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ID PMID Title PublicationDate abstract
15135140 Serum levels of type IIA procollagen amino terminal propeptide (PIIANP) are decreased in p 2004 Jun OBJECTIVE: The aim of this study was to develop a specific immunoassay for PIIANP and measure its serum concentration in healthy controls and in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). In addition, we investigated circulating forms recognized by antiserum IIA in pools of serum from healthy adults, patients with OA and patients with RA. DESIGN: Using as immunogen and standard the recombinant human Glutathione S-Transferase (GST)-exon 2 fusion protein of type II collagen, we developed a competitive polyclonal antibody-based ELISA. We compare serum PIIANP levels in 43 patients with knee OA (23 women and 20 men; mean age: 62.6+/-9.6 yr), 63 women with RA (mean age: 54+/-16 yr) and 88 healthy controls (67 women, mean age: 53+/-13 yr and 21 men, mean age: 63+/-7 yr). We randomly selected serum in each group for analyze circulating forms. RESULTS: The immunoassay we developed demonstrated adequate intra and inter-assay precision (CV<10%) and dilution recovery (mean: 96%), allowing accurate measurements of serum PIIANP from 1.13 to 40 ng/ml. No significant cross-reactivity of the ELISA was observed with purified intact human procollagen type I N-propeptide, circulating thrombospondin and von Willebrand factor, proteins which exhibit significant sequence homology with PIIANP. Western blot analysis showed that antiserum IIA recognized two circulating immunoreactive forms of approximately 80 and 100 KDa respectively in serum from healthy adults, patients with OA and RA but also in a pool of synovial fluids from patients with OA. Serum PIIANP levels were markedly decreased in patients with knee OA (12.0+/-3.2 vs 25.8+/-7.5 ng/ml for OA and controls respectively, P<0.0001) and RA (14.1+/-2.5 ng/ml vs 21.7+/-7.6 ng/ml for RA and controls respectively, P<0.0001). In patients with RA, serum PIIANP levels were higher in those taking low-dose prednisone compared to non-users (15.0+/-2.4 vs 13.5+/-2.4 ng/ml, P<0.05). CONCLUSIONS: We have developed the first specific immunoassay for serum PIIANP which exhibits adequate technical performances. This assay detects specifically two immunoreactive forms both in healthy adults and patients with arthritis and does not cross react with other proteins with sequence homology with PIIANP. Levels of PIIANP were significantly decreased in patients with knee OA and RA suggesting that type IIA collagen synthesis may be altered in these arthritic diseases. The measurement of type IIA collagen synthesis with this new molecular marker may be useful for the clinical investigation of patients with joint diseases.
11945066 In vivo gene delivery to synovium by lentiviral vectors. 2002 Apr The delivery of anti-arthritic genes to the synovial lining of joints is being explored as a strategy for the treatment of rheumatoid arthritis. In this study, we have investigated the use of VSV-G pseudotyped, HIV-1-based lentiviral vectors for gene delivery to articular tissues. Recombinant lentivirus containing a beta-galactosidase/neomycin resistance fusion gene under control of the elongation factor (EF) 1alpha promoter efficiently transduced human and rat synoviocytes and chondrocytes in cell culture. When directly injected into the knees of rats, this vector transduced synovial lining cells, but not other articular tissues such as cartilage. We also constructed a lentiviral vector containing the human interleukin-1 receptor antagonist (IL1RA) cDNA and examined transgene expression in vitro and in vivo following injection into the knee joints of rats. In immunocompetent animals, intra-articular IL1RA expression was high and persisted, at a sharply declining rate, for approximately 20 days. In immunocompromised rats, however, lentivirus-mediated intra-articular expression of human IL1RA was found to persist for at least 6 weeks. Extra-articular expression of the transgene was minimal. These results indicate that lentiviral vectors are capable of efficient in vivo gene transfer to synovium and merit further investigation as a means of providing long-term expression for gene-based treatments of arthritis.
