Endocrine Abstracts

Within the synovium of patients with rheumatoid arthritis (RA), synovial fibroblasts generate active corticosteroids through expression of 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 IL1β. In this study, we determined the relationship between inflammation and global 11β-HSD1 activity 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 of anti-TNFα therapy and calculated as the tetrahydrocortisol+allotetrahydrocortisol/tetrahydrocortisone ((THF+alloTHF)/THE) and the cortols/cortolones ratios. Clinical data including DAS28 and CRP were also collected. Urinary (THF+alloTHF)/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+alloTHF)/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 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 TNFα plays a central role in regulating 11β-HSD1 activity in vivo in patients with inflammatory arthritis.

Declaration of funding

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.