Effects of DMARDs on IL-1Ra levels in rheumatoid arthritis: is there any evidence?

Recent research has shown that in the processes of rheumatoid arthritis (RA), interleukin-1 (IL-1) is one of the pivotal cytokines in initiating and driving the disease, and the body's natural response, IL-1 receptor antagonist (IL-1Ra), has been shown conclusively to block its effects. Several agents used to treat RA such as disease modifying antirheumatic drugs (DMARDs), as well as glucocorticoids (GC), affect the transcription, synthesis, release, and/or activity of cytokines, including the IL-1Ra. A higher ratio of IL-1Ra:IL-1 production by the peripheral blood mononuclear cells (PBMC) of RA patients successfully treated with methotrexate (MTX) is observed when compared with the PBMC of untreated patients or healthy controls. Recent studies have also shown a significant increase in IL-1Ra with low-dose MTX treatment of cultured monocytic cells. Antimalarials (hydroxychloroquine and chloroquine) have been found to increase the monocyte production of IL-1Ra and these changes might explain at least some of their mechanisms of action. Various studies have shown that leflunomide (LF) tends to favor the inhibition of pro-inflammatory and matrix-destructive factors over that of anti-inflammatory factors (i.e. IL-1Ra) and metalloproteinase inhibitors, thus interfering with both inflammation and tissue destruction. Further studies should investigate the effects of LF on synovial tissue/fluid expression of the IL-1Ra in treated RA patients. Regarding cyclosporin A (CyA), considerable evidence shows that the treatment of RA patients induces a decrease in IL-1Ra levels. Similar results with the inhibition of IL-1Ra mRNA and protein have been observed following RA treatment with glucocorticoids. In addition, the oral administration of cortisol to normal subjects also decreased LPS-induced IL-1Ra synthesis in cultured monocytes. The effects of different DMARDs and GC on IL-1Ra levels in RA patients, as reviewed in this paper, support the important role that selected anticytokine treatments might exert in the pathophysiology of the disease.