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TNFα) display a circadian rhythm, with maximum levels in the early morning [ 19 , 20 ]. Cortisol also displays a circadian rhythm, increasing until 4–5 am (in response to increased infl ammatory cytokines), and thus dampens the cytokine peak.
However, in RA, reduced cortisol production downstream of an impaired HPA axis (relative adrenal insuffi ciency) is overwhelmed by proin- fl ammatory cytokine action [ 21 ]. Such condition generally requires hormonal replacement therapy, i.e., exogenous glucocorticoids (see below, Fig. 2 ).
Tailoring Rheumatoid Arthritis
119
awakes in the morning at a time when joint stiff- ness is already at a maximum. However, this is not optimal. In fact, glucocorticoid administra- tion at 2–3 am is recommended, showing a more marked and signifi cant effect on morning stiffness and serum IL-6 decrease [ 22 ].
Consequently, traditional drugs such as pred- nisone (a synthetic corticosteroid with anti- infl ammatory effects and a short half-life) are now administered considering circadian rhythms, to optimize clinical effi cacy (Fig. 2 ) [ 23 ]. This tailored administration has the advantage of min- imizing steroid treatment-related side effects, like systemic hypertension, hyperglycemia, tachycardia, insomnia, osteopenia/osteoporosis, and, especially, HPA inhibition due to negative feedback [ 24 ].
Finally, circannual supplementation therapy with vitamin D (mainly at winter and spring time), in addition to release-modifi ed glucocorti- coids, seems to represent an effective NEI treat- ment strategy in RA management [ 25 , 26 ].
The role of steroid hormone defi ciency in the transition from chronic infl ammation to cancer is currently under investigation [ 27 , 28 ] in particu- lar since RA patients seem at higher risk of devel- oping cancer (see chapter “ Overview ” under par
“Cancer”).
Perspectives
The action of different steroid hormones, infl u- enced by the products of activated immune cells, triggers the immune-infl ammatory response, tar- gets the organs-specifi c microenvironments, and infl uences the rhythms (circadian and circannual) of several other hormones. New therapeutic strat- egies are based on circadian/circannual rhythms and on the recent knowledge of the complex NEI system that is under such rhythm control.
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