Reduced corticosteroid-binding globulin cleavage in active rheumatoid arthritis

Abstract

Objective: Corticosteroid-binding globulin (CBG), the cortisol transport protein, is cleaved from high-affinity (haCBG) to low-affinity (laCBG) CBG at sites of inflammation releasing bioavailable, anti-inflammatory cortisol. Rheumatoid arthritis (RA) is a glucocorticoid-responsive disorder, with paradoxically normal cortisol levels despite elevated inflammatory mediators. Our objective was to determine whether CBG cleavage relates to RA disease activity. We hypothesized that impaired CBG cleavage may limit delivery of free cortisol to inflamed joints in RA. Design: Prospective, cross-sectional observational study. Setting and Participants: Fifty-three patients with RA recruited from a Rheumatology outpatient clinic at a tertiary referral centre in Adelaide, Australia, and 73 healthy controls. Measurements: Total CBG, haCBG and laCBG, total, free and salivary cortisol, inflammatory markers including interleukin-6 soluble receptor (IL-6sR) and macrophage migration inhibitory factor and clinical measures of disease activity. Results: Among patients with RA, a wide range of disease activity scores was observed (DAS28: range 1·2-6·4). laCBG was lower in patients with RA (mean ± SEM); 153 ± 9, compared with healthy controls; 191 ± 8 nmol/l, P = 0·003. Levels of total and haCBG were higher in patients with more severe RA disease activity. Free and total cortisol, free cortisol:IL-6sR ratio and total cortisol:IL-6sR ratio correlated negatively with disease activity. Conclusions: These results suggest that patients with RA have reduced CBG cleavage compared to healthy controls and that cleavage is reduced further with higher RA disease activity. Hence, impaired CBG-mediated delivery of endogenous cortisol may perpetuate chronic inflammation in RA.