Similar effects of disease-modifying antirheumatic drugs, glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including 112 comparisons.

OBJECTIVE To define the differences in effects on joint destruction in rheumatoid arthritis (RA) patients between therapy with single and combination disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and biologic agents. METHODS Randomized controlled trials in RA patients, investigating the effects of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta-analysis performed with the use of Review Manager 5.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. RESULTS Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta-analyses. Compared with placebo, the PARPR was 0.65% smaller in the single-DMARD group (P < 0.002) and 0.54% smaller in the glucocorticoid group (P < 0.00001). Compared with single-DMARD treatment, the PARPR was 0.62% smaller in the combination-DMARD group (P < 0.001) and 0.61% smaller in the biologic agent plus methotrexate (MTX) group (P < 0.00001). The effect of a combination of 2 DMARDs plus step-down glucocorticoids did not differ from the effect of a biologic agent plus MTX (percentage mean difference -0.07% [95% confidence interval -0.25, 0.11]) (P = 0.44). CONCLUSION Treatment with DMARDs, glucocorticoids, biologic agents, and combination agents significantly reduced radiographic progression at 1 year, with a relative effect of 48-84%. A direct comparison between the combination of a biologic agent plus MTX and the combination of 2 DMARDs plus initial glucocorticoids revealed no difference. Consequently, biologic agents should still be reserved for patients whose RA is resistant to DMARD therapy. Future trials of the effects of biologic agents on RA should compare such agents with combination treatments involving DMARDs and glucocorticoids.

[1]  John Wong,et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs , 2010, Annals of the rheumatic diseases.

[2]  S SmolenJosef,et al.  EULAR (欧州リウマチ学会) 合成および疾患修飾性抗リウマチ生物学的製剤による関節リウマチ管理に関する推奨ガイドライン | 文献情報 | J-GLOBAL 科学技術総合リンクセンター , 2010 .

[3]  J. Ioannidis,et al.  The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration , 2009, BMJ : British Medical Journal.

[4]  H. Genant,et al.  Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors , 2009, Annals of the rheumatic diseases.

[5]  D. M. van der Heijde,et al.  Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial , 2008, Annals of the rheumatic diseases.

[6]  M. Dougados,et al.  Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies , 2008, Annals of the rheumatic diseases.

[7]  V. Strand,et al.  Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. , 2008, Arthritis and rheumatism.

[8]  F. Breedveld,et al.  Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial , 2008, The Lancet.

[9]  Jeffrey R Curtis,et al.  American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. , 2008, Arthritis and rheumatism.

[10]  K. Stengaard-Pedersen,et al.  Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study , 2007, Annals of the rheumatic diseases.

[11]  V. Farewell,et al.  Factorial randomised controlled trial of glucocorticoids and combination disease modifying drugs in early rheumatoid arthritis , 2007, Annals of the rheumatic diseases.

[12]  G. A. Bennett,et al.  1958 revision of diagnostic criteria for rheumatoid arthritis. , 1958, Arthritis and rheumatism.

[13]  U Pichlmeier,et al.  Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. , 2008, Arthritis and rheumatism.

[14]  S. Garattini,et al.  New antirheumatic drugs: any real added value? A critical overview of regulatory criteria for their marketing approval , 2007, European Journal of Clinical Pharmacology.

[15]  D. M. van der Heijde,et al.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab , 2007, Annals of the rheumatic diseases.

[16]  B. Dijkmans,et al.  Comparison of Treatment Strategies in Early Rheumatoid Arthritis , 2007, Annals of Internal Medicine.

[17]  Alan Brennan,et al.  Using mixed treatment comparisons and meta‐regression to perform indirect comparisons to estimate the efficacy of biologic treatments in rheumatoid arthritis , 2007, Statistics in Medicine.

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

[19]  H. Genant,et al.  Effects of Abatacept in Patients with Methotrexate-Resistant Active Rheumatoid Arthritis , 2006, Annals of Internal Medicine.

[20]  F. Breedveld,et al.  The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. , 2006, Arthritis and rheumatism.

[21]  R. Rau,et al.  Very low-dose prednisolone in early rheumatoid arthritis retards radiographic progression over two years: a multicenter, double-blind, placebo-controlled trial. , 2005, Arthritis and rheumatism.

