Sixty Years after Hench—Corticosteroids and Chronic Inflammatory Disease

CONTEXT: Proinflammatory cytokines activate the hypothalamic pituitary adrenal axis in the acute phase but not with chronic inflammation; indeed, the hypothalamic pituitary adrenal axis is subtly subnormal, with apparently low ACTH and cortisol secretion. This paper reviews evidence that suggests that this is not simply an adaptation to chronic stress. These patients have increased conversion of inactive cortisone (E) to cortisol (F) by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression of this enzyme is markedly enhanced by TNF, an important autocrine protective mechanism at the inflammatory site. EVIDENCE ACQUISITION AND SYNTHESIS: This report reviews the current understanding of the interaction between TNF and 11β-HSD1 in patients with chronic inflammatory disease. It is based on publications from PubMed and the Science Citation Index. CONCLUSIONS: The systemic effects of enhancing 11β-HSD1 activity may amplify the inflammatory response. Thus, increased conversion of cortisone to cortisol can alter the circadian rhythm of cortisol secretion (lower nadir, later rise, impaired stress response) with consequent relative nocturnal cortisol deficiency when inflammatory cytokines are highest. This could contribute to the circadian symptomatology in rheumatoid arthritis, the effectiveness of early morning (0200 h) low-dose corticosteroids, the significant correlation between total body 11β-HSD1 activity and erythrocyte sedimentation rate, and the effectiveness of 11β-HSD inhibition in both the prevention and treatment of adjuvant arthritis in rat models of rheumatoid arthritis. It could also explain why anti-TNF therapy benefit can be predicted on the basis of the pretreatment plasma cortisol and the subsequent cortisol rise. In contrast, this mechanism is likely to be beneficial in the body's response to chronic infections such as tuberculosis and could explain why anti-TNF treatment markedly increases the risk of reactivation of the disease.