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ID PMID Title PublicationDate abstract
12723739 Discovery, mechanisms of action and safety of ibuprofen. 2003 Apr Ibuprofen was the product of a long research programme during the 1950s and 1960s to develop a 'super aspirin' for the treatment of rheumatoid arthritis which was as effective as current alternatives but safer. Selected for development in 1964 after several promising compounds had proved disappointing at the clinical stage, ibuprofen was found to have a short elimination half-life and exceptional gastrointestinal tolerability. Ibuprofen was introduced in the United Kingdom in 1966 and in the United States in 1974, and was the first non-steroidal anti-inflammatory drug (NSAID) licensed for over-the-counter use in the UK in 1983 and in the US the following year. Ibuprofen is a non-cyclo-oxygenase selective NSAID but recent evidence suggests additional anti-inflammatory properties are due to modulation of leucocyte activity, reduced cytokine production, inhibition of free radicals and signalling transduction. Ibuprofen may also exert a central analgesic action in the dorsal horn. Future roles for ibuprofen may include protection against certain cancers and Alzheimer's disease.
15380047 Antibodies against the CB10 fragment of type II collagen in rheumatoid arthritis. 2004 Antibodies against intact type II collagen (CII) are a feature of rheumatoid arthritis (RA) but have limited diagnostic value. Here we assess whether either of the two major cyanogen bromide fragments of CII, namely CB10 or CB11, are more sensitive substrates for the detection of antibodies in RA. Cleavage of bovine CII with cyanogen bromide yielded CB10 and CB11; these were purified by column chromatography for use in an enzyme-linked immunosorbent assay. Serum antibodies were measured in patients with RA, psoriatic arthritis (PsA), osteoarthritis (OA) and blood donors. Results were compared with those using intact CII. Antibodies against CB10 were found in as many as 88% of 96 patients with long-standing RA, but only 12% of 33 patients with PsA, 6% of 34 patients with OA and 3% of 93 control sera. Lower frequencies for these diseases were obtained on testing for antibodies against CB11: 50%, 6%, 21% and 2%, respectively. The sensitivity of detection in RA of antibodies against CB10 compared with antibodies against intact CII (88% versus 24%) was not at the expense of specificity, which remained high at 94%. The much higher frequency of antibodies against CB10 in RA than in other rheumatic diseases or control sera indicates that CB10 is clearly a more sensitive substrate than the intact collagen molecule and, combined with other assays (rheumatoid factor, anti-cyclic citrullinated peptide [anti-CCP]), might comprise a panel with a highly reliable predictive value. Moreover, our findings should encourage renewed interest in the role of collagen autoimmunity in the pathogenesis of RA.
12056133 [Clinical factors essential for dental caries intensity in rheumatic patients]. 2002 A total of 349 patients with rheumatoid arthritis, 129 with systemic lupus erythematosus, and 92 with systemic scleroderma were examined. A higher incidence of caries (CDL index) in comparison with the norm (p < 0.05) was observed in all patients; the most significant factor promoting caries development was involvement of the salivary glands presenting as Sjogren's syndrome (p < 0.005). The presence and severity of temporomandibular involvement virtually did not affect the intensity of caries (p > 0.1). The highest CDL index was observed in patients with rheumatoid arthritis and systemic scleroderma with pronounced dysfunction of the hand joints (p < 0.01) and higher activity of disease (a higher percentage of patients with Sjogren's diseases of the second and third degrees of activity) (p < 0.05). These data confirmed the multifactorial nature of dental caries etiology in rheumatic diseases.
12967241 Negotiating an innovative uniform infusion therapy fee: a managed care case study. 2003 Fall The medical director of this health plan established an innovative uniform infusion therapy fee whereby the plan pays a uniform infusion fee across all sites of care and contracts separately for delivery of the drug itself. The concept works successfully on three levels: (1) for plan members; (2) for plan providers; and (3) for the plan itself. This case study sets forth the conceptual and operational decisionmaking sequences involved. Establishing the innovative process required two primary elements: (1) coordinated decision making within all departments that were affected by the model; and (2) a champion to carry the project to a successful conclusion.
14558080 Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-mont 2003 Oct OBJECTIVE: To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX. METHODS: This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%). CONCLUSION: In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.
