The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily being expressed as a cell surface molecule and binding a variety of ligands. One of these ligands is high-mobility group box chromosomal protein 1, a potent proinflammatory cytokine, expression of which is increased in synovial tissue and in synovial fluid of rheumatoid arthritis (RA) patients. The interaction of high-mobility group box chromosomal protein 1 with cell-surface RAGE leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) may abrogate cellular activation since the ligand is bound prior to interaction with the surface receptor. Our aim was to analyse to what extent sRAGE is present in patients with chronic joint inflammation (RA) as compared with patients with non-inflammatory joint disease and with healthy subjects, and to assess whether there is an association between sRAGE levels and disease characteristics. Matching samples of blood and synovial fluid were collected from 62 patients with RA with acute joint effusion. Blood from 45 healthy individuals, synovial fluid samples from 33 patients with non-inflammatory joint diseases and blood from six patients with non-inflammatory joint diseases were used for comparison. sRAGE levels were analysed using an ELISA.RA patients displayed significantly decreased blood levels of sRAGE (871 +/- 66 pg/ml, P < 0.0001) as compared with healthy controls (1290 +/- 78 pg/ml) and with patients with non-inflammatory joint disease (1569 +/- 168 pg/ml). Importantly, sRAGE levels in the synovial fluid of RA patients (379 +/- 36 pg/ml) were lower than in corresponding blood samples and correlated significantly with blood sRAGE. Interestingly, a significantly higher sRAGE level was found in synovial fluid of RA patients treated with methotrexate as compared with patients without disease-modifying anti-rheumatic treatment.We conclude that a decreased level of sRAGE in patients with RA might increase the propensity towards inflammation, whereas treatment with methotrexate counteracts this feature.