Rheumatology International

, Volume 32, Issue 3, pp 749–757

Effects of long-term corticosteroid usage on functional disability in patients with early rheumatoid arthritis, regardless of controlled disease activity

  • Eiichi Tanaka
  • Ajitha Mannalithara
  • Eisuke Inoue
  • Noriko Iikuni
  • Atsuo Taniguchi
  • Shigeki Momohara
  • Gurkirpal Singh
  • Hisashi Yamanaka
Original Article


We investigated the effect of long-term corticosteroid usage in suppressing the progression of functional disability in patients with early rheumatoid arthritis (RA). We studied 3,982 RA patients, who had continuous enrollment for at least 3 years, among 9,132 RA patients enrolled in an observational cohort study, IORRA, in Tokyo, Japan, from 2000 to 2007. The DAS28 and Japanese version of Health Assessment Questionnaire (J-HAQ) scores were collected at 6-month intervals (each phase). Among these patients, those with DAS28 values under 3.2 in all phases and RA disease duration under 2 years at study entry were selected as “early RA patients with well-controlled disease”. These patients were further classified into 3 groups based on average months of steroid usage per year: Non-users, Medium-users, and Frequent-users. Multiple linear regression analysis was used to study the relationship between steroid usage and the final J-HAQ scores. Among the 3,982 patients, 109 had DAS28 values under 3.2 in all the phases and were selected as study cohort. The average Final J-HAQ in Non-user (N = 64), in Medium-user (N = 25), in Frequent-user group (N = 20) was 0.04, 0.06, and 0.33, respectively. Multiple linear regression analysis after adjusting for all potential covariates confirmed that frequent steroid usage was the most significant factor associated with higher final J-HAQ scores (P < 0.05). Frequent steroid usage was associated with significantly higher final J-HAQ scores in early RA patients, even though their disease was managed efficiently by maintaining the DAS28 values under 3.2 over a long-term period.


Corticosteroid Rheumatoid arthritis Disability Disease activity score Health assessment questionnaire Cohort studies 


