Exogenous glucocorticoids (GCs) are recommended at low doses and as long-term treatment in chronic immune/inflammatory diseases and exert a sort of “replacement therapy” of the decreased endogenous cortisol availability, due to the chronicity of the disease. But, when it is the best timing for the “replacement”? Is it after sunset (late night) or at sunrise?
GCs interact potentially with almost 3,000-5,000 genes of human DNA, therefore are involved in several biological activities (not only antiinflammatory/immunosuppressive effects) and as consequence, they bring considerable potential for adverse effects, especially if used in high-medium doses and at the wrong time of the day (in long-term treatments).
GCs exert important effects on cellular immunity and given the existence of cellular circadian rhythms, the prevention of the up-regulation of immune cell activity (and related flare of cytokine synthesis) could be more effective than reducing established cellular activity afterwards.
Since in RA, the circadian rhythms of pain, stiffness and functional disability show maximum symptoms in the early morning hours, and are in particular preceded by elevated serum levels of IL-6 (that is also an adrenal gland activator), it was hypothesised that preventing the nocturnal rise of pro-inflammatory cytokines by GC therapy is more effective than treating established symptoms in the morning. The specific timing of prednisone, linked to the interaction between IL-6 and the HPA axis, may correct a postulated deficiency in HPA control in RA, but also in polymyalgia rheumatica (PMR)!. In addition, the proliferation/activation of the cells involved in the immune/inflammatory response represent an important target for the disease modifying treatments (DMARD) in RA patients and the administration of recommended antiproliferative drugs (i.e. methotrexate, leflunomide, cyclophosphamide etc.) might follow the same concepts of chronotherapy (night highest availability).
Early data for the existence of circadian rhythms also in PMR and ankylosing spondyltis are available, but not yet fully comparable to what already described in RA. However, in PMR, important symptoms such as pain and stiffness seem to be typically most intensive during the early morning hours and a circadian variation of TNF and IL-6 secretion, with peak values in the early morning hours, seems very close to the RA chronobiology.
In practice, since GCs start to rise in the early hours of the morning (2-3 am), peak around 06:00–08:00 am and have a nadir around 22:00–02:00, their administration between 6:00 and 8:00 am may not be optimal (too late to prevent the nocturnal activation of the immune resonse). As matter of fact, the current most advanced approach to improve the risk-benefit ratio of GCs is the low-dose prednisone chronotherapy with modified release (MR) prednisone, a timing drug release (releasing prednisone at 2-3 am).
Recent data documented that MR prednisone has greater efficacy for long-term low-dose GC treatment in RA patients, showing a significant reduction in morning joint stiffness, IL-6 rise, and a similar safety profile but without additional suppression of the HPA axis. This approach is absolutely efficient in GC-naive patients.
In conclusion, in term of optimization of the GC “genomic effects” from long-term low dose therapy, the administration/availability of GCs late after sunset (night) it seems superior than at the sunrise time (chronobiological approach!).
Cutolo M, Buttgereit F, Straub RH. Clin Exp Rheumatol. 2011;29(5 Suppl 68):S19-22.
Disclosure of Interest M. Cutolo Conflict with: mundipharm, horizon
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