Clinical Rheumatology

, Volume 37, Issue 8, pp 2027–2034 | Cite as

Safety and efficacy of alternate-day corticosteroid treatment as adjunctive therapy for rheumatoid arthritis: a comparative study

  • Masei SudaEmail author
  • Sachiko Ohde
  • Tokutaro Tsuda
  • Mitsumasa Kishimoto
  • Masato Okada
Original Article


Corticosteroids (CSs), used to treat rheumatoid arthritis (RA), confer a risk of adverse events (AEs). This study investigated the safety and efficacy of alternate-day (QOD) CS therapy for RA. All patients (> 18 years) who started oral CS therapy for RA, between 2005 and 2014, at our hospital were retrospectively analysed. The patients were divided into the daily (QD) and QOD CS therapy groups to investigate the rates of CS-related major AEs (infection, diabetes, hypertension, cardiovascular events and fragility fractures) within the first year of treatment. The number of patients free from CS treatment at 1 year and the mean decreases in C-reactive protein (CRP) levels at 1 month were also investigated. In total, 138 patients were analysed (QD group, 68; QOD group, 70). The maximum daily CS dose was not significantly different between the two groups, but the annual cumulative dose was significantly lower in the QOD group (P < 0.01). The infection rate was significantly lower in the QOD group (24.3%) than in the QD group (50.0%; P < 0.01), whereas the other AE rates were similar between the groups. The CS-free rate at 1 year was significantly higher in the QOD group (58.6%) than in the QD group (26.5%; P < 0.01). The mean CRP decreases over 1 month of CS therapy were not significantly different between the groups. QOD CS treatment leads to a lower infection rate and less CS dependence than does daily treatment; both RA treatments are equally effective.


Adverse events Corticosteroids Infection Rheumatoid arthritis 



The authors thank Hideki Nakajima for technical support.

Compliance with ethical standards

The study was approved by the Ethics Committee of St. Luke’s International Hospital (approval number, 14-R162).