  1. 1.
    Weaver AL (2004) The impact of new biologicals in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 43(suppl 3): iii17–iii23Google Scholar
  2. 2.
    Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW et al. (2005) Updated consensus statement on biological agents, specifically tumor necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis 64(suppl 4): iv2–iv14Google Scholar
  3. 3.
    Albers JM, Paimela L, Kurki P, Eberhardt KB, Emery P, van ‘t Hof MA et al (2001) Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis. Ann Rheum Dis 60:453–458PubMedCrossRefGoogle Scholar
  4. 4.
    van Aken J, Lard LR, le Cessie S, Hazes JM, Breedveld FC, Huizinga TW (2004) Radiological outcome after four years of early versus delayed treatment strategy in patients with recent onset rheumatoid arthritis. Ann Rheum Dis 63:274–279PubMedCrossRefGoogle Scholar
  5. 5.
    Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS (2004) Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 43:906–914CrossRefGoogle Scholar
  6. 6.
    Pincus T, Marcum SB, Callahan LF (1992) Longterm drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second line drugs and prednisone. J Rheumatol 19:1885–1894PubMedGoogle Scholar
  7. 7.
    Solomon DH, Katz JN, Jacobs JP, La Tourette AM, Coblyn J (2002) Management of glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis: rates and predictors of care in an academic rheumatology practice. Arthritis Rheum 46:3136–3142PubMedCrossRefGoogle Scholar
  8. 8.
    Moreland LW, O’Dell JR (2002) Glucocorticoids and rheumatoid arthritis: back to the future? Arthritis Rheum 46:2553–2563PubMedCrossRefGoogle Scholar
  9. 9.
    Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A et al (1999) Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 353:259–266PubMedCrossRefGoogle Scholar
  10. 10.
    Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G et al (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The methotrexate-cyclosporine combination study group. N Engl J Med 333:137–141PubMedCrossRefGoogle Scholar
  11. 11.
    O’Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ et al (1996) Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 334:1287–1291PubMedCrossRefGoogle Scholar
  12. 12.
    Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD et al (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 41:1552–1563PubMedCrossRefGoogle Scholar
  13. 13.
    Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI et al (1999) A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 340:253–259PubMedCrossRefGoogle Scholar
  14. 14.
    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR et al (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group. N Engl J Med 343:1594–1602PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW et al (2002) Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46:614–624PubMedCrossRefGoogle Scholar
  16. 16.
    Kalla AA, Tikly M (2003) Rheumatoid arthritis in the developing world. Best Pract Res Clin Rheumatol 17:863–875PubMedCrossRefGoogle Scholar
  17. 17.
    Kirwan JR (1995) The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The arthritis and rheumatism council low-dose glucocorticoid study group. N Engl J Med 333:142–146PubMedCrossRefGoogle Scholar
  18. 18.
    Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC et al (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309–318PubMedCrossRefGoogle Scholar
  19. 19.
    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 136:1–12PubMedGoogle Scholar
  20. 20.
    Hickling P, Jacoby RK, Kirwan JR (1998) Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Arthritis and rheumatism council low dose glucocorticoid study group. Br J Rheumatol 37:930–936PubMedCrossRefGoogle Scholar
  21. 21.
    Wassenberg S, Rau R, Steinfeld P, Zeidler H (2005) Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 52:3371–3380PubMedCrossRefGoogle Scholar
  22. 22.
    Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C, Hafstrom I (2005) Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial. Arthritis Rheum 52:3360–3370PubMedCrossRefGoogle Scholar
  23. 23.
    Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM et al (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 52:3381–3390PubMedCrossRefGoogle Scholar
  24. 24.
    Kirwan JR, Bijlsma JWJ, Boers M, Shea BJ (2007) Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Rev 1:CD006356Google Scholar
  25. 25.
    Criswell LA, Saag KG, Sems KM, Robinson V, Shea B, Wells G, Suarez-Almazor ME (1998) Moderate-term, low-dose corticosteroids for rheumatoid arthritis. Cochrane Database Rev 3:CD001158Google Scholar
  26. 26.
    Gøtzsche PC, Johansen HK (2005) Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis. Cochrane Database Rev 1:CD000189Google Scholar
  27. 27.
