From bench to bedside: Calprotectin (S100A8/S100A9) as a biomarker in rheumatoid arthritis

Abstract

S100A9/S100A8 (calprotectin), a member of the S100 protein family, has been shown to play a pivotal role in innate immunity activation. Calprotectin plays a critical role in the pathogenesis of rheumatoid arthritis (RA), as it triggers chemotaxis, phagocyte migration and modulation of neutrophils and macrophages. Higher calprotectin levels have been found in synovial fluid, plasma, and serum from RA patients. Recent studies have demonstrated better correlations between serum or plasma calprotectin and composite inflammatory disease activity indexes than c-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR). Calprotectin serum levels decreased after treatment, independently of the DMARD type or strategy. Calprotectin has shown the strongest correlations with other sensitive techniques to detect inflammation, such as ultrasound. Calprotectin independently predicts radiographic progression. However, its value as a biomarker of treatment response and flare after tapering is unclear. This update reviews the current understanding of calprotectin in RA and discusses possible applications as a biomarker in clinical practice.

Keywords: CRP - C-reactive protein; acute phase reactants; biomarker; calprotectin; rheumatoid arthritis.

Figure 1

Calprotectin Functions. Intracellular functions are shown in orange and extracellular functions in green. Calprotectin Intracellular functions includes cytoskeleton cell migration and calcium homeostasis. Extracellular functions involve endothelial cells activation, promoting the adhesion of phagocytes to the vascular endothelium and thrombi formation. Also increase chemotaxis and the activation of PMN. Finally, calprotectin exerts a strong antimicrobial action against a variety of bacterial and fungal pathogens.

Figure 2

Calprotectin activation in Rheumatoid Arthritis. Calprotectin activates nuclear factor κB (NF-κB), and protein kinase-mediated signal transduction pathways, including c-Jun-N-amino-terminal kinase (JNK), extracellular-regulated kinase 1/2 (ERK1/2), and Janus kinase/signal transducers and activators of transcription (JAK/STAT) upregulating proinflammatory cytokines production.