15194571 Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) wid 2004 Jul OBJECTIVES: To investigate the specificity of three anti-CD68 monoclonal antibodies (mAbs) for macrophages (Mphi) in immunohistochemistry (IHC) and flow cytometry (FACS). METHODS: IHC was performed on cryostat sections of rheumatoid arthritis (RA) and osteoarthritis (OA) synovial membranes using the anti-CD68 mAbs KP1, EBM11, and PGM1, and the fibroblast (FB) markers CD90 and prolyl 4-hydroxylase. Expression of CD68 was also analysed by FACS on the monocytic cell lines THP-1 and U937, as well as on synovial fibroblasts (SFB), skin FB, and gingival FB (both surface and intracellular staining). RESULTS: In IHC, there was an overlap between CD68 (mAbs KP1 and EBM11) and the FB markers CD90/prolyl 4-hydroxylase in the lining layer, diffuse infiltrates, and stroma of RA and OA synovial membranes. In FACS analysis of THP-1 and U937 cells, the percentage of cells positive for the anti-CD68 mAbs KP1 and EBM11 progressively increased from surface staining of unfixed cells, to surface staining of pre-fixed cells, to intracellular staining of the cells. Upon intracellular FACS of different FB, nearly all cells were positive for KP1 and EBM11, but only a small percentage for PGM1. In surface staining FACS, a small percentage of FB were positive for all three anti-CD68 mAbs. CONCLUSION: An overlap between CD68 (mAbs KP1 or EBM11) and the FB markers CD90 or prolyl 4-hydroxylase may prevent unequivocal identification of Mphi in synovial tissue by IHC or in monocytic cells and FB upon intracellular FACS. This may be due to sharing of common markers by completely different cell lineages.
15567815 Increased expression of humanin peptide in diffuse-type pigmented villonodular synovitis: 2005 Jun OBJECTIVES: To define the pathogenesis of pigmented villonodular synovitis (PVNS), by searching for highly expressed genes in primary synovial cells from patients with PVNS. METHODS: A combination of subtraction cloning and Southern colony hybridisation was used to detect highly expressed genes in PVNS in comparison with rheumatoid synovial cells. Northern hybridisation was performed to confirm the differential expression of the humanin gene in PVNS. Expression of the humanin peptide was analysed by western blotting and immunohistochemistry. Electron microscopic immunohistochemistry was performed to investigate the distribution of this peptide within the cell. RESULTS: 68 highly expressed genes were identified in PVNS. Humanin genes were strongly expressed in diffuse-type PVNS, but were barely detected in nodular-type PVNS, rheumatoid arthritis, or osteoarthritis. Humanin peptide was identified in synovium from diffuse-type PVNS, and most of the positive cells were distributed in the deep layer of the synovial tissue. Double staining with anti-humanin and anti-heat shock protein 60 showed that humanin was expressed mainly in mitochondria. Electron microscopy disclosed immunolocalisation of this peptide, predominantly around dense iron deposits within the siderosome. CONCLUSIONS: Increased expression of the humanin peptide in mitochondria and siderosomes is characteristic of synovial cells from diffuse-type PVNS. Humanin is an anti-apoptotic peptide which is encoded in the mitochondrial genome. Present findings suggest that mitochondrial dysfunction may be the principal factor in pathogenesis of diffuse-type PVNS and that humanin peptide may play a part in the neoplastic process in this form of PVNS.