    Saag KG, Criswell LA, Sems KM, Nettleman MD, Kolluri S (1996) Low-dose corticosteroids in rheumatoid arthritis. A meta-analysis of their moderate-term effectiveness. Arthritis Rheum 39:1818–1825PubMedCrossRefGoogle Scholar
  28. 28.
    Gotzsche PC, Johansen HK (1998) Meta-analysis of short-term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ 316:811–818PubMedCrossRefGoogle Scholar
  29. 29.
    Paulus HE, Di Primeo D, Sanda M, Lynch JM, Schwartz BA, Sharp JT et al (2000) Progression of radiographic joint erosion during low dose corticosteroid treatment of rheumatoid arthritis. J Rheumatol 27:1632–1637PubMedGoogle Scholar
  30. 30.
    Hansen M, Podenphant J, Florescu A, Stoltenberg M, Borch A, Kluger E et al (1999) A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis. Clinical benefits and skeletal side effects. Ann Rheum Dis 58:713–718PubMedCrossRefGoogle Scholar
  31. 31.
    Capell HA, Madhok R, Hunter JA, Porter D, Morrison E, Larkin J et al (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 63:797–803PubMedCrossRefGoogle Scholar
  32. 32.
    Iikuni N, Inoue E, Tanaka E, Hara M, Tomatsu T, Kamatani N et al (2008) Low disease activity state with corticosteroid may not represent ‘true’ low disease activity state in patients with rheumatoid arthritis. Rheumatology (Oxford) 47:519–521CrossRefGoogle Scholar
  33. 33.
    Yamanaka H, Tohma S (2006) Potential impact of observational cohort studies in Japan on rheumatoid arthritis research and practice. Mod Rheumatol 16:75–76PubMedCrossRefGoogle Scholar
  34. 34.
    Matsuda Y, Singh G, Yamanaka H, Tanaka E, Urano W, Taniguchi A et al (2003) Validation of a Japanese version of the Stanford Health Assessment Questionnaire in 3,763 patients with rheumatoid arthritis. Arthritis Rheum 49:784–788PubMedCrossRefGoogle Scholar
  35. 35.
    Tanaka E, Saito A, Kamitsuji S, Yamada T, Nakajima A, Taniguchi A et al (2005) Impact of shoulder, elbow, and knee joint involvement on assessment of rheumatoid arthritis using the American College of rheumatology core data set. Arthritis Rheum 53:864–871PubMedCrossRefGoogle Scholar
  36. 36.
    Furuya T, Kotake S, Inoue E, Nanke Y, Yago T, Kobashigawa T et al (2007) Risk factors associated with incident clinical vertebral and nonvertebral fractures in Japanese women with rheumatoid arthritis: a prospective 54-month observational study. J Rheumatol 34:303–310PubMedGoogle Scholar
  37. 37.
    Yamanaka H, Inoue E, Singh G, Tanaka E, Nakajima A, Taniguchi A et al (2007) Improvement of disease activity of rheumatoid arthritis patients from 2000 to 2006 in a large observational cohort study IORRA in Japan. Mod Rheumatol 17:283–289PubMedCrossRefGoogle Scholar
  38. 38.
    Nakajima A, Kamitsuji S, Saito A, Tanaka E, Nishimura K, Horikawa N et al (2006) Disability and patient’s appraisal of general health contribute to depressed mood in rheumatoid arthritis in a large clinical study in Japan. Mod Rheumatol 16:151–157PubMedCrossRefGoogle Scholar
  39. 39.
    Yamada T, Nakajima A, Inoue E, Tanaka E, Hara M, Tomatsu T et al (2006) Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan. Ann Rheum Dis 65:1661–1663PubMedCrossRefGoogle Scholar
  40. 40.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1998) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324CrossRefGoogle Scholar
  41. 41.
    van der Heijde DM, van ‘t Hof MA, van Riel PL, Theunisse LA, Lubberts EW, van Leeuwen MA et al. (1990) Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 49:916–920Google Scholar
  42. 42.
    Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL (1995) Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 38:44–48Google Scholar
  43. 43.
    Iikuni N, Nakajima A, Inoue E, Tanaka E, Okamoto H, Hara M et al (2007) What’s in season for rheumatoid arthritis patients? Seasonal fluctuations in disease activity. Rheumatology (Oxford) 46:846–848CrossRefGoogle Scholar
  44. 44.
    Drossaers-Bakker KW, de Buck M, van Zeben D, Zwinderman AH, Breedveld FC, Hazes JM (1999) Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time. Arthritis Rheum 42:1854–1860PubMedCrossRefGoogle Scholar
  45. 45.
    Welsing PM, van Gestel AM, Swinkels HL, Kiemeney LA, van Riel PL (2001) The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum 44:2009–2017PubMedCrossRefGoogle Scholar
  46. 46.
    Guillemin F, Briancon S, Pourel J (1992) Functional disability in rheumatoid arthritis: two different models in early and established disease. J Rheumatol 19:366–369PubMedGoogle Scholar
  47. 47.
    Combe B, Cantagrel A, Goupille P, Bozonnat MC, Sibilia J, Eliaou JF et al (2003) Predictive factors of 5-year health assessment questionnaire disability in early rheumatoid arthritis. J Rheumatol 30:2344–2349PubMedGoogle Scholar
  48. 48.
    Jansen LM, van Schaardenburg D, van Der Horst-Bruinsma IE, Bezemer PD, Dijkmans BA (2000) Predictors of functional status in patients with early rheumatoid arthritis. Ann Rheum Dis 59:223–226PubMedCrossRefGoogle Scholar
  49. 49.
