AB0487 HCQ COULD ACT ON SLE PATIENTS THROUGH THE MODULATING EXPRESSION OF IL-8 ALONG WITH S100 PROTEINS

Abstract

Background: Some reports revealed that S100A8 and S100A9 proteins were associated with disease activity of lupus nephritis(LN) [1]. However, there have been no reports about the mechanism of additional hydroxychloroquine (HCQ) treatment for systemic lupus erythematosus (SLE) patient with low disease activity. Objectives: To clarify the mechanism of additional HCQ treatment for Japanese SLE patients with low disease activity. Methods: All the 44 patients were enrolled in this study. These patients had been receiving additional oral HCQ sulfate continuously for at least 3 months. These patients had no need for additional immunosuppressants including glucocorticoids, during this study because of their sustained low disease activity for 3 months prior to starting HCQ. Low disease activity was defined as SELENA-SLEDAI score of 8 or less with no activity in major organ systems. As conventional immunological and clinical assessment for SLE disease activity were determined to examine the levels of complement (C3, C4, CH50), anti-dsDNA anti-body, blood cell count, SELENA-SLEDAI and CLASI score. Serum levels of S100A8 and S100A9 reported as novel markers for SLE disease activity[1] were measured using ELISA (CircuLex ELISA Kit, MBL) at the time of HCQ administration as well as 3 months later. In addition, several expressions of cytokines (IFN-α, IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, IL-1α, IL-1β, IL-1ra, VEGF, GM-CSF, G-CSF, CCL2, CCL3, CCL4, CXCL) were measured by multiplex assay (Human Luminex assay, R&D systems). Results: We enrolled 44 patients. Prednisolone dose during this study was fixed at the mean of 5.0±2.9 mg per day. SELENA-SLEDAI scores, CLASI scores, anti-dsDNA antibody and serum levels of C3 improved significantly, and serum levels of S100A8 and S100A9 proteins decreased significantly 3 months after additional HCQ treatment. The changes in serum S100A8 and S100A9 levels in SLE patients with LN were more significantly higher than in those without LN. Among these patients, the changes of serum cytokine expressions were measured in 18 patients. The expressions of IFNs were not detected in almost of all patients. Serum levels of TNF-α, IL-6, IL-8, IL-1β, IL-1ra, VEGF, CCL3 and CCL4 decreased significantly 3 months after additional HCQ treatment (Figure1). Seven of 18 SLE patients had a history of LN. These patients have been in sustained complete remission(CR) of LN for over one year(mean duration of CR was 5.0 ± 3.5 years). The reductive effect of additional HCQ treatment on serum S100A9, TNF-α, IL-6 and IL-8 levels was much more apparent in those with history of LN (LN: S100A9, p=0.016, TNF-α, p=0.016, IL-6 p=0.031, IL-8, p=0.031; no LN: S100A9, p=0.065, TNF-α, p=0.083, IL-6 p=0.090, IL-8, p=0.557). The changes of serum S100A8 and S100A9 levels were correlated with those of serum IL-8 and IL-1ra (Figure 2). Conclusion: HCQ could reduce the serum levels of S100 protein and several cytokines in SLE Japanese patients with low disease activity. Recently, some reports showed that novel biomarker including IL-8 or S100 proteins was correlated with severity of LN [1, 2]. Our findings suggest that HCQ treatment without any additional immunosuppressant could reduce the expression of serum S100 proteins, IL-8 and IL-1ra, which were considered to be associated with the improvement of renal and life prognosis. Our data also indicated that S100 protein is closely related to IL-8 or IL-1ra expression in SLE pathogenesis, especially in LN. Farther investigations are needed to more clarify the significance of HCQ treatment in SLE.