TNFα regulates in vivo cortisol metabolism in inflammatory arthritis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 26-40-Glucocorticoid Actions & Disease
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-28
Dominika Ewa Nanus*1, Andrew Filer1, Benjamin Fisher1, Peter Taylor2, Paul Michael Stewart1, Christopher Buckley1, Iain McInnes3, Mark Cooper1 and Karim Raza1
1University of Birmingham, Birmingham, United Kingdom, 2University of Oxford, United Kingdom, 3University of Glasgow, Glasgow, United Kingdom
Abnormalities in endogenous glucocorticoid synthesis or metabolism have been linked to the development of rheumatoid arthritis (RA). Within the synovium of patients with RA, synovial fibroblasts generate active corticosteroids through expression of the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In vitro, this enzyme is strongly up-regulated by pro-inflammatory cytokines such as tumour necrosis factor α (TNFα) and IL-1β. In this study, we determined the relationship between inflammation and glucocorticoid metabolism in vivo, in a clinical study of patients with inflammatory arthritis treated with anti-TNFα therapy. Urine samples were collected from RA (n=20) and psoriatic arthritis (PsA) (n=20) patients as part of a multicentre study assessing responses to infliximab and etanercept and from healthy controls (HC, n=51). Systemic measures of glucocorticoid metabolism were assessed by gas chromatography/mass spectrometry at week 0, 4 and 12 after anti-TNFα therapy and calculated as the tetrahydrocortisol+5αTHF /tetrahydrocortisone ((THF+5αTHF)/THE) and the cortols/cortolones ratios. Clinical data including DAS28 and CRP were also collected. Urinary (THF+5αTHF)/THE (1) and cortols/cortolones (2) ratios were significantly higher in RA and PsA patients prior to treatment compared to HC (1: RA, 1.22(0.93-1.3), P=0.005; PsA, 1.05(0.87-1.41), P=0.02; HC, 0.91(0.75-1.05); 2: RA, 0.66(0.51-0.75), P=0.0001; PsA, 0.60(0.51-0.66), P=0.0005; HC, 0.48(0.41-0.54)). The elevated (THF+5αTHF)/THE ratio fell following anti-TNFα therapy at 4 weeks for RA (1.22(0.93-1.30) vs 0.94(0.81-1.23), P=0.017) and at 12 weeks for PsA (1.05(0.87-1.41) vs 0.96(0.72-1.23), P=0.018). A similar observation was made for the cortols/cortolones ratio at 4 weeks and 12 weeks for RA (0.66(0.51-0.75) vs 0.55(0.51-0.62), P= 0.004 and 0.66(0.51-0.75) vs 0.56(0.50-0.62), P= 0.03). In patients with RA there was a positive correlation between the 12 week change in DAS28 score (1), CRP (2) and the 12 week change in the cortols/cortolones ratio (1: r=0.64, P= 0.003; 2: r=0.45, P= 0.048). This study demonstrates, for the first time, that the increased 11β-HSD1 activity seen in patients with inflammatory arthritis is causally related to the underlying inflammatory disease. Furthermore, the changes in related glucocorticoid metabolising enzymes suggest that there is a coordinated change in glucocorticoid metabolism which promotes higher tissue glucocorticoid levels.

Nothing to Disclose: DEN, AF, BF, PT, PMS, CB, IM, MC, KR

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Sources of Research Support: The study from which patients were recruited was funded by Merck. Dominika Nanus is supported by a PhD studentship from the Sir Jules Thorn Charitable Trust.