A phase I/II dose escalation study of intensified cyclophosphamide and autologous blood stem cell rescue in severe, active rheumatoid arthritis.
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OBJECTIVE: Based on animal studies and anecdotal case reports, high-dose therapy and autologous blood stem cell rescue have been proposed as an experimental treatment for severe, refractory rheumatoid arthritis (RA). This study aimed to establish the toxicity of this treatment and obtain preliminary efficacy data upon which to base future clinical trials. METHODS: Two cohorts of 4 patients who fulfilled criteria for severe, active, treatment-resistant RA were recruited into a dose-escalation study of cyclophosphamide (CYC) (100 mg/kg or 200 mg/kg) followed by unmanipulated peripheral blood stem cell rescue. Patient treatment was managed according to a standard supportive care protocol. Disease-modifying drugs were discontinued before treatment, but corticosteroids were maintained and later tapered where possible. Patients' conditions were assessed using World Health Organization toxicity criteria and standard parameters for rheumatic disease. RESULTS: Dose-dependent differences in hematologic toxicity were observed between cohorts 1 and 2, although toxicity was similar for other systems and was most significant in the gastrointestinal system. Patients in cohort 1 had only transient responses to therapy, lasting 2-3 months. Substantial improvements were sustained beyond 17-19 months in cohort 2, including steroid-independent disease remission for 1 patient, although the procedure did not completely abolish disease activity. CONCLUSION: High-dose CYC and unmanipulated autologous blood stem cell rescue has acceptable dose-dependent toxicity in severe, treatment-resistant RA, and 200 mg/kg of CYC induces substantial clinical responses. Refinement of this intensive approach might include further intensification of the preparation regimen, graft manipulation, and posttransplant immunomodulation. (+info)
Cost effectiveness of replacing diclofenac with a fixed combination of misoprostol and diclofenac in patients with rheumatoid arthritis.
(42/3077)
OBJECTIVE: To estimate the costs and health consequences of replacing treatment with diclofenac 50 mg with a fixed combination of diclofenac 50 mg and misoprostol 0.2 mg 3 times a day in patients with rheumatoid arthritis (RA). METHODS: A decision tree was developed to simulate 6 months of nonsteroidal antiinflammatory drug (NSAID) treatment for RA. The probabilities of the clinical outcomes were based on a literature review. A survey of Norwegian rheumatologists was undertaken to explore their clinical management of dyspepsia in RA patients taking NSAIDs. Valuation of health states was based on results of the Short Form 36 health survey. RESULTS: In female RA patients without any risk factors associated with serious gastrointestinal (GI) complications, the incremental cost of replacing diclofenac with the fixed misoprostol/diclofenac combination therapy was $72,700 per quality-adjusted life-year gained. For patients with 1 risk factor, the cost was less than $16,000. With 2 or 3 risk factors, the use of misoprostol was cost saving. The cost-effectiveness ratios in males were approximately 20% higher than in females. CONCLUSION: Replacing diclofenac with a fixed diclofenac/misoprostol combination is cost effective when restricted to RA patients at increased risk of serious GI events. (+info)
Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: a Department of Veterans Affairs cooperative study.
(43/3077)
OBJECTIVE: To determine if the peripheral articular manifestations of the seronegative spondylarthropathies (SNSA) respond differently than the axial manifestations to treatment with sulfasalazine (SSZ). METHODS: This is a reanalysis of a previously reported series of randomized, double-blind, placebo-controlled, multicenter trials comparing the effects of SSZ, 2,000 mg/day, and placebo on the axial and peripheral articular manifestations of ankylosing spondylitis (AS), psoriatic arthritis (PsA), and reactive arthritis (ReA; Reiter's syndrome). Patients were classified as treatment responders on the basis of meeting predefined improvement criteria in 4 outcome measures: namely, patient and physician global assessments in all patients, morning stiffness and back pain in patients with axial manifestations, and joint pain/tenderness scores and joint swelling scores in patients with peripheral articular manifestations. RESULTS: Six hundred nineteen SNSA patients (264 AS, 221 PsA, and 134 ReA) were studied. One hundred eighty-seven of these patients had only axial manifestations of their disease, while 432 patients had peripheral articular manifestations. Of the patients with axial disease, 40.2% of the SSZ group and 43.3% of the placebo group met the predefined response criteria (P = 0.67). Of the peripheral articular group, 59.0% of the SSZ-treated patients and 42.7% of the placebo-treated patients showed a response (P = 0.0007). CONCLUSION: In a large group of affected individuals, the response of SNSA patients to SSZ appears to be related to the articular manifestations of their disease. These data demonstrate that the axial and peripheral articular manifestations of SNSA respond differently to treatment with SSZ. In SNSA patients with persistently active peripheral arthritis, SSZ is safe, well tolerated, and effective. (+info)
The peripheral benzodiazepine receptor ligand PK 11195 inhibits arthritis in the MRL-lpr mouse model.
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OBJECTIVE: Mice of the MRL-lpr strain develop a severe autoimmune arthritic condition when primed with complete Freund's adjuvant. The pathology is similar to that seen in human rheumatoid arthritis. We investigated whether PK 11195, a powerful ligand for peripheral benzodiazepine receptors, would have preventative or therapeutic effects in this model. METHODS: MRL-lpr mice were primed with complete Freund's adjuvant at 13-14 weeks of age. Daily PK 11195 injections were started on the same day as priming to test for preventative effects. Daily PK 11195 injections were started 10 days after priming to test therapeutic effects. RESULTS: PK 11195 showed both preventative and therapeutic effects. At 1 mg/kg/day, it inhibited disease onset. At 3 mg/kg/day, it inhibited established disease progression. CONCLUSION: The evidence suggests that PK 11195 may be the prototype of a new class of anti-inflammatory agents. (+info)
Effect of diacerein on spontaneous polyarthritis in male New Zealand black/KN mice.
