METHOTREXATE ACTION IN RHEUMATOID ARTHRITIS: STIMULATION OF CYTOKINE INHIBITOR AND INHIBITION OF CHEMOKINE PRODUCTION BY PERIPHERAL BLOOD MONONUCLEAR CELLS

Abstract

This open label study examines whether methotrexate (MTX) treatment modulates ex vivo synthesis of interleukin-1 receptor antagonist (IL-lra), soluble tumour necrosis factor receptors(sTNFR p55 and p75), interleukin-1β (IL-1β), tumour necrosis factor α(TNF-α), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by peripheral blood mononuclear cells (PBMC} and whether changes reflect clinical response. Significant stimulation of IL-lra and sTNFR p75 as well as inhibition of IL-8 production of PBMC were associated with clinical improvement observed in patients treated with MTX. When defining the characteristics of patients at study entry retrospectively in responders and non-responders a significantly lower ratio of IL-lra :IL-1β production before and its increase upon treatment was associated with clinical response in 13 patients compared to five patients not responding to MTX. In addition, clinical improvement was associated with decreased synthesis of IL-1β, TNF-α and IL-8 induced by bacterial lipopolysaccharide, IL-1α and IL-1β in PBMC in vitro. These findings suggest that MTX therapy reverses the inflammatory type of rheumatoid arthritis (RA) blood mononuclear cells by stimulating cytokine inhibitor production while inhibiting inflammatory cytokine release at the same time. This may explain the powerful anti-inflammatory properties of low-dose MTX as observed in most RA patients. Pretreatment determination of the IL-lra: IL-1β ratio in PBMC may be predictive with regard to a favourable therapeutic response and therefore may be useful for the selection of RA patients to be treated with MTX.