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.
Abbreviations
GC: glucocorticoid; RA: rheumatoid arthritis;
Competing interests
The author declares that they have competing interests.