  1. 1.
    Makol A, Davis JM 3rd, Crowson CS, Therneau TM, Gabriel SE, Matteson EL (2014) Time trends in glucocorticoid use in rheumatoid arthritis: results from a population-based inception cohort, 1980-1994 versus 1995-2007. Arthritis Care Res (Hoboken) 66:1482–1488CrossRefGoogle Scholar
  2. 2.
    Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA (2005) Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 52:3381–3390CrossRefPubMedGoogle Scholar
  3. 3.
    Nam JL, Villeneuve E, Hensor EM, Conaghan PG, Keen HI, Buch MH, Gough AK, Green MJ, Helliwell PS, Keenan AM, Morgan AW, Quinn M, Reece R, van der Heijde DM, Wakefield RJ, Emery P (2014) Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study). Ann Rheum Dis 73:75–85CrossRefPubMedGoogle Scholar
  4. 4.
    Choy EH, Kingsley GH, Khoshaba B, Pipitone N, Scott DL, Intramuscular Methylprednisolone Study Group (2005) A two year randomised controlled trial of intramuscular depot steroids in patients with established rheumatoid arthritis who have shown an incomplete response to disease modifying antirheumatic drugs. Ann Rheum Dis 64:1288–1293CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Bijlsma JW (2012) Disease control with glucocorticoid therapy in rheumatoid arthritis. Rheumatology 51(suppl 4):iv9–iv13PubMedGoogle Scholar
  6. 6.
    Sokka T, Toloza S, Cutolo M, Kautiainen H, Makinen H, Gogus F, Skakic V, Badsha H, Peets T, Baranauskaite A, Géher P, Ujfalussy I, Skopouli FN, Mavrommati M, Alten R, Pohl C, Sibilia J, Stancati A, Salaffi F, Romanowski W, Zarowny-Wierzbinska D, Henrohn D, Bresnihan B, Minnock P, Knudsen LS, Jacobs JW, Calvo-Alen J, Lazovskis J, Pinheiro Gda R, Karateev D, Andersone D, Rexhepi S, Yazici Y, Pincus T, QUEST-RA Group (2009) Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA study. Arthritis Res Ther 11:R7PubMedPubMedCentralGoogle Scholar
  7. 7.
    Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poór G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D (2017) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 76:960–977CrossRefPubMedGoogle Scholar
  8. 8.
    van der Goes MC, Jacobs JW, Boers M, Andrews T, Blom-Bakkers MA, Buttgereit F, Caeyers N, Cutolo M, Da Silva JA, Guillevin L, Kirwan JR, Rovensky J, Severijns G, Webber S, Westhovens R, Bijlsma JW (2010) Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice. Ann Rheum Dis 69:1913–1319CrossRefPubMedGoogle Scholar
  9. 9.
    Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, Nallamothu BK (2017) Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 357:j1415CrossRefPubMedGoogle Scholar
  10. 10.
    van der Goes MC, Jacobs JW, Boers M, Andrews T, Blom-Bakkers MA, Buttgereit F, Caeyers N, Choy EH, Cutolo M, Da Silva JA, Guillevin L, Holland M, Kirwan JR, Rovensky J, Saag KG, Severijns G, Webber S, Westhovens R, Bijlsma JW (2010) Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 69:1015–1021CrossRefPubMedGoogle Scholar
  11. 11.
    van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW (2002) Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 136:1–12CrossRefPubMedGoogle Scholar
  12. 12.
    Capell HA, Madhok R, Hunter JA, Porter D, Morrison E, Larkin J, Thomson EA, Hampson R, Poon FW (2004) Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. Ann Rheum Dis 63:797–803CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Inês LB, de Koning EJ, Buttgereit F, Cutolo M, Capell H, Rau R, Bijlsma JW (2006) Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 65:285–293CrossRefPubMedGoogle Scholar
  14. 14.
    Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, Kohler JA, Furst DE (1994) Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 96:115–123CrossRefPubMedGoogle Scholar
  15. 15.
    Strehl C, Bijlsma JW, de Wit M, Caeyers N, Cutolo M, Dasgupta B, Dixon WG, Geenen R, Huizinga TW, Kent A, de Thurah AL, Listing J, Mariette X, Ray DW, Scherer HU, Seror R, Spies CM, Tarp S, Wiek D, Winthrop KL, Buttgereit F (2016) Defining conditions where long-term glucocorticoid treatment has an acceptably low level of harm to facilitate implementation of existing recommendations: viewpoints from an EULAR task force. Ann Rheum Dis 75:952–957CrossRefPubMedGoogle Scholar
  16. 16.
    MacGregor RR, Sheagren JN, Lipsett MB, Wolff SM (1969) Alternate-day prednisone therapy. Evaluation of delayed hypersensitivity responses, control of disease and steroid side effects. N Engl J Med 280:1427–1431CrossRefPubMedGoogle Scholar
  17. 17.
    Dale DC, Fauci AS, Wolff SM (1974) Alternate-day prednisone. Leukocyte kinetics and susceptibility to infections. N Engl J Med 291:1154–1158CrossRefPubMedGoogle Scholar
  18. 18.
    Hunder GG, Sheps SG, Allen GL, Joyce JW (1975) Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study. Ann Intern Med 82:613–618CrossRefPubMedGoogle Scholar
  19. 19.
    Stuck AE, Minder CE, Frey FJ (1989) Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 11:954–963CrossRefPubMedGoogle Scholar
  20. 20.
    Migita K, Sasaki Y, Ishizuka N, Arai T, Kiyokawa T, Suematsu E, Yoshimura M, Kawabe Y, Matsumura R, Akagawa S, Mori S, Shirai M, Watanabe Y, Minami N, Soga T, Owan I, Ohshima S, Yoshizawa S, Matsui T, Tohma S, Bito S (2013) Glucocorticoid therapy and the risk of infection in patients with newly diagnosed autoimmune disease. Medicine 92(5):285Google Scholar
  21. 21.
    Mor A, Berencsi K, Nielsen JS, Rungby J, Friborg S, Brandslund I, Christiansen JS, Vaag A, Beck-Nielsen H, Sørensen HT, Thomsen RW (2016) Rates of community-based antibiotic prescriptions and hospital-treated infections in individuals with and without type 2 diabetes: a Danish nationwide cohort study, 2004-2012. Clin Infect Dis 63:501–511CrossRefPubMedGoogle Scholar
  22. 22.
    Singh JA, Cameron C, Noorbaloochi S, Cullis T, Tucker M, Christensen R, Ghogomu ET, Coyle D, Clifford T, Tugwell P6 Wells GA (2015) Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet 386:258–265CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Panoulas VF, Douglas KM, Stavropoulos-Kalinoglou A, Metsios GS, Nightingale P, Kita MD, Elisaf MS, Kitas GD (2008) Long-term exposure to medium-dose glucocorticoid therapy associates with hypertension in patients with rheumatoid arthritis. Rheumatology (Oxford) 47:72–75CrossRefGoogle Scholar
  24. 24.
    Wei L, MacDonald TM, Walker BR (2004) Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 141:764–770CrossRefPubMedGoogle Scholar
  25. 25.
    Ueshima H, Sekikawa A, Miura K, Turin TC, Takashima N, Kita Y, Watanabe M, Kadota A, Okuda N, Kadowaki T, Nakamura Y, Okamura T (2008) Cardiovascular disease and risk factors in Asia: a selected review. Circulation 118:2702–2709CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gluck OS, Murphy WA, Hahn TJ, Hahn B (1981) Bone loss in adults receiving alternate day glucocorticoid therapy. A comparison with daily therapy. Arthritis Rheum 24:892–898CrossRefPubMedGoogle Scholar
  27. 27.
    Crowson CS, Rahman MU, Matteson EL (2009) Which measure of inflammation to use? A comparison of erythrocyte sedimentation rate and C-reactive protein measurements from randomized clinical trials of golimumab in rheumatoid arthritis. J Rheumatol 36:1606–1610CrossRefPubMedGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Immuno-Rheumatology Centre, St. Luke’s International HospitalSt. Luke’s International UniversityTokyoJapan
  2. 2.Graduate School of Public Health, OMURA Susumu and Mieko Memorial St. Luke’s Centre for Clinical AcademiaSt. Luke’s International UniversityTokyoJapan

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