14657510 Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthrit 2004 Apr OBJECTIVE: Vasoactive intestinal peptide (VIP) has demonstrated beneficial effects in several murine models of immune-mediated inflammation by inhibiting both the inflammatory and the autoimmune components of the disease. We investigate its potential to modulate the release of proinflammatory cytokines and chemokines by human synovial cells from patients with rheumatoid arthritis (RA). METHODS: Fresh suspensions of synovial tissue cells (STC) or cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA or osteoarthritis (OA). The effects of VIP on basal or tumour necrosis factor alpha (TNF-alpha)-stimulated production of CCL2 (MCP-1, monocyte chemotactic protein 1), CXCL8 [interleukin (IL)-8], IL-6 and TNF-alpha were studied by specific ELISAs (enzyme-linked immunosorbent assays). The mRNAs for CCL2, CXCL8 and IL-6 in FLS were analysed by real-time reverse transcription-polymerase chain reaction. RESULTS: VIP at 10 nm down-regulated chemokine production by STC and FLS from RA and OA patients. VIP also down-regulated the expression of mRNAs for CCL2, CXCL8 and IL-6. The effects of VIP were more clearly detected in RA samples and after stimulation with TNF-alpha. CONCLUSION: Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.
12048295 The impact of coexisting connective tissue disease on survival in patients with fibrosing 2002 Jun OBJECTIVES: Previous reports have suggested that patients who have fibrosing alveolitis in association with a connective tissue disease (FA-CTD) have a better prognosis than patients with 'lone' cryptogenic fibrosing alveolitis (LCFA). The present study was designed to compare the survival of a general population-based sample of patients with FA-CTD and LCFA both with each other and with the general population. METHODS: A survival analysis was performed using data for 107 patients with FA-CTD, 872 with LCFA and 5958 controls matched for age, sex and general practice, drawn from the General Practice Research Database. The data were analysed using Cox regression, adjusting for a number of potential confounders, including age, gender, smoking habit and use of oral corticosteroids. RESULTS: The median follow-up period was 2.1 yr and during this time 54 (50%) patients with FA-CFA, 386 (44%) patients with LCFA and 601 (10%) controls died. The mortality rates for patients with FA-CTD, LCFA and the controls were 284, 270 and 41 per 1000 person-yr respectively. After adjusting for age, gender, smoking habit and exposure to oral corticosteroids, patients with FA-CTD had a marginally worse survival than patients with LCFA (hazard ratio 1.20, 95% confidence interval 0.90-1.61). Compared with the general population controls, patients with either LCFA or FA-CTD had a considerably worse prognosis (hazard ratio 5.56, 95% confidence interval 4.77-6.49). CONCLUSIONS: The median survival in patients with fibrosing alveolitis is less then 3 yr. We found no evidence to support previous reports of a better prognosis amongst patients with FA-CTD.
12887234 Invasive pulmonary aspergillosis soon after therapy with infliximab, a tumor necrosis fact 2003 Jul BACKGROUND: Infliximab is a chimeric monoclonal antibody against tumor necrosis factor (TNF)-alpha, used for the treatment of Crohn's disease and rheumatoid arthritis. Recently, an increased risk of infection due to Mycobacterium tuberculosis and rare cases of invasive fungal disease have been reported following infliximab therapy. CASE REPORT: A 73-year-old woman with chronic rheumatoid arthritis who had been treated with methotrexate, leflunomide, and prednisone was given the first of three doses of infliximab in June 2001. In July 2001, she presented with cough, and in August, she had a right upper lobe infiltrate that was treated with levofloxacin without improvement. In October, the patient had right upper and middle lobe infiltrates on a chest X-ray and computed tomography scan. At bronchoscopy, an endobronchial mass was biopsied, which demonstrated Aspergills fumigatus. Our patient had frequently accompanied her daughter on visits to another medical center following a stem cell transplant, where her daughter was instructed to wear a mask during all visits because of extensive building construction. We postulate that our patient may have acquired pulmonary aspergillosis during this period. Literature reviews on granulomatous diseases following infliximab therapy and hospital-acquired aspergillosis are presented. CONCLUSION: The temporal relationship between the administration of infliximab and A. fumigatus infection in this patient suggests a causal relationship and possible healthcare-associated acquisition. These data underscore the importance of both patient and family education on prevention strategies when potent immune-modulating medications such as infliximab have been prescribed.
