The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis

Background Glucocorticoids (GCs) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis (RA) and the need to start disease-modifying antirheumatic drugs (DMARDs). Objective To test the effect of GCs on patients with very early arthritis (symptom duration of <16 weeks) in a randomised controlled trial. Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo (PL) and were followed up for 52 weeks. Primary end point was drug-free clinical remission, both at weeks 12 and 52. Among secondary outcomes were fulfilment of remission criteria at weeks 2, 12 or 52, time course of ‘core set variables’ and proportion of patients starting DMARDs. Results 17.0% of all analysed subjects (65/383) achieved persistent remission: 17.8% (33/185) of the PL group, 16.2% (32/198) of the patients receiving methylprednisolone (OR=1.13, 95% CI 0.66 to 1.92, p=0.6847). Analyses of secondary end points showed significant clinical benefits of the GC only at week 2. These differences subsequently disappeared. DMARDs were started in 162 patients: 50.3% methylprednisolone and 56.7% PL patients had to start DMARD treatment (OR=0.78, 95% CI 0.49 to 1.22, p=0.30). Significantly more patients with polyarthritis than with oligoarthritis received DMARDs (OR=2.84, 95% CI 1.75 to 4.60, p<0.0001). Conclusions Neither remission nor development of RA is delayed by GC treatment. Remission is rare in the first year of very early arthritis, occurring in <20% of the patients. Also, the need to start DMARDs was not influenced by GC treatment.

[1]  D. Symmons,et al.  Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial , 2009, Annals of the rheumatic diseases.

[2]  M. Boers,et al.  Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study , 2009, Annals of the rheumatic diseases.

[3]  T. Pincus,et al.  Mortality in rheumatoid arthritis: 2008 update. , 2008, Clinical and experimental rheumatology.

[4]  W. Gross,et al.  A phase II study of interferon-alpha for the treatment of refractory Churg-Strauss syndrome. , 2008, Clinical and experimental rheumatology.

[5]  M. Boers,et al.  Effects of glucocorticoids on radiological progression in rheumatoid arthritis. , 2007, The Cochrane database of systematic reviews.

[6]  M. Salmon,et al.  Treating very early rheumatoid arthritis. , 2006, Best practice & research. Clinical rheumatology.

[7]  F. Breedveld,et al.  The need for new classification criteria for rheumatoid arthritis. , 2005, Arthritis and rheumatism.

[8]  B. Dijkmans,et al.  Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. , 2005, Arthritis and rheumatism.

[9]  B. Combe.  Should patients with recent-onset polyarthritis receive aggressive treatment? , 2004, Joint, bone, spine : revue du rhumatisme.

[10]  D. M. van der Heijde,et al.  Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. , 2004, Arthritis and rheumatism.

[11]  A. McMahon,et al.  Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial , 2004, The Lancet.

[12]  G. Eberl,et al.  Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. , 2004, Rheumatology.

[13]  P. Riel.  EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT) , 2003 .

[14]  Michael J. Green,et al.  Prognostic factors in a large cohort of patients with early undifferentiated inflammatory arthritis after application of a structured management protocol. , 2003, Arthritis and rheumatism.

[15]  H. Zeidler,et al.  Early arthritis and rheumatoid arthritis in Germany. , 2003, Clinical and experimental rheumatology.

[16]  T. Sokka.  Early rheumatoid arthritis in Finland. , 2003, Clinical and experimental rheumatology.

[17]  J. Smolen,et al.  The Austrian Early Arthritis Registry. , 2003, Clinical and experimental rheumatology.

[18]  P. Emery,et al.  Window of opportunity in early rheumatoid arthritis: possibility of altering the disease process with early intervention. , 2003, Clinical and experimental rheumatology.

[19]  A. Silman,et al.  The Norfolk Arthritis Register (NOAR). , 2003, Clinical and experimental rheumatology.

[20]  G. Alarcón,et al.  Early rheumatoid arthritis in African-Americans: the CLEAR Registry. , 2003, Clinical and experimental rheumatology.

[21]  J. Cush.  Early arthritis clinic: a USA perspective. , 2003, Clinical and experimental rheumatology.

[22]  C. Allaart,et al.  The Leiden Early Arthritis Clinic. , 2003, Clinical and experimental rheumatology.

[23]  B. Combe.  The French early arthritis registry. , 2003, Clinical and experimental rheumatology.

[24]  T. Kvien,et al.  The Oslo experience with arthritis registries. , 2003, Clinical and experimental rheumatology.

[25]  Theodore Raphan,et al.  The Nodulus and Uvula: Source of Cerebellar Control of Spatial Orientation of the Angular Vestibulo‐Ocular Reflex , 2002, Annals of the New York Academy of Sciences.