13130464 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as k 2003 Sep OBJECTIVE: The mitogen-activated protein (MAP) kinase JNK is a key regulator of interleukin-1 (IL-1)-induced collagenase gene expression and joint destruction in arthritis. Two upstream kinases, MKK-4 and MKK-7, have been identified as potential activators of JNK. However, the role of MAP kinase kinases (MAPKKs) and their functional organization within fibroblast-like synoviocytes (FLS) have not been defined. We therefore evaluated the interactions between the various MAP kinase components and determined their subcellular localization. METHODS: MKKs were identified by immunohistochemistry of rheumatoid arthritis (RA) and osteoarthritis (OA) synovium. Western blotting was used to determine the expression of FLS. Immunoprecipitation experiments using antibodies specific for MKK-4, MKK-7, and JNK were performed. Phosphospecific antibodies and immunohistochemistry were used to evaluate the activation state of synovial MKK-4 and MKK-7. Confocal microscopy was used to determine the subcellular location of the kinases. RESULTS: Immunohistochemistry studies demonstrated abundant MKK-4 and MKK-7 in RA and OA synovium, but the levels of phosphorylated kinases were significantly higher in RA synovium. MKK-4 and MKK-7 were constitutively expressed by cultured RA and OA FLS, and IL-1 stimulation resulted in rapid phosphorylation of both kinases. JNK was detected in MKK-4 and MKK-7 immunoprecipitates. Furthermore, MKK-4 coprecipitated with MKK-7 and vice versa, indicating that the 3 kinases form a stable complex in FLS. Confocal microscopy confirmed that JNK, MKK-4, and MKK-7 colocalized in the cytoplasm, with JNK migrating to the nucleus after IL-1 stimulation. The signal complex containing MKK-4, MKK-7, and JNK was functionally active and able to phosphorylate c-Jun after IL-1 stimulation of FLS. CONCLUSION: These studies demonstrate that JNK, MKK-4, and MKK-7 form an active signaling complex in FLS. This novel JNK signalsome is activated in response to IL-1 and migrates to the nucleus. The JNK signalsome represents a new target for therapeutic interventions designed to prevent joint destruction.
15454231 A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arth 2004 Nov 1 A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
12950235 Clinical features in T-cell vs. natural killer-cell variants of large granular lymphocyte 2003 Oct OBJECTIVE: Standard clinical and laboratory evaluations and novel laboratory techniques were used to identify patients with T-cell large granular lymphocyte leukemia (LGLL) and those with natural killer-cell variants of LGLL for comprehensive clinical evaluation. METHODS: We used bone marrow histologic analysis, immunophenotypic markers of clonality, and T-cell-receptor gene rearrangement studies to identify patients. RESULTS: The study identified 44 patients with T-cell LGLL and 14 with natural killer-cell LGLL. The two disorders were similar in sex and age distribution of patients; peripheral blood lymphocyte, neutrophil, and platelet counts; and incidence of rheumatoid arthritis. Among the two groups, patients with the T-cell LGLL presented with significantly lower hemoglobin concentrations (P < 0.04) and a higher frequency of palpable splenomegaly (P < 0.01). CONCLUSION: Overall disease progression and response to immunosuppressive therapy are similar between T-cell and natural killer-cell variants of LGLL.
12412207 Thalidomide: focus on its employment in rheumatologic diseases. 2002 Sep Thalidomide is an immunomodulatory agent; although its mechanisms of action are not fully understood, many authors have described its anti-inflammatory and immunosuppressive properties. More interestingly, thalidomide has shown the ability to suppress tumor necrosis factor alpha (TNF alpha) production and to modify the expression of TNF alpha induced adhesion molecules on endothelial cells and on human leukocytes. Thalidomide has been used in several diseases (i.e. dermatological, autoimmune, gastrointestinal). In this review we focus specifically on the use of this drug in disorders with rheumatological features such as lupus erythematosus, rheumatoid arthritis and Still's disease, ankylosing spondylitis, and Behçet's disease. Despite its well known side effects, first of all peripheral nerve involvement and teratogenesis, which can be avoided by following strict guidelines, thalidomide could represent an alternative drug in some rheumatological conditions, particularly in patients who show resistance, contraindication or toxicity with other conventional treatments.