    Guillemin F, Suurmeijer T, Krol B, Bombardier C, Briancon S, Doeglas D et al (1994) Functional disability in early rheumatoid arthritis: description and risk factors. J Rheumatol 21:1051–1055PubMedGoogle Scholar
  50. 50.
    van der Heijde DM, van’t Hof MA, van Riel PL, van Leeuwen MA, van Rijswijk MH, van de Putte LB (1992) Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis 51:177–181Google Scholar
  51. 51.
    Smedstad LM, Kvien TK, Moum T, Vaglum P (1995) Life events, psychosocial factors, and demographic variables in early rheumatoid arthritis: relations to one-year changes in functional disability. J Rheumatol 22:2218–2225PubMedGoogle Scholar
  52. 52.
    Uhlig T, Smedstad LM, Vaglum P, Moum T, Gerard N, Kvien TK (2000) The course of rheumatoid arthritis and predictors of psychological, physical and radiographic outcome after 5 years of follow-up. Rheumatology (Oxford) 39:732–741CrossRefGoogle Scholar
  53. 53.
    Townsend HB, Saag KG (2004) Glucocorticoid use in rheumatoid arthritis: benefits, mechanisms, and risks. Clin Exp Rheumatol 22:S77–S82PubMedGoogle Scholar
  54. 54.
    Bijlsma JW, Hoes JN, Van Everdingen AA, Verstappen SM, Jacobs JW (2006) Are glucocorticoids DMARDs? Ann N Y Acad Sci 1069:268–274PubMedCrossRefGoogle Scholar
  55. 55.
    Bijlsma JW, Van Everdingen AA, Huisman M, De Nijs RN, Jacobs JW (2002) Glucocorticoids in rheumatoid arthritis: effects on erosions and bone. Ann N Y Acad Sci 966:82–90PubMedCrossRefGoogle Scholar
  56. 56.
    Guidelines for the management of rheumatoid arthritis (2002) 2002 Update. American College of rheumatology subcommittee on rheumatoid arthritis guidelines. Arthritis Rheum 46:328–346CrossRefGoogle Scholar
  57. 57.
    van Gestel AM, Haagsma CJ, van Riel PL (1998) Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis Rheum 41:1845–1850PubMedCrossRefGoogle Scholar
  58. 58.
    Makinen H, Kautiainen H, Hannonen P, Mottonen T, Leirisalo-Repo M, Laasonen L et al (2007) Sustained remission and reduced radiographic progression with combination disease modifying antirheumatic drugs in early rheumatoid arthritis. J Rheumatol 34:316–321PubMedGoogle Scholar
  59. 59.
    Pincus T, Yazici Y, Bergman M, Swearingen C, Harrington T (2006) A proposed approach to recognise “near-remission” quantitatively without formal joint counts or laboratory tests: a patient self-report questionnaire routine assessment of patient index data (RAPID) score as a guide to a “continuous quality improvement” s. Clin Exp Rheumatol 24:S060–S073Google Scholar
  60. 60.
    Fransen J, Moens HB, Speyer I, van Riel PL (2005) Effectiveness of systematic monitoring of rheumatoid arthritis disease activity in daily practice: a multicentre, cluster randomised controlled trial. Ann Rheum Dis 64:1294–1298PubMedCrossRefGoogle Scholar
  61. 61.
    Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V (2004) Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: a randomized, controlled trial. Arthritis Rheum 50:364–371PubMedCrossRefGoogle Scholar
  62. 62.
    Fransen J, Creemers MC, Van Riel PL (2004) Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria. Rheumatology (Oxford) 43:1252–1255CrossRefGoogle Scholar
  63. 63.
    van Riel PL, van Gestel AM (2000) Clinical outcome measures in rheumatoid arthritis. Ann Rheum Dis 59(suppl 1):i28–i31Google Scholar
  64. 64.
    Sesin CA, Bingham CO (2005) Remission in rheumatoid arthritis: wishful thinking or clinical reality? Semin Arthritis Rheum 35:185–196PubMedCrossRefGoogle Scholar
  65. 65.
    Tanaka E, Mannalithara A, Inoue E, Hara M, Tomatsu T, Kamatani N et al (2008) Efficient management of rheumatoid arthritis significantly reduces long-term functional disability. Ann Rheum Dis 67:1153–1158PubMedCrossRefGoogle Scholar
  66. 66.
    Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM (1995) Effects of low dose corticosteroids on the bone mineral density of patients with rheumatoid arthritis. J Rheumatol 22:1055–1059PubMedGoogle Scholar
  67. 67.
    McDougall R, Sibley J, Haga M, Russell A (1994) Outcome in patients with rheumatoid arthritis receiving prednisone compared to matched controls. J Rheumatol 21:1207–1213PubMedGoogle Scholar
  68. 68.
    Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B et al (1994) Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med 96:115–123PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Eiichi Tanaka
    • 1
    • 2
    • 3
  • Ajitha Mannalithara
    • 1
    • 2
  • Eisuke Inoue
    • 3
  • Noriko Iikuni
    • 3
  • Atsuo Taniguchi
    • 3
  • Shigeki Momohara
    • 3
  • Gurkirpal Singh
    • 1
    • 2
  • Hisashi Yamanaka
    • 3
  1. 1.Division of Gastroenterology and HepatologyStanford University School of MedicineStanfordUSA
  2. 2.Institute of Clinical Outcomes Research and EducationPalo AltoUSA
  3. 3.Institute of RheumatologyTokyo Women’s Medical UniversityShinjuku-ku, TokyoJapan

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