JIA is the most common rheumatic disease in children, Several studies have shown that patients with JIA have low early morning serum cortisol levels and low urinary free cortisol levels [12] [13].

Studies in adult patients with RA have shown that anti-TNFα therapy normalized the HPA axis, by increasing ACTH and cortisol levels and by decreasing the ratio of ACTH to cortisol [14]. These findings suggest that anti-TNFα treatment has an effect on the HPA axis and that it improves adrenal hormone secretion, but comparable findings have never been reported in pediatric JIA patients [13] [14] [15] [16].

The aim of the current study was to evaluate the role of anti-TNF α therapy on the pediatric adrenal steroid hormone metabolism as reflected by urinary steroid metabolites determined by GC-MS. We found that 21 urine metabolite levels were significantly lower in JIA patients before they underwent etanercept treatment: 16 of them normalized 1 day post-treatment and only 5 remained lower than normal after 3 days. The five urinary metabolites included two C19 metabolites An and 11-OH-An, two C21 intermediate metabolites Pt and P5D and one cortisol metabolite α-Cl.

Jäättelä et al. [8] showed in a seminal study that TNFα inhibits the expression of mRNAs of adrenal cytochrome P450 oxygenases, CYP11A1 (cholesterol side-chain cleavage enzyme/cholesterol 20-22-desmolase), P450c11 (11 beta-hydroxylase/18-hydroxylase/18-methyl oxidase), P450c17 (17 alpha-hydroxylase/17, 20-lyase) and P450 C21 (21-hydroxylase) in human fetal adrenals. The decrease in gene expression was accompanied by a decrease in cortisol but not in either dehydroepiandrosterone sulphate (DHEAS) or in androstenedione. All of the effects of TNFα were neutralized by the addition of monoclonal anti-TNFα antibody. These results demonstrated that TNFα suppresses the synthesis of cortisol and shifts the steroid secretory pattern towards androgen production, at least partially, by suppressing the accumulation of mRNAs for adrenal cytochrome P450 oxygenases.

The finding that five urine metabolites (An, 11-OH-An, Pt, P5D and a-Cl) remained significantly low 3 days after etanercept treatment may indicate that the enzymes that are involved in their metabolism are more affected by TNFα than the other enzymes. Urine metabolite ratios reflect enzymatic activities. Although there was no significant difference in most of those ratios between the control group and the patient group before and after etanercept treatment, the ratios that reflect 21 hydroxylase and 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 activity were very close to being significantly different between the groups. That finding indicates that these 2 enzymes were more affected by TNFα in the patient group. Notably, these 2 enzymes are involved in cortisol production and cortisol conversion to cortisone. Active cortisol is converted to inactive cortisone mainly by the kidney via 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2 in order to protect the nonspecific mineralocorticoid receptor from activation by cortisol. The liver is the major organ for converting inactive cortisone to active cortisol, and it does so via 11β-HSD1 (Fig − 1). The expression of 11β-HSD1 is enhanced by TNF and proinflammatory cytokines. mainly at the intracellular compartment, however, it can induce a change in the HPA axis [15].

Although most of the patients in the current study were either free of active disease or had mild disease activity, their urine cortisol metabolites were low compared to the normal controls indicating that they had an interrupted HPA axis and that anti-TNFα therapy had a significant effect restoring the HPA axis in these patents.

One of the challenges in treating JIA patients is to decide when to stop treatment, such as anti-TNF α, and to try to predict who will need to resume therapy. Toward this end, the interrupted HPA axis in JIA patients with active as well as subclinical disease may be able to identify the patients for whom it is safe to stop therapy Furthermore the recovery of the HPA axis by anti TNFα improves not only the inflamed joints but also other important health aspects, such as growth, bone health and general wellbeing.

Our study has a few limitations that bear mention. The main limitation is our small number of patients, and another is their range of ages and different stages of sexual development that may influence the HPA axis. We tried to overcome this latter limitation by matching them with a control group by age and Tanner stage development. Another drawback is that we do not have 24-hour urinary samples to precisely calculate the excretion rates of urinary steroid hormone metabolites and thereby assess hormonal production rates.

Two patients were treated during the study with methotrexate. Methotrexate effect as an anti-inflammatory drug is mainly due to its effect on the accumulation of adenosine triphosphate and its ability to inhibit nucleotide synthesis and cell division. [16]. Given that methotrexate’s is not involved in cortisol metabolism, we did not exclude these patients from the study.