(45/3077)
OBJECTIVE: Male New Zealand black/KN (NZB/KN) mice spontaneously develop polyarthritis, characterized by destructive damages to the articular cartilage and bone. We assessed effects of diacerein in male NZB/KN mice by radiographic and histopathologic examinations. DESIGN: Diacerein, cyclosporin A or vehicle for the control were orally administered for 7 months, initiating at 8 weeks of age when the arthritis became apparent. RESULTS: At 39 weeks of age, the NZB/KN mice developed polyarthritis in the joints of the forelimbs and hind legs, radiographically characterized by joint space narrowing, deformation of the joint surfaces, and bone erosions. Histopathologic findings showed that the tarsal joints and knee sections from the NZB/KN mice exhibited overt arthritic lesion. Radiographic and histopathologic findings showed that diacerein and cyclosporin A at a dose of 30 mg/kg/day significantly reduced the progression of arthritis. CONCLUSIONS: Diacerein shows articular protecting effects against the development of spontaneous arthritis in male NZB/KN mice and diacerein might be useful in the treatment of chronic inflammatory joint diseases during clinical use. (+info)
Liposome encapsulated aurothiomalate reduces collagen-induced arthritis in DBA/1J mice.
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Collagen-induced arthritis (CIA) generated in rats or mice has long been a model system for the study of rheumatoid arthritis in humans. In particular, this system has been used to study the mechanisms and effects of anti-arthritic drugs in the treatment of the disease. Sodium aurothiomalate (ATM) is an agent often used to treat rheumatoid arthritis in humans; however, it possesses inherent toxicities which limits its usefulness. Liposome-encapsulated drugs are currently being developed to minimize the toxicities associated with a variety of potentially beneficial drugs. We have chosen to encapsulate ATM into small unilamellar vesicles (SUVs) to determine whether greater efficacy would be achieved in treating CIA with SUV ATM as compared to using the free drug. SUVs were prepared from hydrogenated egg phosphatidylcholine and cholesterol. These SUVs were very stable. Vesicles stored at 4 degrees C lost only 0.09% of encapsulated ATM (SUV ATM) after 14 days and were able to reduce collagen-induced arthritis in these mice. Animals treated by i.m. injections of SUV ATM exhibited a 50% reduction in symptoms. More importantly, histological examination of knee joints of the affected animals verified that SUV ATM treatment prevented cellular infiltration of lymphocytes into the synovia of the collagen-sensitized mice. Conditioned media from spleen cell cultures was assayed for the presence of inflammatory lymphokines that might be affected by SUV ATM to account for the success in suppressing collagen-induced arthritis. (+info)
The rationale for the current boom in anti-TNFalpha treatment. Is there an effective means to define therapeutic targets for drugs that provide all the benefits of anti-TNFalpha and minimise hazards?
(47/3077)
Progress in understanding mechanisms of disease are necessary to usher in major changes in treatment. A new era in rheumatoid arthritis (RA) and related chronic autoimmune/inflammatory diseases is now beginning, with a variety of anti-TNFalpha treatments licensed for use in both RA and Crohn's disease. The rationale for this new treatment lies in an understanding that cytokines are critical, rate limiting molecules lying at the heart of the chronic autoimmune/inflammatory disease process. This understanding was developed from the critical evaluation of a hypothesis that was proposed linking cytokines, antigen presentation and autoimmunity in 1983. Detailed analysis focusing on the major site of the disease, the rheumatoid synovium was essential to developing indications that blockade of TNFalpha might be efficacious. This clue was validated using anti-TNFalpha treatment of an animal model of RA, murine collagen induced arthritis, and by immunohistochemical demonstration of upregulated TNF and TNF-R expression in the synovium. With this three pronged rationale, the authors were able to convince Centocor, Inc, which had developed a chimaeric anti-TNFalpha antibody for use in sepsis, to work with them to test the concept that TNFalpha blockade would be beneficial in RA. With the success of that first trial, other companies have subsequently tested their anti-TNF strategies successfully. Current interests extend to understanding the processes that regulate TNF production in the rheumatoid joint. Progress in this area is discussed, using adenoviruses to infect normal macrophages and rheumatoid synovium. (+info)
Etanercept: therapeutic use in patients with rheumatoid arthritis.
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Tumour necrosis factor (TNF) plays a central part in the pathophysiology of rheumatoid arthritis (RA). TNF initiates signal transduction by interacting with surface bound TNF receptors. Soluble tumour necrosis factor receptors (sTNFRs) act as natural inhibitors of TNF activity. Etanercept, recombinant p75 sTNFR:Fc fusion protein, has received approval from the US Food and Drug Administration for patients with RA and juvenile RA (JRA) who have failed treatment with at least one other drug. Etanercept has demonstrated excellent safety and efficacy in large scale, randomised, double blind, placebo controlled trials of patients with RA and JRA who are refractory to other disease modifying anti-rheumatic drugs. The therapeutic effects mediated by etanercept are rapid and sustained. Combining etanercept with methotrexate was found to be safe and more effective than treatment with methotrexate alone in the treatment of RA. These clinical findings demonstrate that etanercept can result in symptomatic improvement in patients with RA and JRA. Etanercept is an important new addition to the treatment of these diseases. (+info)