and a model-based economic evaluation were undertaken. Meta-analyses were undertaken for each COX-2 selective NSAID compared with placebo and non-selective NSAIDs. The model was designed to run in two forms: the 'full Assessment Group Model (AGM)', which includes an initial drug switching cycle, and the 'simpler AGM', where there is no initial cycle and no opportunity for the patient to switch NSAID. RESULTS: Compared with non-selective NSAIDs, the COX-2 selective NSAIDs were found to be equally as efficacious as the non-selective NSAIDs (although meloxicam was found to be of inferior or equivalent efficacy) and also to be associated with significantly fewer clinical upper gastrointestinal (UGI) events (although relatively small numbers of clinical gastrointestinal (GI) and myocardial infarction (MI) events were reported across trials). Subgroup analyses of clinical and complicated UGI events and MI events in relation to aspirin use, steroid use, prior GI history and Helicobacter pylori status were based on relatively small numbers and were inconclusive. In the RCTs that included direct COX-2 comparisons, the drugs were equally tolerated and of equal efficacy. Trials were of insufficient size and duration to allow comparison of risk of clinical UGI events, complicated UGI events and MIs. One RCT compared COX-2 (celecoxib) with a non-selective NSAID combined with a gastroprotective agent (diclofenac combined with omeprazole); this included arthritis patients who had recently suffered a GI haemorrhage. Although no significant difference in clinical GI events was reported, the number of events was small and more such studies, where patients genuinely need NSAIDs, are required to confirm these data. A second trial showed that rofecoxib was associated with fewer diarrhoea events than a combination of diclofenac and misoprostol (Arthrotec). Previously published cost-effectiveness analyses indicated a wide of range of possible incremental cost per quality-adjusted life-year (QALY) gained estimates. Using the simpler AGM, with ibuprofen or diclofenac alone as the comparator, all of the COX-2 products are associated with higher costs (i.e. positive incremental costs) and small increases in effectiveness (i.e. positive incremental effectiveness), measured in terms of QALYs. The magnitude of the incremental costs and the incremental effects, and therefore the incremental cost-effectiveness ratios, vary considerably across all COX-2 selective NSAIDs. The base-case incremental cost per QALY results for COX-2 selective NSAIDs compared with diclofenac for the simpler model are: celecoxib (low dose) 68,400 pounds; celecoxib (high dose) 151,000 pounds; etodolac (branded) 42,400 pounds; etodolac (generic) 17,700 pounds; etoricoxib 31,300 pounds; lumiracoxib 70,400 pounds; meloxicam (low dose) 10,300 pounds; meloxicam (high dose) 17,800 pounds; rofecoxib 97,400 pounds; and valdecoxib 35,500 pounds. When the simpler AGM was run using ibuprofen or diclofenac combined with proton pump inhibitor (PPI) as the comparator, the results change substantially, with the COX-2 selective NSAIDs looking generally unattractive from a cost-effectiveness point of view (COX-2 selective NSAIDs were dominated by ibuprofen or diclofenac combined with PPI in most cases). This applies both to 'standard' and 'high-risk' arthritis patients defined in terms of previous GI ulcers. The full AGM produced results broadly in line with the simpler model. CONCLUSIONS: The COX-2 selective NSAIDs examined were found to be similar to non-selective NSAIDs for the symptomatic relief of RA and OA and to provide superior GI tolerability (the majority of evidence is in patients with OA). Although COX-2 selective NSAIDs offer protection against serious GI events, the amount of evidence for this protective effect varied considerably across individual drugs. The volume of trial evidence with regard to cardiovascular safety also varied substantially between COX-2 selective NSAIDs. Increased risk of MI compared to non-selective NSAIDs was observed among those drugs with greater volume of evidence in terms of exposure in patient-years. Economic modelling shows a wide range of possible costs per QALY gained in patients with OA and RA. Costs per QALY also varied if individual drugs were used in 'standard' or 'high'-risk patients, the choice of non-selective NSAID comparator and whether that NSAID was combined with a PPI. With reduced costs of PPIs, future primary research needs to compare the effectiveness and cost-effectiveness of COX-2 selective NSAIDs relative to non-selective NSAIDs with a PPI. Direct comparisons of different COX-2 selective NSAIDs, using equivalent doses, that compare GI and MI risk are needed. Pragmatic studies that include a wider range of people, including the older age groups with a greater burden of arthritis, are also necessary to inform clinical practice.
18356177 Low disease activity state with corticosteroid may not represent 'true' low disease activi 2008 Apr OBJECTIVE: Corticosteroids constitute one of the most common treatments of RA. The purpose of this study is to investigate whether long-term corticosteroid use suppresses the progression of disability in RA patients with low disease activity state. METHODS: Data collected from a large observational cohort of RA patients at our institution were analysed for 214 RA patients whose disease activity score (DAS) 28 and HAQ were available consecutively from October 2000 to October 2004. All 214 patients had average DAS 28 <3.2, meaning only those who had well-controlled RA disease activity were chosen as subjects. The subjects were divided into steroid users who received continuous corticosteroids every month and non-steroid users who did not receive consecutive corticosteroids continuously every month. RESULTS: Fifty-five patients (25.7%) were corticosteroid users and 159 (74.3%) were non-users. Average prednisolone for the former group was 4.2 mg/day. No significant differences were observed among baseline variables and RA disease activity variables. However, for steroid users, HAQ progressively worsened with time and for non-steroid users, HAQ progressively improved. CONCLUSIONS: Although DAS 28 and other variables may suggest well-controlled RA disease activity, functional capacity of patients on low-dose corticosteroids deteriorated. Thus, low disease activity state with corticosteroid may not represent the 'true' low disease activity state. Along with the achievement of a low disease activity state, long-term efficacy, prognosis, and the quality of remission need to be also considered in the tight control of RA activity.
16917817 A comparison of methods for intermediate fine mapping. 2006 Dec The arrival of highly dense genetic maps at low cost has geared the focus of linkage analysis studies toward developing methods for placing putative trait loci in narrow regions with high confidence. This shift has led to a new analytic scheme that expands the traditional two-stage protocol of preliminary genome scan followed by fine mapping through inserting a new stage in between the two. The goal of this new "intermediate" fine mapping stage is to isolate disease loci to narrow intervals with high confidence so that association studies can be more focused, efficient, and cost-effective. In this paper, we compared and contrasted five methods that can be used for performing this intermediate step. These methods are: the lod support approach, the generalized estimating equations (GEE) method, the confidence set inference (CSI) procedure, and two bootstrap methods. We compared these methods in terms of the coverage probability and precision of localization of the resulting intervals. Results from a simulation study considering several two-locus models demonstrated that the two bootstrap methods yield intervals with approximately correct coverage. On the other hand, the 1-lod support intervals, and those produced by the GEE method, tend to significantly undercover the trait locus, while the regions obtained by the CSI incline to overcover the gene position. When the observed coverage of the confidence intervals produced by all the methods was held to be the same, those obtained through the CSI procedure displayed a higher ability to localize loci, especially when these loci have a minor contribution to the trait and when the amount of data available for the analysis is relatively small. However, with very large sample sizes, lod support intervals emerged as a winner. Application of the methods to the data from the Arthritis Research Campaign National Repository led to intervals containing the position of a known trait locus for all methods, with the greatest precision achieved by the CSI.