The effect of slow-acting anti-rheumatic drugs (SAARDs) and combinations of SAARDs on monokine production in vitro.

The mode of action of slow-acting anti-rheumatic drugs (SAARDs) is complex but may often include effects on cytokine (interleukin-1, IL-1, and tumour necrosis factor, TNF) production by monocytes/macrophages. Different SAARDs may have variable effects on cytokine production in vitro depending on the concentration of drug, the presence of other SAARDs and individual variation. The gold compounds gold sodium thiomalate (GST) and auranofin (AF) had a bimodal effect on cytokine production. High concentrations of GST (greater than 1 microgram/ml) weakly inhibited IL-1-beta secretion (without affecting IL-1-alpha or TNF secretion and without affecting cell-associated IL-1-alpha and IL-1-beta accumulation), and although AF (greater than 100 ng/ml) inhibited cytokine production it did so at concentrations near to the toxic range for the drug (greater than 200 ng/ml). GST and AF when used in combination inhibited cytokine production in a synergistic manner even at concentrations that would potentiate cytokine production if used individually. Hydroxychloroquine (HCQ) and sulfasalazine (SAP) were two other inhibitory SAARDs which acted synergistically in combination. Combination of HCQ and SAP with gold drugs gave variable results. D-penicillamine (D-pen) and methotrexate (MTX) were two SAARDs that generally did not affect cytokine production individually or in combination with other SAARDs. These results suggest that combination SAARD therapy may more effectively target excessive cytokine production, which is a hallmark of rheumatoid arthritis.