[22]  A. Boonen,et al.  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. , 2005, Arthritis and rheumatism.

[23]  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.

[24]  G. Kingsley,et al.  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 , 2005, Annals of the rheumatic diseases.

[25]  A. Larsen,et al.  Effects of aurothioglucose and auranofin on radiographic progression in rheumatoid arthritis , 1986, Clinical Rheumatology.

[26]  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.

[27]  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.

[28]  R. Madhok,et al.  Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial , 2004, Annals of the rheumatic diseases.

[29]  E. Keystone,et al.  Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. , 2004, Arthritis and rheumatism.

[30]  L. Klareskog,et al.  Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial , 2004, The Lancet.

[31]  N. Graudal.  The natural history and prognosis of rheumatoid arthritis: association of radiographic outcome with process variables, joint motion and immune proteins , 2004, Scandinavian journal of rheumatology. Supplement.

[32]  M. Arreghini,et al.  Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. , 2003, Rheumatology.

[33]  M. Ahlmén,et al.  Treatment of early RA in clinical practice: a comparative study of two different DMARD/corticosteroid options. , 2003, Clinical and experimental rheumatology.

[34]  R. Laan,et al.  Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial , 2003, Annals of the rheumatic diseases.

[35]  H. Pettersson,et al.  Reumacon (CPH82) showed similar x‐ray progression and clinical effects as methotrexate in a two year comparative study on patients with early rheumatoid arthritis , 2003, Scandinavian journal of rheumatology.

[36]  G. Jones,et al.  The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials. , 2003, Rheumatology.

[37]  P. Sarzi-Puttini,et al.  An open, randomized comparison study of cyclosporine A, cyclosporine A + methotrexate and cyclosporine A + hydroxychloroquine in the treatment of early severe rheumatoid arthritis , 2003, Rheumatology International.

[38]  G. Kingsley,et al.  Treating rheumatoid arthritis early with disease modifying drugs reduces joint damage: a randomised double blind trial of sulphasalazine vs diclofenac sodium. , 2002, Clinical and experimental rheumatology.

[39]  M. Arreghini,et al.  Step-down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[40]  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.

[41]  R N Maini,et al.  Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. , 2000, The New England journal of medicine.

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

[43]  Michael J. Green,et al.  Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone. , 2000, Arthritis and rheumatism.

[44]  R. Dahl,et al.  A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. , 2000, Rheumatology.

[45]  J. Jacobs,et al.  Aggressive treatment in early rheumatoid arthritis: a randomised controlled trial , 2000, Annals of the rheumatic diseases.

[46]  N. Milman,et al.  Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender joints, the erythrocyte sedimentation rate, and hemoglobin: longterm course and association to radiographic progression. , 2000, The Journal of rheumatology.

[47]  M. Lassere.  Pooled metaanalysis of radiographic progression: comparison of Sharp and Larsen methods. , 2000, The Journal of rheumatology.

[48]  V. Strand,et al.  Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. , 1999, Archives of internal medicine.

[49]  J. Pødenphant,et al.  A randomised trial of differentiated prednisolone treatment in active rheumatoid arthritis. Clinical benefits and skeletal side effects , 1999, Annals of the rheumatic diseases.

[50]  S. Pay,et al.  Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. , 1999, Clinical and experimental rheumatology.

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

[52]  M. Dougados,et al.  Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components , 1999, Annals of the rheumatic diseases.

[53]  J. Smolen,et al.  Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial , 1999, The Lancet.

[54]  Z Domljan,et al.  Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. , 1998, Arthritis and rheumatism.

[55]  P. Voulgari,et al.  Cyclosporine A in the treatment of early rheumatoid arthritis. A prospective, randomized 24-month study. , 1998, Clinical and Experimental Rheumatology.

[56]  R. Rau,et al.  Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate. , 1998, British journal of rheumatology.

[57]  E. Coles,et al.  A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis. , 1998, British journal of rheumatology.

[58]  J. Kirwan,et al.  Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. , 1998, British journal of rheumatology.

[59]  N. Graudal,et al.  Radiographic progression in rheumatoid arthritis: a long-term prospective study of 109 patients. , 1998, Arthritis and rheumatism.

