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OBJECTIVE: Intramuscular gold is a well documented treatment in rheumatoid arthritis (RA), but its mechanism of action is still poorly understood. From an observation that gold sodium thiomalate (GSTM) induces monocyte-derived interleukin 6 (IL-6) and IL-10 production in vitro, a hypothesis has been proposed that gold exerts its action mainly as a selective immunostimulator rather than as a general immunosuppressant. In this prospective study we investigated cytokine production in peripheral blood from patients with RA during treatment with GSTM. METHODS: A total of 20 patients with RA were treated with GSTM for at least 3 months. Disease activity was recorded at baseline, 12, 20, and 28 weeks. The ELISPOT method was used to measure spontaneous production of IL-6, IL-10, and interferon-g (IFN-g) from peripheral blood mononuclear cells (PBMC) at baseline and 4 and 12 weeks and production after incubation with GSTM in vitro, at different concentrations (0, 3, 12.5, 40 µg/ml) at baseline. IL-6 and IL-10 concentrations in serum were measured with ELISA. RESULTS: The numbers of IL-10-producing cells were increased after 4 weeks' treatment with GSTM (p < 0.01). The numbers of cells spontaneously producing IL-6 were increased after 4 weeks (p < 0.01) and 12 weeks (p < 0.01). The numbers of IFN-g-producing cells were increased after 4 weeks (p < 0.01). Serum concentrations of IL-10 were increased after 4 weeks (p < 0.01). Serum concentrations of IL-6 were not changed at any timepoint. The in vitro effect of GSTM on IL-10 production from PBMC at baseline predicted development of skin reactions during GSTM treatment, with lack of skin reactions being associated with high gold induced IL-10 production (p < 0.05). There was no correlation between clinical response and cytokine production. CONCLUSION: This study indicates an immunostimulatory effect of GSTM treatment in patients with RA. The increase in IL-10 production during GSTM treatment may contribute to the positive effects of gold in RA.

OBJECTIVE: To investigate the effects of gold salt on the differential production of proinflammatory and antiinflammatory cytokines in vitro. METHODS: Heparinized blood from 10 blood donors and 10 patients with polyarthritis was density separated and incubated with various concentrations of gold salt [Myocrisin gold sodium thiomalate (GSTM) plus phenyl mercury nitrate]. Cytokine production was measured after incubation for 16-20 h using an Elispot method detecting interleukin 10 (IL-10), IL-6, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) producing cells. In addition, parallel cell culture supernatants were collected and analyzed by ELISA for IL-10, IL-6, TNF-alpha, IFN-gamma, and IL-2. In some cultures phytohemagglutinin A (PHA) was added in predefined concentrations. RESULTS: GSTM increased the number of cells producing IL-6 and IL-10 in a dose dependent manner, both with and without simultaneous addition of PHA. These effects were seen in samples from both healthy blood donors and patients with polyarthritis. The increase in IL-10 production was inhibited when monocytes were depleted. No effects of GSTM were seen on IFN-gamma or TNF-alpha producing cells. Parallel supernatant cultures displayed a GSTM dose dependent decrease in IFN-gamma levels after mitogen stimulation, whereas no changes were seen in IL-6 or TNF-alpha levels. CONCLUSION: The differential effects of gold salt on cytokine production, with a marked stimulatory effect on IL- 10 and IL-6, indicate that gold salt may act as a relatively selective immunostimulator rather than as a general immunosuppressant.