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Extended report
Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis
  1. Frank Buttgereit1,
  2. Gisela Doering2,
  3. Achim Schaeffler3,
  4. Stephan Witte3,
  5. Stanislaw Sierakowski4,
  6. Erika Gromnica-Ihle5,
  7. Slawomir Jeka6,
  8. Klaus Krueger7,
  9. Jacek Szechinski8,
  10. Rieke Alten9
  1. 1Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany
  2. 2Merck KGaA, Darmstadt, Germany
  3. 3Nitec Pharma GmbH, Mannheim, Germany
  4. 4Department of Rheumatology, Medical University, Bialystok, Poland
  5. 5Immanuel Krankenhaus, Berlin-Buch, Germany
  6. 6Clinical Trials Office, Torun, Poland
  7. 7Praxiszentrum St Bonifatius, München, Germany
  8. 8Katedra i Klinika Reumatologii i Chorob Wewnetrznych AM, Wroclaw, Poland
  9. 9Department of Internal Medicine, Rheumatology, Charité Teaching Hospital – Schlosspark-Klinik, Berlin, Germany
  1. Correspondence to Professor Frank Buttgereit, Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany; frank.buttgereit{at}


Objective This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months.

Methods Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2–10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations.

Results During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone.

Conclusions Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.

This paper is freely available online under the BMJ Journals unlocked scheme, see

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  • Investigators Germany F Buttgereit, co-ordinating investigator for entire study, Germany (Charité University Medicine, Berlin), R Alten, co-ordinating investigator for CRH test substudy (Schlosspark-Klinik, Berlin), E Gromnica-Ihle (Rheumaklinik Berlin-Buch, Berlin), H Häntzschel (Medizinische Klinik und Poliklinik IV, Leipzig), G Hein (Friedrich Schiller Universität, Jena), S Mindt-Prüfert (Klinische Forschung Hamburg, Hamburg), JR Kalden (Medizinische Klinik III, Erlangen), T Karger (Rheumatologische Schwerpunktpraxis, Eduardus-Krankenhaus, Köln), A Krause (Immanuel-Krankenhaus, Berlin), K Krüger (Praxiszentrum St. Bonifatius, München), G Neeck (Biomedizinische Forschung und Entwicklung Rostock GmbH, Rostock), H Nüsslein (Krankenhaus Friedrichstadt, Dresden), S Wassenberg (Evangelisches Fachkrankenhaus GmbH, Ratingen), J Wollenhaupt (Allgemeines Krankenhaus Eilbeck, Hamburg), H Zeidler (Medizinische Hochschule, Hannover). Poland: J Szechinski, co-ordinating investigator for Poland (Katedra i Klinika Reumatologii i Chorob Wewnetrznych AM, Wroclaw), A Filipowicz-Sosnowska (Zaklad Reumatologii Szpital Kolejowy, Warszawa), S Jeka (Clinical Trials Office NZOZ ‘Nasz Lekarz’, Torun), EJ Kucharz (Katowice), S Mackiewicz (Klinika Reumatologii, Poznan), M Misterska-Skóra (NZOZ Materia Medica, Wroclaw), M Rell-Bakalarska (Przychodnia Przykliniczna Instytutu Reumatologii, Warszawa), L Szczepanski (Gabinety Profesorów, Lublin), S Sierakowski Department of Rheumatology Medical University, Bialystok), J Szerla (Krakowski Szpital Reumatologii i Rehabilitacja, Kraków), D Wierzbinska-Zarowny (Wojewodzki Zespol Rheumatologiczny, Sopot), I Zimmermann-Gorska (Katedra i Klinika Reumatologiczno Rehabilitacyjna i Chorob Wewnetrznych, Poznan).

  • Competing interests FB has received lecture fees and grant support from Merck Pharma GmbH and Nitec Pharma GmbH and is a consultant for these companies. GD was an employee of Merck KGaA and holds company stocks; she is also a consultant for NitecPharma AG, Reinach, Switzerland. AS and SW are employees of Nitec Pharma GmbH and hold company stocks. RA has received lecture fees from Merck Pharma GmbH and Nitec Pharma GmbH and is a consultant for these companies. JS, EG-I, SJ, KK and SS have no conflicts of interest.

  • Funding The study was supported by Merck KGaA, Darmstadt, Germany and NitecPharma AG, Reinach, Switzerland. Investigators were remunerated according to patient enrolment and suitable documentation. The study coordinator of Merck KGaA was involved in the analysis of the data and the reporting. The corresponding author had full access to all data at all times, had a major influence on the manuscript at all stages and had the final responsibility for the decision to submit for publication.

  • Ethics approval This study was conducted with the approval of the Ethikkommission der Charite, Berlin, Germany.

  • Provenance and peer review Not commissioned; externally peer reviewed.