Down-regulation of activating Fcγ receptors on monocytes of patients with rheumatoid arthritis upon methotrexate treatment

Objective. To determine the effect of methotrexate (MTX) on expression levels of activating receptors for IgG (Fc gamma Rs) on monocytes of rheumatoid arthritis (RA) patients in relation to changes in disease activity. Methods. The effect of MTX on Fc gamma Rs on monocytes of RA patients was evaluated ex vivo as well as in vitro. Recently diagnosed, disease-modifying antirheumatic drug (DMARD)-naive RA patients were treated with low-dose MTX. At baseline and 16 weeks after the start of MTX treatment, changes in Fc gamma R expression levels on peripheral blood monocytes were evaluated by fluorescence-activated cell sorting analysis and were correlated to changes in disease parameters. To study the direct effects of MTX on monocytes, these cells were isolated from peripheral blood monocytes of healthy controls and cultured with MTX. Other monocyte surface molecules (CD40, CD80, CD86, MHC class II) were also determined to test the specificity of the effect on Fc gamma R expression levels. Results. Eleven out of 15 patients improved clinically (mean disease activity score before 6.2 +/- 0.8 vs 4.3 +/- 1.7 after). Sixteen weeks after the start of MTX therapy, the expression levels of Fc gamma RI and IIa on monocytes were significantly decreased, whereas the decreases in Fc gamma RIIIa expression levels on monocytes were less marked. The percentage decrease in Fc gamma RI expression correlated with the percentage decrease in CRP and well-being. In vitro MTX selectively decreased Fc gamma RI and Fc gamma RIIa expression levels of isolated monocytes, in contrast to other surface molecules. Conclusion. The disease-modifying effect of MTX in the treatment of RA is accompanied by down-regulation of activating Fc gamma RI and IIa on monocytes, which could be a direct effect of MTX on monocytes. This down-regulation represents a new mode of action of MTX which should be considered in RA patients, especially during conditions that could give rise to monocyte activation by IgG-containing immune complexes, e.g. during antibody-based therapy of RA.