Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control

Abstract

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.

Figure 1

Levels of soluble receptor for advanced glycation end products (soluble RAGE) in blood and synovial fluid (SF) of rheumatoid arthritis (RA) patients and in patients with degenerative/traumatic joint diseases (non-inflammatory joint disease [NID]). In addition, blood levels of soluble RAGE were assessed in healthy controls. Box plots show the 25th and 75th percentiles. Horizontal lines in bold within boxes indicate medians, and dashed lines indicate means. Vertical bars indicate the 5th and 95th percentiles. Statistical differences with respect to soluble RAGE levels between groups were calculated using the Mann–Whitney U test, and differences between paired samples were calculated by the Wilcoxon signed rank test. Mean ± standard error of the mean (median) values are shown. NS, not significant.

Figure 2

Scattergram showing an association between blood and synovial soluble receptor for advanced glycation end products (sRAGE) levels in rheumatoid arthritis patients. The Spearman rank correlation coefficient (r_s) and P value are given.

Figure 3

Blood soluble receptor for advanced glycation end products (sRAGE) levels in age-matched groups of rheumatoid arthritis (RA) patients and healthy controls. Box plots show the 25th and 75th percentiles. Horizontal lines within boxes in bold indicate medians, and dashed lines indicate means. Vertical bars indicate the 5th and 95th percentiles. Statistical differences with respect to sRAGE levels between groups were calculated using the Mann–Whitney U test.

Figure 4

Blood soluble receptor for advanced glycation end products (sRAGE) levels of rheumatoid arthritis patients stratified with respect to seropositivity and erosivity in comparison with healthy controls. Box plots show the 25th and 75th percentiles. Horizontal lines in bold within boxes indicate medians, and dashed lines indicate means. Vertical bars indicate the 5th and 95th percentiles. Statistical differences with respect to sRAGE levels between groups were calculated using the Mann–Whitney U test. The mean ± standard deviation (median) values are shown. * P < 0.01 as compared with healthy controls. RF, rheumatoid factor; no eros, no erosion.

Figure 5

Levels of soluble receptor for advanced glycation end products (soluble RAGE) in blood and synovial fluids of rheumatoid arthritis (RA) patients who received methotrexate treatment or were not treated with disease-modifying antirheumatic drugs (DMARDs) at all. Box plots show the 25th and 75th percentiles. Horizontal lines in bold within boxes indicate medians, and dashed lines indicate means. Vertical bars indicate the 5th and 95th percentiles. Statistical differences with respect to soluble RAGE levels between groups were calculated using the Mann–Whitney U test. Mean ± standard error of the mean (median) values are shown. NS, not significant.