14606981 A cross-sectional retrospective assessment of anti-arthritic drugs in patients with arthri 2003 BACKGROUND: Selective cyclo-oxygenase-2 (COX-2) inhibitors were recently introduced for the treatment of arthritis because of their lower rates of gastrointestinal adverse events compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To examine the medication usage patterns for both osteoarthritis (OA) and rheumatoid arthritis (RA) in Korea. METHODS: The medical charts of a convenience sample of 402 patients with OA or RA were reviewed by the Arthritis Study Group in 14 hospitals and ten clinics in Korea. RESULTS: Traditional oral NSAIDs were the most commonly prescribed drugs for OA (68.3%) and RA (65.1%) patients. Two-thirds (66.7%) of the RA patients taking COX-2 inhibitors were prescribed other arthritis medications concurrently and 85.1% of RA patients taking NSAIDs were prescribed other arthritis medications concurrently. Patients on NSAIDs were almost twice as likely to have a gastroprotective agent (GPA) concurrently compared to COX-2 inhibitor users (OA patients 38.1% vs 21.2%; RA patients 57.9% vs 30.6%). Overall, patients taking COX-2 inhibitors were less likely to take GPAs concurrently compared to patients not taking COX-2 inhibitors (unadjusted OR 0.36; adjusted OR 0.39). CONCLUSIONS: Traditional oral NSAIDs were commonly prescribed to arthritis patients in Korea. In this study, patients taking COX-2 inhibitors were prescribed less adjunctive arthritis treatments and less gastroprotective agents than traditional oral NSAID users.
15142270 Treatment with recombinant interferon-beta reduces inflammation and slows cartilage destru 2004 We investigated the therapeutic potential and mechanism of action of IFN-beta protein for the treatment of rheumatoid arthritis (RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections of recombinant mouse IFN-beta or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-kappaB ligand, and c-Fos was evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-beta. We also examined the effect of IFN-beta on NF-kappaB activity. IFN-beta, at 0.25 microg/injection and higher, significantly reduced disease severity in two experiments, each using 8-10 mice per treatment group. IFN-beta-treated animals displayed significantly less cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required for osteoclastogenesis, receptor activator of NF-kappaB ligand and c-Fos. Tumor necrosis factor alpha and IL-6 expression were significantly reduced, while IL-10 production was increased after IFN-beta treatment. IFN-beta reduced expression of IL-6, IL-8, and GM-CSF in RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-kappaB activity. The data support the view that IFN-beta is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation.
15528349 Expression and characterization of a novel CD6 ligand in cells derived from joint and epit 2004 Nov 15 CD6 is a T cell surface glycoprotein that plays an important role in interactions of thymocytes with thymic epithelial cells and in mature T cell interactions with selected nonprofessional tissue APCs. We describe a novel CD6 ligand (CD6L) 3A11 Ag that is distinct from the known CD6L (CD166). The 3A11 protein is expressed on cells derived from human thymus, skin, synovium, and cartilage, and its expression is enhanced by IFN-gamma. mAbs directed against the 3A11 Ag and CD166 exhibit distinct patterns of binding to a panel of cell lines. Confocal microscopy shows that both CD166 and the 3A11 Ag are expressed at the cell surface, and that these proteins colocalize. The 3A11 Ag has a molecular mass of 130 kDa and is immunoprecipitated using either mAb 3A11 or soluble CD6-Ig fusion protein. mAbs directed against individual CD6L were less potent than was soluble CD6-Ig fusion protein in reducing adhesion of T cells to adherent 3A11-positive epithelial cells in vitro, suggesting that these Abs recognize epitopes on the 3A11 Ag and CD166 that are distinct from CD6 binding sites. Finally, transfection of epithelial cells with CD166-specific small interfering RNAs significantly decreased CD166 expression without alteration in 3A11 Ag levels, and thus confirmed that these two CD6L are distinct. Taken together, our data identifies a novel 130-kDa CD6L that may mediate interactions of synovial and epithelial cells with T lymphocytes.