[60]  P. Hannonen,et al.  Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: comparison of low-dose cyclosporin and parenteral gold. , 1998, British journal of rheumatology.

[61]  S. van der Linden,et al.  Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis , 1997, The Lancet.

[62]  U. Brodin,et al.  Auranofin is safe and superior to placebo in elderly-onset rheumatoid arthritis. , 1997, British journal of rheumatology.

[63]  K. Eberhardt,et al.  D-penicillamine in early rheumatoid arthritis: experience from a 2-year double blind placebo controlled study. , 1996, Clinical and experimental rheumatology.

[64]  G. Pasero,et al.  Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. , 1996, Arthritis and rheumatism.

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

[66]  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.

[67]  L. V. D. van de Putte,et al.  Oral steroids as bridge therapy in rheumatoid arthritis patients starting with parenteral gold. A randomized double-blind placebo-controlled trial. , 1995, British journal of rheumatology.

[68]  A. Zwinderman,et al.  Prednisone treatment of elderly-onset rheumatoid arthritis. Disease activity and bone mass in comparison with chloroquine treatment. , 1995, Arthritis and rheumatism.

[69]  O. Førre.  Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine. Results of a 48-week multicenter study comparing low-dose cyclosporine with placebo. Norwegian Arthritis Study Group. , 1994, Arthritis and rheumatism.

[70]  P. Hannonen,et al.  Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study. , 1993, Arthritis and rheumatism.

[71]  G. Alarcón,et al.  Radiographic assessment of disease progression in rheumatoid arthritis patients enrolled in the cooperative systematic studies of the rheumatic diseases program randomized clinical trial of methotrexate, auranofin, or a combination of the two. , 1993, Arthritis and rheumatism.

[72]  M. Weinblatt,et al.  The effects of drug therapy on radiographic progression of rheumatoid arthritis. Results of a 36-week randomized trial comparing methotrexate and auranofin. , 1993, Arthritis and rheumatism.

[73]  L. van de Putte,et al.  Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study. , 1991, Annals of internal medicine.

[74]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[75]  D. Heijde,et al.  EFFECTS OF HYDROXYCHLOROQUINE AND SULPHASALAZINE ON PROGRESSION OF JOINT DAMAGE IN RHEUMATOID ARTHRITIS , 1989, The Lancet.

[76]  P. Bacon,et al.  Combination therapy with gold and hydroxychloroquine in rheumatoid arthritis: a prospective, randomized, placebo-controlled study. , 1989, British journal of rheumatology.

[77]  U. Brodin,et al.  Auranofin improves outcome in early rheumatoid arthritis. Results from a 2-year, double blind placebo controlled study. , 1988, The Journal of rheumatology.

[78]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[79]  Hassan Khaled Hamdy,et al.  Low-dose methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A twenty-four-week controlled clinical trial. , 1987, Arthritis and rheumatism.

[80]  O'brien Wm,et al.  Radiographic evaluation of erosion in rheumatoid arthritis: double blind study of auranofin vs placebo. , 1984 .

[81]  W. O'Fallon,et al.  Controlled trial of hydroxychloroquine and D-penicillamine singly and in combination in the treatment of rheumatoid arthritis. , 1984, Arthritis and rheumatism.

[82]  J. Gofton,et al.  Roentgenographic findings during auranofin treatment. , 1983, The American journal of medicine.

[83]  A. Larsen,et al.  Radiographic Evaluation of Rheumatoid Arthritis and Related Conditions by Standard Reference Films , 1977, Acta radiologica: diagnosis.

[84]  W. R. Mccrum,et al.  Gold salts in the treatment of rheumatoid arthritis. A double-blind study. , 2020, Annals of internal medicine.

[85]  J. Sharp,et al.  Double-blind study of cyclophosphamide in rheumatoid arthritis. , 1973, Arthritis and rheumatism.

[86]  J. Moreland,et al.  Methods of scoring the progression of radiologic changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. , 1971, Arthritis and rheumatism.

[87]  F. Bier,et al.  Chloroquine Diphosphate in Rheumatoid Arthritis * , 1961, Annals of the rheumatic diseases.

[88]  A. Freedman,et al.  Chloroquine in Rheumatoid Arthritis , 1960, Annals of the rheumatic diseases.