15153172 Reduced incidence of gastroduodenal ulcers associated with lumiracoxib compared with ibupr 2004 Jun 1 BACKGROUND: Lumiracoxib (Prexige; Novartis Pharma AG, Basel, Switzerland) is a cyclooxygenase-2 selective inhibitor associated with improved gastrointestinal safety compared with nonsteroidal anti-inflammatory drugs, in patients with osteoarthritis. AIM: To compare the gastroduodenal safety of lumiracoxib with ibuprofen and celecoxib in patients with rheumatoid arthritis. METHODS: A total of 893 patients with rheumatoid arthritis were randomized to lumiracoxib 400 mg once daily, lumiracoxib 800 mg once daily, ibuprofen 800 mg three times daily or celecoxib 200 mg twice daily for 13 weeks, in a double-blind randomised controlled clinical trial. The primary endpoint was the cumulative incidence of gastroduodenal ulcers over 13 weeks. RESULTS: The incidence of gastroduodenal ulcers >/=3 mm with lumiracoxib 400 mg once daily (2.8%) or lumiracoxib 800 mg once daily (4.3%) was significantly lower than with ibuprofen (13.6%, all P < 0.01) and not different from celecoxib (1.9%). The incidence of adverse events was similar for lumiracoxib 400, 800 mg and celecoxib (78, 75 and 77%, respectively) and higher with ibuprofen (86%). Discontinuation for adverse events was highest for ibuprofen (12.5% vs. 7.9-8.8% for the other groups). CONCLUSIONS: Lumiracoxib demonstrated gastroduodenal safety superior to ibuprofen and similar to celecoxib in patients with rheumatoid arthritis.
15173643 [Analysis of 925 patients on long-term hydroxychloroquine or chloroquine treatment: result 2004 Apr PURPOSE: The aim of this 4-Year study was to analyze the population referred to our laboratory for the visual follow-up of hydroxychloroquine or chloroquine treatment. MATERIAL AND METHODS: We received 925 patients: 78% female, 22% male. For each patient, a 13-item criteria was filled out and regular exams were performed. The pathologies were divided in to 4 groups: rheumatoid polyarthritis (P), lupus (L), sarcoidosis (S), others (O). RESULTS: The pathologies were distributed as follows: 48% "P", 29% "L", 3% "S", 1% "P + L", 19% "O". Of these patients, 19% had less than 1 Year of treatment, 73% 1-10 Years and 8% more than 10 Years. The screening exposed no retinal intoxications but 3% presented pre-clinical intoxication (PCI) and 80% were allowed to continue their treatment. The most important statistical results were: 1) a significant relation between the PCI and the duration of the treatment (p<0.001); 2) a non-significant relation between the PCI and the daily dose (p=0.417); and 3) a significant relation between PCI and the cumulative dose (p=0.003). CONCLUSION: The results shows the advantage of the ERG in screening to prevent anti-malarial retinal toxicity. This study confirms that the cumulative dose seems to be more important than the daily dose, but we agree with the international consensus to respect a daily dose under 6.5 mg/kg/d. The results also demonstrated that, with this large and diversified population, there is a need for prospective and multi-centric studies. With the above results, international standards should be established in order to obtain the most efficient screening for each category of patient.
15024704 Human articular chondrocytes, synoviocytes and synovial microvessels express aquaporin wat 2004 Apr Recent studies have shown that aquaporin water channels are expressed in human Meckel's cartilage. The aim of the present investigation was to determine if human articular chondrocytes and synoviocytes express aquaporin 1 (AQP1) water channels and to establish if there are any alterations in AQP1 expression in osteoarticular disorders such as osteoarthritis (OA) and rheumatoid arthritis (RA). Immunohistochemistry was employed semi-quantitatively to compare the expression of AQP1 in human chondrocytes derived from normal, OA and RA joints. PCR, cloning and sequencing confirmed the presence of AQP1 transcripts in chondrocytes. Normal human tissue microarrays including samples of kidney, choroid plexus and pancreas were used as positive controls for AQP1 expression. In most tissues AQP1 was expressed along endothelial barriers. In the kidney AQP1 was present in the glomerular capillary endothelium, proximal tubule and descending thin limbs. AQP1 was also localized to pancreatic ducts and acini and the apical membrane domain of the choroid plexus. Immunohistochemistry showed that AQP1 is expressed in synovial micro-vessels, synoviocytes and predominantly in chondrocytes located in the deep zone of articular cartilage. Image analysis of normal, OA and RA cartilage suggested that AQP1 may be upregulated in RA. This is the first report of AQP1 mRNA and protein expression in articular chondrocytes and synoviocytes. These findings suggest a potential role for AQP1 and possibly other members of the AQP gene family in the movement of extracellular matrix and metabolic water across the membranes of chondrocytes and synoviocytes for the purposes of chondrocyte volume regulation and synovial homeostasis.
