TLR4 endogenous ligand S100A8/A9 levels in adult-onset Still’s disease and their association with disease activity and clinical manifestations

Abstract

Objective: S100A8/A9 has been suggested as a biomarker of disease activity in patients with systemic juvenile idiopathic arthritis or adult-onset Still’s disease (AOSD). We investigated the clinical significance and the pathogenic role of this marker in AOSD.

Materials and Methods: Serum samples were collected from 36 AOSD patients, 40 rheumatoid arthritis (RA) patients, and 33 healthy controls (HC) for enzyme-linked immunosorbent assay (ELISA) of S100A8/A9, follistatin-like protein 1 and interleukin-18 (IL-18). Of the AOSD patients, follow-up samples were collected from 16 patients after resolution of disease activity. Furthermore, S100A8/A9 expression levels in biopsy specimens obtained from 26 AOSD patients with skin rashes and 8 AOSD with lymphadenopathy were investigated via immunohistochemistry. Peripheral blood mononuclear cells (PBMC) from active AOSD and HC were evaluated for IL-1β release, and in vitro study with PBMC and THP-1 cell line was done for cell signal of S100A8/A9.

Results: Serum S100A8/A9 in AOSD patients was higher than those of RA patients and HC. However, follistatin-like protein 1 in AOSD was not different from RA and HC. The IL-18 levels of AOSD were higher than those of RA and HC. Serum S100A8/A9 correlated with leukocyte count, erythrocyte sedimentation rate, C-reactive protein (CRP), ferritin, and systemic score, however the IL-18 correlated only with ferritin and systemic score. In addition, S100A8/A9 was decreased after disease activity was resolved in followed-up AOSD patients. Furthermore, the IL-1β and TNF-α levels of AOSD were higher than those of HC. Serum S100A8/A9 levels correlated with IL-1β, TNF-α, ferritin, and CRP. The grade of inflammatory cells expressing S100A8/A9 ranged from 1 to 3 in skin and lymph node biopsies of active AOSD. The grading of staining of S100A8/A9 was more intense in inflammatory cells of skin lesions with karyrrhexis (p=0.028), mucin deposition (p=0.014), and neutrophil infiltration (p=0.006). Furthermore, the correlation between inflammatory cell grading of CD68 and that of S100A8/A9 was shown (p<0.001) in skin biopsies. S100A9 was a strong inducer of IL-1β expression in peripheral blood mononuclear cells. S100A9 induced signal transduction pathways, including JNK and p38 in PBMC from HC and AOSD patients.

Conclusion: The data suggest that serum S100A8/A9 may be a useful biomarker for evaluating disease activity in AOSD patients. Furthermore, S100A8/A9 may contribute to the inflammatory response by induction of inflammatory cytokines, and serve as a clinicopathological marker for assessment of disease activity in AOSD.