Background and Objectives Variation in endogenous glucocorticoid (GC) activity during inflammation has been linked to susceptibility to developing rheumatoid arthritis (RA). In RA patients, inflamed synovial tissue can generate active GCs through the expression of the 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1), which converts cortisone to cortisol. We examined whether the total body activity of 11β-HSD1 or its expression within synovium was associated with the risk of developing RA in patients with newly presenting joint inflammation.
Materials and Methods Blood and urine were collected from 42 patients with inflammatory arthritis and a clinical symptom duration of less than 12 weeks; of these 17 developed RA and 25 resolved spontaneously. Total body 11β-HSD1 activity was determined by urinary gas chromatography/mass spectrometry and calculated as the tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone ((THF + alloTHF)/THE) ratio and the cortols/cortolones ratio. Urinary 11β-HSD2 activity was measured as the urinary free cortisol/ urinary free cortisone (UFF/UFE) ratio. Synovial tissue expression of 11β-HSD1 and 11β-HSD2 was assessed by qPCR. Inflammatory disease activity was assessed by ESR, CRP and DAS28.
Results Total body 11β-HSD1 activity was significantly lower in patients with arthritis that subsequently resolved compared with patients whose arthritis developed into RA (RA 1.34 ± 0.013, Resolving arthritis, 0.96 ± 0.07, P = 0.012). Similar changes were seen in the cortols/cortolones ratio (RA 0.64 ± 0.05, Resolving arthritis, 0.43 ± 0.03, P = 0.0002). There was no significant difference in renal 11β-HSD2 activity between patients with resolving disease and those that developed RA. Despite the difference in total body 11β-HSD1 activity there was no significant difference between groups in synovial tissue 11β-HSD1 expression. There was no difference in ESR or DAS28 between patients with resolving arthritis or RA although the former had a significantly lower level of CRP (RA, 49 ± 16.7 mg/dL, Resolving arthritis 19 ± 5.7 mg/dL, P = 0.018). All values are represented as mean ± SEM.
Conclusions These studies demonstrate that a high total body 11β-HSD1 activity during early arthritis is associated with a reduced probability of resolution. The excess 11β-HSD1 may have an articular and/or extra-articular origin. This work raises the possibility that targeting 11β-HSD1 activity in early arthritis could impact on the development of RA.