Rheumatoid arthritis - a neuroendocrine immune disorder: glucocorticoid resistance, relative glucocorticoid deficiency, low-dose glucocorticoid therapy, and insulin resistance

sighted work of Philip S Hench, who together with Edward C Kendall and Tadeus Reichstein introduced glucocorticoids (GCs) into clinical medicine. Since the 1990s, more than 40 years after adding GC to the therapeutic armamentarium, important work has been carried out to understand GC action. Th ere were three major pathways of discoveries between 1990 and today. Firstly, the groups of George Chrousos and of Steven Lamberts defi ned hereditary GC resistance due to abnormalities of the GC receptor (fi rst reviewed in [1,2]). While genetically determined alterations of the GC receptor were rare in the population, infl ammation-induced local GC receptor resistance became an important concept of infl ammation research [3]. Th e concept gained momentum, particularly in asthma research. Indeed, the local proinfl ammatory load negatively infl u-ences anti-infl ammatory GC action [3], but a workable therapeutic approach was not yet introduced into the rheumatology hospital. Secondly, several groups recognized inadequate secretion of GC in relation to infl ammation (reviewed by Maurizio Cutolo and colleagues in this supplement). While an acute infl ammatory trigger can increase GC serum levels, this response did not appear after repeated administration of the same trigger [4]. Several studies demonstrated that proinfl ammatory cytokines such as interleukin-6, interferon alpha, interferon gamma, and others can stimulate the hypothalamic–pituitary–adrenal axis, but responses to repeated stimuli were much less pronounced. While inadequacy of GC secretion is typical for most active infl ammatory diseases, the phenomenon can exist for a long time beyond acute infl ammation control (that is, imprinting). In such a situation, long-term therapy with low-dose GC must be recognized as a supplementary therapy for the adrenal glands. Indeed, between 1990 and today the outstanding role of low-dose GC (approximately 5 mg/day) was discovered in rheumatoid arthritis (RA) patients using placebo-controlled randomized clinical trials, as summarized in this supplement by Marlies van der Goes and colleagues. In an unstressed individual, the usual daily production of endogenous cortisol mounts to 5.7 mg/m 2 (depending on body surface, ≈10 to 14 mg/day) [5], which equals 2.5 to 3.5 mg prednisolone/day. Th us, under real-life conditions, doses of prednisolone between 2 and 5 mg/day represent an adrenocortical substitution therapy. Importantly, low-dose GC has disease-modifying antirheumatic drug eff ects as demonstrated in this supplement. Th irdly, timing of daily GC administration reached a new level of precision with a clear pathophysiological concept (reviewed by Cornelia Spies and colleagues). In …