The Journal of Rheumatology Arthritis Treated with Nighttime-Release Prednisone Hypothalamus-Pituitary-Adrenal Axis Function in Patients with Rheumatoid

Objective. To investigate the effects of longterm low-dose chronotherapy with modified-release (MR) prednisone for rheumatoid arthritis (RA) on the hypothalamus-pituitary-adrenal (HPA) axis as part of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) study. This consisted of a 3-month active-controlled phase and a 9-month open-label extension with MR prednisone including patients previously treated with prednisone (Clinical Trials.gov number NCT00146640). Methods. Corticotropin-releasing hormone (CRH) tests were performed on 28 patients at 3 timepoints: at baseline on prestudy immediate-release (IR) prednisone, after the 3-month double-blind phase on either IR prednisone or MR prednisone, and after the 9-month open-label extension on MR prednisone. Changes of cortisol were assessed and compared to individual patients’ efficacy and safety data. Results. The increase (mean, SD) of cortisol plasma concentrations after injection of corticorelin was 5.5 (4.37) μg/dl on IR prednisone at baseline (n = 21) and 5.3 (4.07) μg/dl on MR prednisone at 12 months (n = 22). Numbers of normal/suppressed/no response reactions did not differ among treatments. Switching from IR to MR prednisone did not influence responses, nor did longterm treatment of up to 12 months with MR prednisone. No worsening of adrenal impairment was observed on treatment with nighttime-release prednisone in patients with low responsiveness to CRH testing before the treatment with MR prednisone. Conclusion. Treatment with nighttime-release prednisone did not change adrenocortical function over 12 months. We presume that chronotherapy with this nighttime-release prednisone may improve the efficacy of longterm low-dose glucocorticoid treatment in patients with RA. (J Rheumatol First Release August 1 2010; doi:10.3899/jrheum.100051) Key Indexing Terms: CHRONOTHERAPY CIRCADIAN RHYTHMS GLUCOCORTICOID PROINFLAMMATORY CYTOKINES INTERLEUKIN 6 From the Department of Internal Medicine, Rheumatology, Clinical Immunology, Schlosspark-Klinik, Teaching Hospital, Charité University Medicine, Berlin; Merck KGaA, Darmstadt; Immanuel Krankenhaus, Berlin-Buch; Nitec Pharma GmbH, Mannheim; University Hospital Regensburg, Regensburg, Germany; and Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa, Genoa, Italy. Supported by Merck KGaA, Darmstadt, Germany, and Nitec Pharma AG, Reinach, Switzerland. Dr. Alten is a consultant for Merck Pharma GmbH and has received lecture fees. Dr. Döring is an employee of Merck KGaA and holds company stock and is a consultant for Nitec Pharma AG. Dr. Witte is an employee of Nitec Pharma GmbH, Mannheim, Germany, and holds company stock. Dr. Straub has received consulting fees from Merck Pharma GmbH, Germany. Dr. Buttgereit is a consultant for Merck Pharma GmbH and Nitec Pharma GmbH and has received grant support from both. He has also received lecture fees from Merck Pharma GmbH. R. Alten, MD, Department of Internal Medicine, Rheumatology, Clinical Immunology, Schlosspark-Klinik, Teaching Hospital, Charité University Medicine; G. Döring, MD, Merck KGaA; M. Cutolo, MD, Research Laboratory and Academic Unit of Clinical Rheumatology, University of Genoa; E. Gromnica-Ihle, MD, Immanuel Krankenhaus; S. Witte, PhD, Nitec Pharma GmbH; R.H. Straub, MD, University Hospital Regensburg; F. Buttgereit, MD, Department of Rheumatology and Clinical Immunology, Charité University Medicine. Address correspondence to Dr. R. Alten, Department of Internal Medicine II, Rheumatology, Clinical Immunology, Schlosspark-Klinik, Teaching Hospital, Charité University Medicine, Heubnerweg 2, 14059 Berlin, Germany. E-mail: [email protected] Full Release Article. For details see Reprints/Permissions at jrheum.org Accepted for publication May 17, 2010. Rheumatoid arthritis (RA) is a chronic inflammatory disease in which circadian rhythms of proinflammatory and antiinflammatory mediators play key roles1,2,3,4. Early morning increase of proinflammatory cytokines, particularly interleukin 6 (IL-6), has been shown to coincide closely with the diurnal variations of RA symptoms and also with changes in the physiologic rhythm of endogenous cortisol and reduced hypothalamic-pituitary-adrenal (HPA) axis function2,3,4,5,6,7,8,9. Glucocorticoids (GC) have been among the most important drugs for the treatment of RA as well as for other inflammatory diseases10,11, despite their potential to cause frequent and sometimes serious side Rheumatology The Journal of on June 25, 2017 Published by www.jrheum.org Downloaded from effects. In particular, higher doses and longer treatment durations are still matters of concern4,12,13,14. Nevertheless, evidence-based knowledge on the effects of prednisone therapy in RA is rather limited, especially concerning longterm nighttime application, which to our knowledge has not been investigated yet. This is particularly true for effects of such a treatment scheme on the HPA axis function. The low-dose regimen for longterm treatment of RA recommends < 10 mg/day prednisone as a single dose early in the morning14. This in general reduces the risk of adverse effects, but patients with RA still wake up in the morning with painful joint stiffness despite otherwise effective standard treatments. Chronotherapy in RA, with application of prednisone before the daily increase of proinflammatory activity, was realized for the first time with a novel modified-release (MR) prednisone formulation, which releases prednisone at about 2 A.M. when taken at bedtime15. Hence prednisone is released during the rising