Effect of novel therapeutic glucocorticoids on circadian rhythms of hormones and cytokines in rheumatoid arthritis

Abstract

The morning stiffness and pain of rheumatoid arthritis (RA) is accompanied by a rise in serum interleukin-6 (IL-6) from 2 am to 7 am. Using a formulation that releases prednisone at 2 am (after ingestion at 10 pm), we studied the circadian dynamics of serum IL-6, other cytokines, and cortisol in 9 patients before and after 2 weeks, therapy. Significant improvements occurred in morning stiffness, pain, disease activity, and the acute-phase response. Only IL-6 showed measurable cytokine circadian variation, its high pretreatment peak was abolished, and changes in IL-6 correlated with the changes in morning stiffness. Following treatment, afternoon and evening serum cortisol was reduced, but in the early morning cortisol peak concentration increased. Thus the severity of morning symptoms is related to nocturnal serum IL-6 concentration. The specific timing of the medication, linked to the interaction between IL-6 and the hypothalamic-pituitary-adrenal (HPA) axis, may correct a postulated deficiency in HPA control in RA.

Chronotherapy with modified-release prednisone in patients with rheumatoid arthritis

“…There was a statistically significant (p < 0.05) increase in the cortisol released after chronotherapy (Table 5) [2,36]. The study of nine patients with RA also found evidence of increased HPA axis responsiveness after treatment with modified-release prednisone for 2 weeks [20,30]. In this study, the early morning peak of endogenous cortisol increased from 14.3 µg/dl to 19.3 µg/dl, while the afternoon trough changed from 2.8 µg/dl to 2.1 µg/dl, a statistically significant effect (p < 0.001) [30].…”

“…The impact of modified-release prednisone on the circadian pattern of cytokines was assessed [20,30,36] in the study of nine patients with RA included in the pharmacokinetic evaluation [35]. The patients were aged 51-79 years and had active RA, defined as three or more tender and swollen joints with raised inflammatory markers [30].…”

“…Cytokines activate the HPA axis, inducing the metabolic changes characteristic of chronic inflammatory conditions such as RA [19]. There also appears to be a close correlation between levels of IL-6 and the occurrence of morning stiffness [20]. In patients with RA, endogenous cortisol production does not appear to be sufficient to counteract the inflammatory effects arising from high levels of cytokines, leading to the concept that exogenous glucocorticoid may be required [6].…”

Oral Low-Dose Glucocorticoids Should Be Included in Any Recommendation for the Use of Non-Biologic and Biologic Disease-Modifying Antirheumatic Drugs in the Treatment of Rheumatoid Arthritis

“…New modified-release GC formulations optimize the timing of administration in order to coincide with the maximal inflammatory activity, so that therapeutic effect might be improved [45]. The circadian rhythm of pain, hormone levels and cytokine concentrations is a well-known phenomenon in patients with RA, and explains the circadian presentation of the most severe symptoms in the morning [46,47,48]. GC treatment traditionally has been given in the morning, when cytokines have already passed their peak.…”

Hypothalamic-Pituitary-Adrenal Axis Function in Patients with Rheumatoid Arthritis Treated with Different Glucocorticoid Approaches

“…This clearly indicated that chronotherapy with MR prednisone has no adverse effect on HPA axis function. Also, although the plasma cortisol level in this study did not change between the start and endpoint, a separate detailed study of plasma cortisol concentrations in patients treated with MR prednisone showed an enhanced nocturnal cortisol peak after 2 weeks of treatment [39]. This potential beneficial effect of chronotherapy on HPA axis function was corroborated by a within-patient analysis of the CAPRA-1 patients who, after being on conventional prednisone from baseline for the first 12 weeks, switched to MR prednisone for 9 months.…”