[26]  M. Uffmann,et al.  Very recent onset arthritis--clinical, laboratory, and radiological findings during the first year of disease. , 2002, The Journal of rheumatology.

[27]  H. Schumacher.  Early arthritis clinics. Much early arthritis is unclassified. , 2002, The Journal of rheumatology.

[28]  G. Neeck.  Fifty Years of Experience with Cortisone Therapy in the Study and Treatment of Rheumatoid Arthritis , 2002, Annals of the New York Academy of Sciences.

[29]  P. Lipsky,et al.  Criteria for early rheumatoid arthritis: from Bayes' law revisited to new thoughts on pathogenesis. , 2002, Arthritis and rheumatism.

[30]  M. Dougados,et al.  Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide , 2002, Annals of the rheumatic diseases.

[31]  Koen Vos,et al.  How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. , 2002, Arthritis and rheumatism.

[32]  Rene Westhovens,et al.  COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. , 2002, Arthritis and rheumatism.

[33]  A. Zwinderman,et al.  Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. , 2001, The American journal of medicine.

[34]  M. A. van 't Hof,et al.  Treatment strategy, disease activity, and outcome in four cohorts of patients with early rheumatoid arthritis , 2001, Annals of the rheumatic diseases.

[35]  Richard W. Martin,et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. , 2000, The New England journal of medicine.

[36]  J. Jover,et al.  Lag time between onset of symptoms and access to rheumatology care and DMARD therapy in a cohort of patients with rheumatoid arthritis. , 2000, The Journal of rheumatology.

[37]  P. Emery,et al.  How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS) , 2000, Rheumatology.

[38]  Michael J. Green,et al.  Persistence of mild, early inflammatory arthritis: the importance of disease duration, rheumatoid factor, and the shared epitope. , 1999, Arthritis and rheumatism.

[39]  S. Bale,et al.  Association of HLA alleles and clinical features in patients with synovitis of recent onset. , 1999, Arthritis and rheumatism.

[40]  P. Hannonen,et al.  Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial , 1999, The Lancet.

[41]  M. Boers.  The case for corticosteroids in the treatment of early rheumatoid arthritis. , 1999, Rheumatology.

[42]  F. Breedveld,et al.  Diagnosis and course of early-onset arthritis: results of a special early arthritis clinic compared to routine patient care. , 1998, British journal of rheumatology.

[43]  B. Leeb,et al.  Early arthritis therapy: rationale and current approach. , 1998, The Journal of rheumatology. Supplement.

[44]  T. Pincus.  Limitations of randomized controlled clinical trials to depict accurately long-term outcomes in rheumatoid arthritis , 1998, Zeitschrift für Rheumatologie.

[45]  A. Silman,et al.  Natural remission in inflammatory polyarthritis: issues of definition and prediction. , 1996, British journal of rheumatology.

[46]  A. van der Heide,et al.  The Effectiveness of Early Treatment with Second-Line Antirheumatic Drugs , 1996, Annals of Internal Medicine.

[47]  J. Kirwan,et al.  The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. , 1995, The New England journal of medicine.

[48]  P. Tugwell,et al.  World Health Organization and International League of Associations for Rheumatology core endpoints for symptom modifying antirheumatic drugs in rheumatoid arthritis clinical trials. , 1994, The Journal of rheumatology. Supplement.

[49]  J. McDonagh,et al.  Differentiating persistent from self-limiting symmetrical synovitis in an early arthritis clinic. , 1993, British journal of rheumatology.

[50]  J J Anderson,et al.  The American college of rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials , 1993 .

[51]  D. Felson.  Choosing a core set of disease activity measures for rheumatoid arthritis clinical trials. , 1993, The Journal of rheumatology.

[52]  A. Masi.  Articular patterns in the early course of rheumatoid arthritis. , 1983, The American journal of medicine.

[53]  A. Masi,et al.  Prognosis in rheumatoid arthritis. A longitudinal study of newly diagnosed younger adult patients. , 1979, The American journal of medicine.

[54]  A. Masi,et al.  Proceedings: Comparison of early patterns of rheumatoid arthritis (RA) in juveniles and young adults: data supporting a unified disease concept. , 1975, Arthritis and rheumatism.

[55]  D. Scott.  Early rheumatoid arthritis. , 2007, British medical bulletin.

[56]  K. Eberhardt,et al.  Early rheumatoid arthritis —onset, course, and outcome over 2 years , 2005, Rheumatology International.

[57]  K. Steinhauser,et al.  Aggressive rheumatoid arthritis registry in Italy. Characteristics of the early rheumatoid arthritis subtype among patients classified according to the ACR criteria. , 2003, Clinical and experimental rheumatology.

[58]  J. Jacobs,et al.  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 , 2002, Annals of Internal Medicine.