Objective. To verify the hypothesis that in rheu-matoid arthritis (RA), tumor necrosis factor (TNF) plays a critical role in regulating leukocyte trafficking and chemokine levels. Methods. Ten patients with longstanding RA received a single 10 mg/kg infusion of anti-TNF mono-clonal antibody (cA2). The articular localization of autologous granulocytes, separated in vitro and labeled with 111 In, was studied by analysis of gamma-camera images both before and 2 weeks after treatment. At the same sequential time points, synovial biopsy samples were assessed for infiltrating CD3 T cells, CD22 B cells, and CD68 macrophages. Synovial tissue expression of the chemokines interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), macrophage inflamma-tory protein 1 (MIP-1), MIP-1, Gro, and RANTES was also determined. Serum IL-8 and MCP-1 concentrations were measured by enzyme-linked immunosor-bent assay. Results. Anti-TNF therapy in RA significantly reduced 111 In-labeled granulocyte migration into affected joints. There was a simultaneous and significant reduction in the numbers of infiltrating synovial CD3 T cells, CD22 B cells, and CD68 macrophages and in the expression of IL-8 and MCP-1, with a trend toward a reduction in serum concentrations of these chemokines. Conclusion. TNF blockade reduces synovial expression of the chemokines IL-8 and MCP-1 and diminishes inflammatory cell migration into RA joints.
Objective. To determine the efficacy and safety of increasing the allopurinol dose above the proposed creatinine clearance-based dose in patients with gout.Methods. Patients with gout who had been receiving a stable dose of allopurinol for >1 month were recruited. The dose of allopurinol was increased to obtain the target serum urate level of <0.36 mmoles/ liter (<6 mg/dl). Patients were seen monthly until the serum urate concentration was <0.36 mmoles/liter for 3 consecutive months and then were seen every 3 months for at least 12 months. Data were analyzed using the dosage of allopurinol (mg/day) greater than the recommended dosage, as defined by the Hande criteria.Results. Ninety patients were enrolled. The mean age of the patients was 58.7 years (range 27-83 years), 87.9% were male, and 81.9% were of European ancestry. Forty-five patients had a serum urate concentration of >0.36 mmoles/liter, and the dose of allopurinol was increased in these patients. Rashes developed in 3 patients, and either allopurinol was discontinued or dose escalation was ceased in these patients. Seven patients were lost to followup or developed intervening medical problems that precluded dose escalation. In 31 (88.8%) of 35 patients who completed the study, the serum urate level was <0.36 mmoles/liter at 12 months. Two of the 5 patients who had a serum urate level >0.36 mmoles/liter had undetectable levels of plasma oxypurinol, indicating noncompliance with allopurinol treatment. A significant reduction in the serum urate concentration was observed for all allopurinol doses above the recommended dose. Eighteen of 45 patients were receiving furosemide; those receiving furosemide were just as likely as those not receiving furosemide to achieve a serum urate concentration of <0.36 mmoles/ liter (72% versus 88.5%; P ؍ 0.24). Patients receiving furosemide required a higher dose of allopurinol to achieve the target serum urate concentration. No serious adverse events were observed.Conclusion. Increasing the dose of allopurinol above the proposed creatinine clearance-based dose led to a significant reduction in the serum urate concentration. Approximately 89% of patients achieved a serum urate concentration of <0.36 mmoles/liter. In this cohort, toxicity was not increased in patients receiving higher doses of allopurinol, including those with renal impairment.Gout is the most common form of arthritis in men older than age 40 years, and the incidence of gout is increasing (1). Gout is a complex inflammatory response to the presence of monosodium urate (MSU) crystals in joints. MSU crystals can form when serum urate supersaturation concentrations are reached (ϳ0.4 mmoles/liter [6.7 mg/dl] at 37°C). Gout typically presents as self-limiting episodes of acute inflammatory arthritis. With time, untreated hyperuricemia and recurrent attacks of gout lead to bone and joint damage, deposition of MSU as tophi, and ultimately disability. Gout is also associated with increased mortality, especially that related to cardiovascular disease (2-4).Lowerin...
Objective. There is evidence supporting a therapeutic range for methotrexate polyglutamate ( Conclusion. There is wide interpatient variability of RBC MTXGlu 1-5 accumulation and elimination in adults with RA. These data also suggest that after a dose change, >6 months are required for RBC MTXGlu 1-5 to reach steady state. Such delays in achieving steady state suggest that more rapid dose escalation or subcutaneous administration from the outset should be considered.
These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.
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