12597281 Management of bilateral arytenoid cartilage fixation versus recurrent laryngeal nerve para 2003 Feb Bilateral arytenoid cartilage fixation (ACF) closely resembles vocal cord immobility due to recurrent laryngeal nerve paralysis (RLNP). This study sought to determine the etiologic differences between these two entities and to derive conclusions about treatment. The charts of 218 consecutive adult patients with immobility of both vocal cords requiring surgery for airway restoration were reviewed. The results of laryngeal electromyography and laryngotracheoscopy were used to distinguish ACF from RLNP. In 186 patients (85.3%), RLNP was identified. Of these, 154 paralyses (82.8%) were caused by surgical interventions, 5 (2.7%) were caused by previous intubation, 16 (8.6%) were caused by various malignancies, and 7 (3.8%) were neurogenic. In 4 patients (2.2%), the cause remained unclear. We identified ACF in 32 patients. The etiologic factors included previous long-term intubation in 22 patients (68.8%), short-term intubation in 3 patients (9.4%), Wegener's granulomatosis in 3 patients (9.4%), rheumatoid arthritis in 2 patients (6.3%), previous laryngeal surgery in 1 patient (3.1%), and caustic ingestion in 1 patient (3.1%). Additional second-site airway stenosis was found in 10 of the RLNP patients (5.4%) and in 15 of the ACF patients (46.9%). All RLNP patients had endoscopic surgery without temporary tracheotomy. Eighteen ACF patients required open surgery, and 4 were managed endoscopically but required temporary tracheotomy. The etiologic factors were significantly different for the two entities under study. Additional sites of stenosis were more frequent in ACF patients. Stenosis due to RLNP could be managed endoscopically without preliminary tracheotomy, while ACF frequently required open surgery and temporary tracheotomy.
12364631 Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitide 2002 Oct OBJECTIVE: Evidence indicates that tumour necrosis factor (TNF) is a major agent in the pathogenesis of vasculitis. We studied the short-term effect of anti-TNF-alpha antibody in systemic vasculitis patients refractory to steroids and immunosuppressive agents. METHODS: Ten patients refractory to corticosteroids and at least one immunosuppressant and who had persistently active disease or a new flare were included. Seven had Wegener's granulomatosis, two had rheumatoid arthritis-associated vasculitis and one had cryoglobulinaemia with mean duration of 9.1, 21.5 and 17 yr. They received infliximab (5 mg/kg) on days 1, 14, 42 and then every 8 weeks. Immunosuppressants were stopped between days 0 and 42 for eight patients, while the steroid dose was maintained or lowered. The treatment response was evaluated clinically with the Birmingham Vasculitis Activity Score 2000 (BVAS). RESULTS: Complete or partial remission was observed in all patients. The mean BVAS at entry was 9.1 (range 4-15) and had declined to 1.9 (range 0-4) by day 42 and 1.3 (range 0-4) at 6 months; BVAS of 0 was recorded for four patients on day 42 and for five at 6 months. The only adverse effect was cutaneous eruption in two patients. CONCLUSION: Anti-TNF-alpha successfully induced prompt symptomatic responses in patients with systemic vasculitis not responding to conventional treatment. Infliximab was well tolerated during the short-term follow-up.
14998551 Differential effect of phosphodiesterase IV inhibitor RP73401 on various inflammatory and 2004 May Phosphodiesterase (PDE) IV inhibitors have been reported to possess potent anti-inflammatory activities through enhancement of cAMP. In this study, the immunopharmacological effect of PDE IV inhibitor (RP73401) was further carefully evaluated. RP73401 strongly blocked the production of tumor necrosis factor (TNF)-alpha from lipopolysaccharide (LPS)-stimulated murine macrophages (RAW264.7) and human peripheral blood mononuclear cells (PBMC) and LPS-primed mice. RP73401 did not relieve joint inflammation in adjuvant-arthritis (RA) model, whereas the compound attenuated arachidonic acid-induced inflammation. RP73401 displayed weak or no modulatory effects on the activation of macrophage and lymphocytes (assessed by proliferation, nitric oxide (NO) release and cell-cell adhesion, TNF-alpha production upon phorbol 12-myristate 13-acetate (PMA) treatment), and fluorescein-isothiocynate (FITC)-induced ear oedema. Collectively, these data suggest that PDE IV inhibitor RP73401 may differentially modulate various immune responses and these may explain its inability to inhibit adjuvant-induced joint inflammation or FITC-induced ear oedema.