phase of the circadian cortisol cycle4. This mechanism by itself overcomes an inadequate cortisol release in RA, presumably leading to better clinical effects, and it mimics the physiological circadian rhythm of endogenous cortisol. The HPA axis might be less disturbed by this timing of prednisone application. The clinical benefit of these characteristics of the new MR formulation was shown in the Circadian Administration of Prednisone in Rheumatoid Arthritis trial (CAPRA-1), an active-controlled clinical trial in which MR prednisone demonstrated a clinically relevant reduction of morning stiffness of the joints and of IL-6 after 3 months15; both effects were sustained over the entire study period of up to 12 months16. We report, for the first time, the effects of longterm, lowdose prednisone chronotherapy on the HPA axis function in patients with RA. These are the results of an additional investigation with corticotropin-releasing hormone (CRH) stimulation tests in a subgroup of patients. Our investigation was included in the CAPRA-1 protocol, in addition to the controlled study and the open-label extension15,16,17. MATERIALS AND METHODS We performed our study between August 2004 and January 2007 in 28 patients with RA who participated in the CAPRA-1 trial15. The protocol was reviewed and accepted by the responsible national ethics committees in Germany (University Hospital Charité, Berlin) and Poland (University Hospital Wroclaw) and was conducted according to the principles set up in the Declaration of Helsinki. The study is registered in Clinical Trials.gov number NCT00146640. Study protocol of the CAPRA-1 clinical study. CAPRA-1 was a randomized, multicenter, double-blind, active-controlled phase III study to investigate the safety and efficacy of the application of MR prednisone at bedtime in comparison with standard immediate-release (IR) prednisone given in the morning. A total of 288 patients, previously treated with stable doses of low-dose glucocorticoids (2.5–10 mg/day prednisone or equivalent), disease-modifying antirheumatic drugs, nonsteroidal antiinflammatory drugs, and nonantiinflammatory analgesics were randomized to 3–10 mg/day IR or MR prednisone with no change of individual doses for 3 months. During the 9-month open-label extension with MR prednisone, dose changes were allowed for MR prednisone as well as for the other RA treatments. The treatment periods with MR prednisone were up to 9 months for those patients randomized to IR prednisone (IR/MR group) and up to 12 months for those treated with MR prednisone in the double-blind phase (MR/MR group). Patients treated at German centers with 5 mg prednisone/prednisolone or equivalent and complying with all other entry criteria of the study were eligible to participate in the test series if additional informed consent was given. The tests were performed during the screening phase on treatment with prestudy IR prednisone, at the end of the double-blind phase, and at the end of open-label extension. For this additional CRH stimulation testing, 32 patients (16 patients per group at the end of the double-blind phase) were considered appropriate. Due to an inadequate recruitment of volunteers for the test series, the initial dose restriction to 5 mg prednisone was lifted and patients with doses 5 to 10 mg per day, as well as patients who took part in only 1 test at the end of the study, were also included per protocol amendment. Study design, types of treatment, visit schedule, and number and timepoints of tests are summarized in Figure 1. CRH testing.According to the test kit manufacturer’s instructions, intervals of at least 24 hours from the last dose of prednisone to the test drug injection were mandatory18. During the screening phase, for Test 1 on IR prednisone, no morning medication was given on the test day. At the end of the double-blind phase, for Test 2, with randomized double-dummy study medication being either IR prednisone in the morning or MR prednisone in the evening, no evening dose was taken the day before and no morning dose on the test day. At the end of the open-label study on MR prednisone, for Test 3, no evening dose was applied before the test day. This resulted in intervals between the last glucocorticoid intake and the tests of > 24 hours for IR prednisone and > 36 hours for the tests for MR prednisone. Tests were performed in the morning. They consisted of an intravenous 30-second bolus injection of 100 μg of human corticorelin (CRH Ferring, Ferring Pharmaceuticals Inc., Tarrytown, NY, USA). Blood samples of 1 ml were drawn 15 min prior to and immediately before, and 60 and 90 min after injection. Cortisol plasma concentrations were analyzed centrally by the Bio Analytical Research Corporation, Ghent, Belgium. Statistical analysis. The data were analyzed by means of exploratory descriptive statistics. In the CAPRA-1 protocol, no tests for significance of findings were defined, because at that time we were not aware of any published experience on longterm nighttime application of prednisone in patients with RA, which could have been used for a statistical sample size calculation and hypotheses to be tested. Cortisol concentrations of each blood sample were analyzed. Serum cortisol values measured immediately before the test injection, and the higher one of the 2 postinjection values per test, are reported as mean (SD) and median (minimum/maximum). Descriptive comparisons of treatments were calculated for pairs of tests done by the same patient on the same treatment (Tests 1 and 2 for the IR/MR group; Tests 2 and 3 for the MR/MR group) and after change of treatments (Tests 2 and 3 for the IR/MR group; Tests 1 and 2 for the