15146415 Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophage 2004 May OBJECTIVE: CD16 (IgG Fcgamma receptor type IIIA [FcgammaRIIIA])-expressing CD14+ monocytes express high levels of Toll-like receptor 2 (TLR-2) and are able to efficiently produce proinflammatory cytokines such as tumor necrosis factor alpha (TNFalpha). To understand the role of CD16 and TLR-2 in monocyte and macrophage activation in rheumatoid arthritis (RA), we investigated the expression of TLR-2 on CD16+ blood monocytes and synovial tissue macrophages and the effect of CD16 and TLR-2 activation on cytokine production. METHODS: The expression of CD14, CD16, TLR-2, and TLR-4 on blood monocytes was measured by flow cytometric analysis. CD16 and TLR-2 expression in RA synovial tissue was detected by 2-color immunofluorescence labeling. CD16+ mature monocytes were prepared by incubating blood monocytes in plastic plates for 24 hours. These adhered monocytes were stimulated with lipoteichoic acid (LTA), anti-FcgammaRIII antibody, and Hsp60 for 5 hours, and culture supernatants were measured for various cytokines by immunoassay. The activation of NF-kappaB was detected by electrophoretic mobility shift assay. RESULTS: The frequency of CD16+ cells in all blood monocytes was significantly increased in patients with RA compared with healthy controls. TLR-2 was expressed at higher levels on CD16+ monocytes than on CD16- monocytes, while TLR-4 was expressed similarly on both monocytes. In RA synovial tissue, CD16+/TLR-2+ cells were distributed mainly in the lining layer. TLR-2 expression on monocytes was enhanced by macrophage colony-stimulating factor (M-CSF) and interleukin-10 (IL-10), but was reduced by transforming growth factor beta1, while CD16 expression was inducible by these cytokines. Adhered monocytes ( approximately 50% CD16+) produced TNFalpha, IL-1beta, IL-6, IL-8, IL-12 p40, IL-1 receptor antagonist, and IL-10 after LTA stimulation. This cytokine response was inhibited significantly by anti-TLR-2 antibody and partly by anti-TLR-4 antibody. Anti-FcgammaRIII antibody stimulation markedly enhanced the LTA-induced TNFalpha response. Hsp60 could stimulate TNFalpha production by adhered monocytes, which was inhibited similarly by anti-TLR-2 antibody and anti-TLR-4 antibody. NF-kappaB activation in adhered monocytes was induced by LTA, but this NF-kappaB activity was not augmented by anti-FcgammaRIII antibody stimulation. CONCLUSION: These results suggest that CD16+ monocytes and synovial tissue macrophages with high TLR-2 expression may be induced by M-CSF and IL-10, and their production of TNFalpha could be simulated by endogenous TLR ligands such as Hsp60 and FcgammaRIIIA ligation by small immune complexes in RA joints.
15225359 4th meeting of the EU research network EUROME: from the identification of genes and cellul 2004 Rheumatoid arthritis (RA) is a common human disease with a prevalence of about 1% in most parts of the world. At the time of symptom onset it is difficult to predict the severity of subsequent disease course. After 2 years joint erosions are seen in most patients, and most patients become clinically disabled within 20 years. A recent meeting at the Kennedy Institute of Rheumatology (Imperial College, London) brought together representatives from several European centres of excellence, to discuss research funded by the EU Framework 5 Quality of Life Programme. This research network combines gene and protein expression profiling with different animal models of RA to identify cells, genes and pathways contributing to arthritis initiation, progression and chronicity. The studies discussed highlight the reality that collaboration between different research groups is the basis of groundbreaking research and, it is hoped, eventual new therapies for RA.
15182039 [Valdecoxib (Bextra)]. 2004 Apr Valdecoxib (Bextra tablets of 10 mg and 20 mg) is a new non steroidal antiinflammatory drug (NSAID) that selectively inhibits COX-2 isoform of cyclo-oxygenase. It is indicated for the symptomatic treatment of osteoarthritis or rheumatoid arthritis (10 to 20 mg once a day) and for the treatment of primary dysmenorrhea (40 mg once a day). Valdecoxib is as efficacious as conventional non-COX-2 selective NSAIDs, but offers the advantage of a much better gastrointestinal tolerance. Valdecoxib has a prodrug that can be administered intravenously or intramuscularly (parecoxib, Dynastat) and has been developed for the short-term treatment of postsurgical pain.