11985662 Human monoclonal natural autoantibodies against the T-cell receptor inhibit interleukin-2 2002 Apr Natural autoantibodies (NAAbs) specific for the T-cell receptor (TCR) are present in all human sera, but individuals with rheumatoid arthritis (RA) generally produce higher titres of immunoglobulin M (IgM) isotype autoantibodies (AAbs) against Vbeta TCR epitopes. To investigate possible correlations between the specificity of such AAbs and their role in immunomodulation, we generated seven B-cell hetero-hybridomas, secreting monoclonal IgM NAAbs, from the synovial tissue and peripheral blood of patients with RA. Here we report three anti-TCR monoclonal autoantibodies (mAAbs)--OR2, OR5 and Syn 2H-11--with the ability to bind subsets of murine T cells, including the ovalbumin-specific DO-11.10 clone. These antibodies did not induce apoptosis in vitro, but prevented interleukin-2 (IL-2) production by antigen-specific T cells. These findings suggest an immunomodulatory function for NAAbs to TCR V-region epitopes and serve as the foundation for testing human anti-TCR mAAbs in animal models with the eventual goal of using them as therapeutic agents in human disease.
12387696 Meloxicam. 2002 Oct Meloxicam (Mobic trade mark, Boehringer Ingelheim) is a relatively new oral non-steroidal anti-inflammatory drug (NSAID) approved for the treatment of osteoarthritis in the US. It has also been evaluated for the treatment of rheumatoid arthritis, ankylosing spondylitis and acute 'rheumatic' pain. Meloxicam has been shown to be COX-2 preferential, particularly at its lowest therapeutic dose, and is anti-inflammatory by inhibiting prostanoid synthesis in inflammatory cells. Since it is COX-2 preferential, it would be expected to have less gastrointestinal toxicity than non-selective NSAIDs. In clinical trials of meloxicam in osteoarthritis, it was found to be as effective as piroxicam, diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations, obstructions and bleeds by meta-analysis. Adverse events, including peripheral oedema and hypertension, occurred at a similar rate as with traditional NSAIDs.
12820688 Effect of pro-inflammatory/anti-inflammatory agents on cytokine secretion by peripheral bl 2003 Mar We studied a well-selected population of patients with active rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) without immunosuppressive therapy. Control and patient peripheral blood mononuclear cells (PBMC) were incubated with IL-1beta, IL-10, TGF-beta or LPS for 20 h and the in vitro basal and stimulated secretions of IL-6, TNF-alpha, IL-1beta and IL-1ra were measured by ELISA. We found that in the SLE patients the basal secretion of IL-6 was significantly lower and that of IL-1ra significantly higher than in control subjects, while in the RA group the basal IL-1ra secretion was higher than in healthy subjects. SLE and RA PBMC responded to LPS and IL-1beta reaching higher cytokine secretion values than controls. The in vitro response of SLE and RA PBMC to TGFbeta was normal, while that to IL-10 was defective: IL-10 was able to stimulate the production of IL-6 and IL-1ra in PBMC from normal subjects, but it was unable to enhance IL-6 secretion in RA cells and it was also completely ineffective in inducing IL-1ra secretion in both SLE and RA PBMC. Our work add new data useful for the evaluation of IL-10 and IL-1ra as therapeutic agents in rheumatic diseases.
