Serum Advanced Glycation End Products and Their Soluble Receptor as New Biomarkers in Systemic Lupus Erythematosus

Abstract

It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE-sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.

Keywords: activity index; advanced glycation end products; cardiovascular disease; systemic lupus erythematosus.

Figure 1

Associations between pentosidine levels and different SLE characteristics, with only pulmonary manifestations being significant.

Figure 2

Statistically significant associations between CML and different systemic lupus erythematosus characteristics: (a) disease duration; (b) non-Caucasian ethnicities; (c) anti-dsDNA values; (d) IL-6 values. CML Nξ-(carboxymethyl)lysine; OLS: ordinary least squares; GLM: generalized linear model; IL-6: interleukin 6.

Figure 3

Statistically significant associations between CEL and different systemic lupus erythematosus characteristics: (a) anti-dsDNA values; (b) IL-6 values; (c) positivity of anti-dsDNA antiboides; (d) number of accumulated SLE manifestations throughout the disease. CEL: Nξ-(carboxyethyl)lysine; OLS: ordinary least squares; GLM: generalized linear model; IL-6: interleukin 6.

Figure 4

Statistically significant associations between the serum receptor for advanced glycation end products and different systemic lupus erythematosus characteristics: (a) male gender; (b) having ever had photosensitivity; (c) current treatment with bDMARD; (d) current treatment with mycophenolic acid OLS: ordinary least squares; GLM: generalized linear model; bDMARD: biological disease-modifying antirheumatic drugs.

Figure 5

Statistically significant associations between pentosidine/sRAGE and different systemic lupus erythematosus characteristics: (a) current treatment with bDMARD; (b) positive anti-Ro52 antibodies sRAGE: soluble receptor for advanced glycation end products; OLS: ordinary least squares; GLM: generalized linear model. bDMARD: biological disease-modifying antirheumatic drugs.

Figure 6

Statistically significant associations between CML/sRAGE and different systemic lupus erythematosus characteristics: (a) non-Caucasian ethnicities; (b) SDI score; (c) densitometric osteroporosis; (d) dyslipidemia drugs treatment CML: Nξ-(carboxymethyl)lysine; sRAGE: soluble receptor for advanced glycation end products; OLS: ordinary least squares; GLM: generalized linear model. SDI: systemic lupus erythematosus damage index.

Figure 7

Statistically significant associations between CEL/sRAGE and different systemic lupus erythematosus characteristics: (a) CRP values, (b) IL-6 values; (c) pathological (>7 pg/mL) IL-6 values. CEL: Nξ-(carboxyethyl)lysine; sRAGE: soluble receptor for advanced glycation end products; OLS: ordinary least squares; GLM: generalized linear model. CRP: C-reactive protein; IL-6: interleukin 6.

Figure 8

Statistically significant associations between skin AGEs/sRAGE and different systemic lupus erythematosus characteristics: (a) male gender; (b) disease duration in tertiles AGEs: advanced glycation end products; sRAGE: soluble receptor for advanced glycation end products OLS: ordinary least squares; GLM: generalized linear model.