12904159 Cardiovascular hazard of selective COX-2 inhibitors: myth or reality? 2002 May Since 1998, two selective inhibitors of COX-2 have been approved in many countries for the treatment of rheumatoid arthritis, osteoarthritis and acute pain. These new drugs have a significantly reduced gastrointestinal toxicity when compared with non-selective COX inhibitors. However, the results of two large clinical trials conducted in patients with osteoarthritis and rheumatoid arthritis have recently raised some concerns regarding the cardiovascular safety of these new drugs. The purpose of this paper is to review the potential mechanisms whereby selective COX-2 inhibitors could increase the cardiovascular risk of patients and to analyse the data indicating that this clinical risk indeed exists. The authors' analysis shows that even though there are pathophysiological mechanisms which could explain why selective COX-2 inhibition might increase the cardiovascular risk in patients, the actual level of evidence demonstrating that the risk is indeed increased is weak. Because of the importance of the issue, additional studies must be conducted with this class of agents. Meanwhile, it is crucial to emphasise that neither selective COX-2 inhibitors nor conventional NSAIDs replace aspirin in patients with a high cardiovascular risk.
12458820 Treatment of rheumatoid arthritis and osteoarthritis with COX-2-selective inhibitors: a ma 2002 Nov The development of cyclooxygenase (COX)-2-selective inhibitors represents a major advance in the management of chronic pain and inflammation that may satisfy an unmet medical need for agents with improved gastrointestinal (GI) safety. This article is a review of the pharmacology, clinical efficacy, and safety of COX-2-selective inhibitors in the managed healthcare setting. The efficacy of COX-2-selective inhibitors in relieving chronic pain from osteoarthritis and rheumatoid arthritis is comparable to that of traditional nonsteroidal anti-inflammatory drugs (NSAIDs). However, the occurrence of GI complications may be less frequent in patients who receive COX-2-selective inhibitors than in patients receiving traditional NSAIDs. Thus, the use of COX-2-selective inhibitors for the management of chronic pain may reduce overall costs and provide an alternative with an improved safety profile compared with traditional NSAIDs.
12022706 Low-molecular-weight protein tyrosine phosphatase and human disease: in search of biochemi 2002 A major challenge in the post-genomic era is to identify the physiological functions of genes and elucidate the molecular basis for human disease. Genetic polymorphisms offer a convenient avenue for these efforts by providing evidence for the involvement of a given gene in human pathophysiology. Here we review the current evidence linking the low-molecular-weight protein tyrosine phosphatase (LMPTP) to several common diseases, including allergy, asthma, obesity, myocardial hypertrophy, and Alzheimer's disease. Based on the known effects of the genetic polymorphisms on the alternative mRNA splicing and enzyme levels of LMPTP, we discuss the possible molecular mechanisms of LMPTP involvement in these diseases.
14663288 Etiologic diagnosis of 204 pericardial effusions. 2003 Nov The etiologic evaluation of pericardial effusion is frequently unsuccessful when noninvasive methods are used. To determine the cause of the current episode, all patients with echographically identified pericardial effusion from May 1998 to December 2002 underwent noninvasive diagnostic testing of blood, throat, and stool samples. Patients with postpericardiotomy syndrome were excluded. To analyze the value of our tests, we tested randomly selected blood donors as negative controls. Among 204 included patients, 107 (52.4%) had a final etiologic diagnosis: the etiology of 52 was highly suspected at first examination and later confirmed (thyroid deficiency, 5 cases; systemic lupus erythematous, 7; rheumatoid arthritis, 7; scleroderma, 3; cancer, 25; and renal insufficiency, 5). A definite etiologic diagnosis was made in 11 patients from pericardial fluid analysis (cancer, 5 cases; tuberculosis, 3; Streptococcus pneumoniae, Citrobacter freundii, and Actinomyces, 1 case each). Among 141 patients considered to have idiopathic pericarditis, 44 (32.1%) gained an etiologic diagnosis by our systematic testing strategy. This included serologic evaluation of serum (Coxiella burnetii, 10 cases; Bartonella quintana, 1; Legionella pneumophila, 1; Mycoplasma pneumoniae, 4; influenza virus, 1), viral culture of throat swabs (enterovirus, 8 cases; and adenovirus, 1), high-level antinuclear antibodies (>1/400, 3 cases), and thyroid-stimulating hormone (15 abnormal results). Antibodies to Toxoplasma and cytomegalovirus, enterovirus recovered from rectal swabs, and low-level antinuclear antibodies were seen with equal frequency in patients and controls. Using our evaluation strategy, the number of pericardial effusions classified as idiopathic was less than in other series. Systematic testing for Q fever, Mycoplasma pneumoniae, thyroid abnormalities, and antinuclear antibodies, accompanied by viral throat cultures, frequently enabled us to diagnose diseases not initially suspected in patients with pericardial effusion.
15077264 The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthri 2004 Apr 15 OBJECTIVE: To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis. METHODS: In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF. RESULTS: Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer. CONCLUSIONS: The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.