12622757 Review article: The pharmacological properties and clinical use of valdecoxib, a new cyclo 2003 Feb 15 Cyclo-oxygenase-2-selective inhibitors produce less gastric damage than conventional non-steroidal anti-inflammatory drugs. Valdecoxib is a new orally administered cyclo-oxygenase-2-selective inhibitor, recently approved for use in osteoarthritis, rheumatoid arthritis and primary dysmenorrhoea in the USA. The drug has been evaluated in more than 60 clinical studies involving more than 14 000 patients and healthy volunteers. The analgesic efficacy of valdecoxib at a dose of 10 mg once daily in both osteoarthritis and rheumatoid arthritis is superior to that of placebo and similar to that of traditional non-steroidal anti-inflammatory drugs. Valdecoxib is effective in single doses of up to 40 mg for the alleviation of acute menstrual pain and has a rapid onset of action (within 30 min) and a long duration of analgesia (up to 24 h). Valdecoxib is well tolerated and has safety advantages compared with traditional non-steroidal anti-inflammatory drugs in terms of less gastrointestinal toxicity and a lack of an effect on platelet function. The incidence of adverse effects involving the kidney (fluid retention, oedema and hypertension) is similar to that of non-selective, non-steroidal anti-inflammatory drugs.
11911727 Aseptic meningitis associated with rofecoxib. 2002 Mar 25 Rofecoxib is a nonsteroidal anti-inflammatory drug that is reported to act by selectively inhibiting cyclooxygenase-2. A review and analysis of reports sent to the Spontaneous Reporting System of the Food and Drug Administration, Rockville, Md, suggest that aseptic meningitis is associated with rofecoxib use. To our knowledge, there have been no published reports of aseptic meningitis occurring in association with rofecoxib use to date. We report 5 serious cases of aseptic meningitis associated with rofecoxib use.
12557133 Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use. 2003 Feb BACKGROUND & AIMS: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2-selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2-selective agent in a prospective, double-blind, randomized GI outcomes trial. METHODS: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. RESULTS: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22-0.93; P = 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. CONCLUSIONS: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.
12364628 Rescue of combination therapy failures using infliximab, while maintaining the combination 2002 Oct OBJECTIVE: To assess the possible clinical and biological rescue of rheumatoid arthritis (RA) in 16 patients who were still active despite intensive combination therapy after receiving infliximab following the Anti-Tumour necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) schedule. METHODS: Sixteen patients who were still active despite combination therapy with optimal doses of methotrexate (MTX 15-17.5 mg/week) and cyclosporin A (CsA 2.5-3.5 mg/day) received infliximab. Ten received their combination plus infliximab (Combi), and six received infliximab plus MTX alone (Mono). The follow-up was carried out for 30 weeks in all patients and for 46 weeks in eight. Efficacy and safety were examined. RESULTS: At entry, the mean disease activity score (DAS) was 5.6 (all patients had a DAS >3.7). After therapy, eight of 10 patients in Combi and four out of six in Mono showed an improvement of >50% in the initial swollen joint count, yet only one patient reached 50% improvement in the initial DAS after 30 weeks, and one patient had a DAS <2.4 (low disease activity). Of the eight patients who reached 46 weeks of follow-up, three showed an improvement in DAS of 50% and two had a DAS <2.4. When considering the change over time, the difference between DAS at entry and at week 30 was statistically significant only in patients receiving MTX plus CsA, while it was not significant in those receiving MTX only. Two patients developed recurrent febrile upper respiratory infections in the Combi therapy group, while two had a single febrile infection in the MTX alone group. Two patients became strongly anti-cardiolipin positive (IgM >40 MPL) and one developed a coronary syndrome. CONCLUSION: Infliximab can be added incrementally to MTX plus CsA, with favourable results in terms of efficacy and safety over time in severe rapidly aggressive and progressive RA. Finally, minor evidence emerged for a stronger efficacy of the Combi treatment compared with Mono.