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

Neuroendocrine immunology owes much to the foresighted work of Philip S Hench, who together withEdward 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 carriedout to understand GC action. There were three major pathways of discoveries between 1990 and today. 
 
Firstly, the groups of George Chrousos and of Steven Lamberts defined hereditary GC resistance due to abnormalities of the GC receptor (first reviewed in [1,2]). While genetically determined alterations of the GCreceptor were rare in the population, inflammation induced local GC receptor resistance became an important concept of inflammation research [3]. Th e concept gained momentum, particularly in asthma research. Indeed, the local proinflammatory load negatively influences anti-inflammatory 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 inflammation (reviewed by Maurizio Cutolo and colleagues in this supplement). While an acute inflammatory trigger can increase GCserum levels, this response did not appear after repeated administration of the same trigger [4]. Several studies demonstrated that proinflammatory cytokines such asinterleukin-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 inflammatory diseases, the phenomenon can exist for a long time beyond acute inflammation 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 discoveredin 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/m2 (depending on body surface, ≈10 to 14 mg/day) [5], which equals 2.5 to 3.5 mg prednisolone/day. Thus, 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 effects as demonstrated in this supplement. 
 
Thirdly, timing of daily GC administration reached a new level of precision with a clear pathophysiological concept (reviewed by Cornelia Spies and colleagues). In the early days of GC therapy, doctors and patientsexperienced that GC administration in the evening can sometimes have beneficial effects the following morning. However, these positive effects were accompanied by GC-induced sleep disturbances during the early night. Driven by RA patients' experiences, Arvidson and colleagues overcame this problem by administering GCat 2:00 a.m., and observed a highly beneficial effect in the morning [6]. A more sophisticated method of GC administration was developed during the 2000s - modified GC release, which makes use of GC-loaded pills taken at bedtime and showing abrupt GC release at 2:00 a.m. Under these conditions, GC release occurs at a time when endogenous inflammatory pathways are switched on in a circadian manner [7]. Th e positive effects of nightly GC therapy, as demonstrated in RA[8,9], are due to immediate inhibition of proinflammatory pathways in the increasing flank of nightly inflammation induction [7]. 
 
Finally, this supplement presents an article on insulin resistance in chronic inflammatory systemic diseases. While it seems, at first glance, that GCs are not related toinsulin resistance, it turns out that the hypothalamic-pituitary-adrenal axis and thus endogenous GC play an important role in inducing insulin resistance. Pleaserecall that GC can induce elevated levels of glucose, freefatty acids, and glucogenic amino acids in a physiological setting. Insulin resistance is a common phenomenon of physiological states, disease states, and diseases. Th is resistance typically appears in patients with diabetes mellitus, obesity, infection, sepsis, arthritis of different types (including RA), systemic lupus erythematosus, ankylosing spondylitis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, and mental stress. By presenting an integrated theory on insulin resistance, Straub puts forward the concept that insulin resistance is an evolutionarily positively selected program of an activated selfish brain or a stimulated selfish immune system. Long-term use of this adaptive program during chronic activation of the brain or the immune system turns out to be a misguided program that perpetuates the disease process.

Neuroendocrine immunology owes much to the foresighted 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 ammationinduced 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 uences 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, longterm 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 placebocontrolled 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, lowdose 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 the early days of GC therapy, doctors and patients experienced that GC administration in the evening can sometimes have benefi cial eff ects the following morning. However, these positive eff ects were accompanied by GC-induced sleep disturbances during the early night. Driven by RA patients' experiences, Arvidson and colleagues overcame this problem by administering GC at 2:00 a.m., and observed a highly benefi cial eff ect in the morning [6]. A more sophisticated method of GC administration was developed during the 2000smodifi ed GC release, which makes use of GC-loaded pills taken at bedtime and showing abrupt GC release at 2:00 a.m. Under these conditions, GC release occurs at a time when endogenous infl ammatory pathways are switched on in a circadian manner [7]. Th e positive eff ects of nightly GC therapy, as demonstrated in RA [8,9], are due to immediate inhibition of proinfl ammatory pathways in the increasing fl ank of nightly infl ammation induction [7]. Finally, this supplement presents an article on insulin resistance in chronic infl ammatory systemic diseases. While it seems, at fi rst glance, that GCs are not related to insulin resistance, it turns out that the hypothalamicpituitary-adrenal axis and thus endogenous GC play an important role in inducing insulin resistance. Please recall that GC can induce elevated levels of glucose, free fatty acids, and glucogenic amino acids in a physiological setting. Insulin resistance is a common phenomenon of physiological states, disease states, and diseases. Th is resistance typically appears in patients with diabetes mellitus, obesity, infection, sepsis, arthritis of diff erent types (including RA), systemic lupus erythematosus, ankylosing spondylitis, trauma, painful states such as postoperative pain and migraine, schizophrenia, major depression, and mental stress. By presenting an integrated theory on insulin resistance, Straub puts forward the concept that insulin resistance is an evolutionarily positively selected program of an activated selfi sh brain or a stimulated selfi sh immune system. Long-term use of this adaptive program during chronic activation of the brain or the immune system turns out to be a misguided program that perpetuates the disease process.

Competing interests
The author declares that he has no competing interests.

Declaration
This article has been published as part of Arthritis Research & Therapy Volume 16 Suppl 2, 2014: At the interface between immunology and endocrinology in rheumatic diseases. The full contents of the supplement are available at http://arthritis-research.com/supplements/16/S2.