Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Members of the Receptor for Advanced Glycation Endproducts Axis Associate with Systemic Lupus Erythematosus, and May Serve As a Brake to Disease Activity.

Jain,  Manish, Amato,  Michael, Clancy,  Robert M., Izmirly,  Peter M., Buyon,  Jill P.

Background/Purpose:

The Receptor for Advanced Glycation Endproducts (RAGE) is a transmembrane cell-surface receptor found on a variety of immune and endothelial cells, which is upregulated in stress situations and mediates a pro-inflammatory response. RAGE has been implicated in the pathogenesis of diverse disease states characterized by vascular insult. Soluble forms of RAGE exist, with the total circulating pool of soluble RAGE (sRAGE) including both membrane-cleaved RAGE, as well as an alternative mRNA spliced form—endogenous soluble RAGE (esRAGE)—both with common ligand affinity. Isoforms of soluble RAGE may be protective by serving as decoy receptors. Simultaneous measurement of sRAGE and esRAGE, with attention to relative proportion, may be informative. Accordingly, RAGE axis markers in an SLE cohort with characterization of disease activity and subclinical atherosclerosis was assessed to provide insight into pathogenesis of SLE.

Methods:

sRAGE and esRAGE were measured by ELISA in a cross sectional study of 99 SLE patients and 40 healthy controls in whom carotid ultrasonography was performed to evaluate for carotid plaque. SLEDAI for SLE patients was also calculated at the same visit.

Results:

Median esRAGE level was higher in patients (288±262 pg/mL) than controls (171±162 pg/mL) (p=.0031), as was percent esRAGE/sRAGE (25.4±17.7 in SLE vs.14.9±11.6 in controls, p<.0001). In contrast, sRAGE levels did not differ between SLE patients and controls. A negative correlation was observed between SLEDAI score and esRAGE (rho=-.197, p=.049), and sRAGE (rho=-.303, p=.0014). SLE patients with high disease activity defined as SLEDAI >4 (23% of cohort) had lower median esRAGE levels (153±216) than patients with SLEDAI<=4 (295±269) (p=.029), with a trend for lower percent esRAGE/sRAGE in the high disease group as well (22.3±13.7 in high group vs. 27.5±18.2 in low group, p=.071). While median esRAGE in the low disease activity group was significantly different from controls (p=.0016), no significant difference in median esRAGE existed between patients with high disease activity and controls. When serologic factors (C3, C4, dsDNA) were excluded from disease activity, C3 and C4 had the strongest negative correlation with non-serologic disease activity (rho=-.294 and -.291, p=.0087 and p=.0097, respectively), followed by percent esRAGE/sRAGE (rho=-.235, p=.0438), followed by anti-dsDNA (rho=.150, p=.195). No association was noted between RAGE axis levels and the individual ACR criteria or medications. In both SLE patients and controls, no association with carotid plaque was noted with RAGE axis levels.

Conclusion:

This study highlights the potential role of the RAGE axis in pathogenesis of SLE. The elevation of both esRAGE and percent esRAGE/sRAGE in SLE patients compared to controls may represent a compensatory attempt at protection. However, among SLE patients, the RAGE axis may serve as a brake to disease activity, reflected in part by inverse correlations of RAGE isoforms to disease activity, and lower esRAGE levels and percent esRAGE/sRAGE in high disease activity patients on cross-sectional analysis. Thus soluble forms of RAGE may have therapeutic value warranting further study.

To cite this abstract, please use the following information:
Jain, Manish, Amato, Michael, Clancy, Robert M., Izmirly, Peter M., Buyon, Jill P.; Members of the Receptor for Advanced Glycation Endproducts Axis Associate with Systemic Lupus Erythematosus, and May Serve As a Brake to Disease Activity. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2597
DOI:

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