University of Birmingham Differential glucocorticoid metabolism in patients with persistent versus resolving inflammatory arthritis

Introduction: Impairment in the ability of the inflamed synovium to generate cortisol has been proposed to be a factor in the persistence and severity of inflammatory arthritis. In the inflamed synovium, cortisol is generated from cortisone by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme. The objective of this study was to determine the role of endogenous glucocorticoid metabolism in the development of persistent inflammatory arthritis. Methods: Urine samples were collected from patients with early arthritis (symptoms ≤12 weeks duration) whose final diagnostic outcomes were established after clinical follow-up and from patients with established rheumatoid arthritis (RA). All patients were free of disease-modifying anti-rheumatic drugs at the time of sample collection. Systemic measures of glucocorticoid metabolism were assessed in the urine samples by gas chromatography/mass spectrometry. Clinical data including CRP and ESR were also collected at baseline. Results: Systemic measures of 11β-HSD1 activity were significantly higher in patients with early arthritis whose disease went on to persist, and also in the subgroup of patients with persistent disease who developed RA, when compared with patients whose synovitis resolved over time. We observed a significant positive correlation between systemic 11β-HSD1 activity and ESR/CRP in patients with established RA but not in any of the early arthritis patients group. Conclusions: The present study demonstrates that patients with a new onset of synovitis whose disease subsequently resolved had significantly lower levels of systemic 11β-HSD1 activity when compared with patients whose synovitis developed into RA or other forms of persistent arthritis. Low absolute levels of 11β-HSD1 activity do not therefore appear to be a major contributor to the development of RA and it is possible that a high total body 11β-HSD1 activity during early arthritis may reduce the probability of disease resolution. Introduction Glucocorticoids (GCs) regulate the body’s response to stress and inflammation, glucose metabolism and many other physiological processes. Secretion of endogenous GCs from the adrenal cortex is controlled by the hypothalamic-pituitary-adrenal (HPA) axis. In contrast to exogenous GCs, which are widely prescribed for the treatment of chronic inflammatory conditions, the role of endogenous GCs in the development and resolution of inflammation is less well characterised. Inadequate endogenous GC synthesis during inflammation has been proposed as an aetiological factor in the development of rheumatoid arthritis (RA). The link between endogenous GCs and the development of RA was initially thought due to defects in the HPA axis [1]. This hypothesis has been supported by clinical trials in which early GC treatment has reduced the risk of patients with early inflammatory arthritis developing persistent disease [2]. It is now known that GC action at a tissue level can also be regulated by local metabolism of GCs [3]. It has been previously demonstrated that inflamed synovial tissue in patients with RA can interconvert inactive and active GCs through the expression of the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSDs) [4,5]. The two primary isoenzymes * Correspondence: [email protected] ANZAC Research Institute, Concord Repatriation General Hospital, University of Sydney, Hospital Road, Sydney NSW 2139, Australia Full list of author information is available at the end of the article © 2015 Nanus et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Nanus et al. Arthritis Research & Therapy (2015) 17:121 DOI 10.1186/s13075-015-0633-2