The Effect of Etanercept Therapy on Adrenal Steroid Metabolism in Juvenile Idiopathic Arthritis: A Steroid Metabolomics Approach

Abstract Objective To evaluate the impact of anti-tumor necrosis factor-alpha (TNFα: etanercept [Enbrel®]) on adrenal activity in the acute phase of juvenile idiopathic arthritis (JIA) during which there is a decrease in adrenal androgen and cortisol levels. Method Eleven JIA patients aged 12±6.2 years with a disease duration of 6.3±5.2 years were enrolled. They were treated once weekly with etanercept (0.8 mg/kg) for 3±2.8 years. Urine samples for gas chromatography-mass spectrometry steroid hormone analysis were collected before, and 1 and 3 days after etanercept injection and compared to age- and sex-matched healthy control. Results The levels of 23 of the 35 metabolites were low before etanercept treatment. Those 23 metabolites included 2 C 19 steroids (androgens), 3 C 21 steroid hormone intermediates, 14 cortisol metabolites, 2 corticosterone metabolites and 2 C 18 steroids (estrogens). One day post-treatment, only 5 of the 23 metabolite levels remained low. They included 2 C19 metabolites, 2 21 steroid metabolites and 1 cortisol metabolite b-c. Three days post-treatment, the only metabolite levels that continued to be low were 1 C19 metabolite, 2 C21 steroid hormone intermediates and 1 cortisol metabolite (a-Cl), while the remaining 18 metabolites had already normalized after 1 day. DHEAS and 17 OH pregnenolone metabolite levels were the last ones to recover. Urinary metabolite ratios reflecting CYP21 and 11β-HSD2 enzymatic activities were lower in JIA patients than in controls. Conclusion Almost all of the pre-etanercept treatment cortisol urinary metabolite levels were significantly lower than normal, and almost all rose to normal values by 1 day post-treatment. Blocking TNFα restores adrenal function in JIA.