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Meta-Analysis
. 2010 Apr 14;2010(4):CD008495.
doi: 10.1002/14651858.CD008495.

Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis

Wanruchada Katchamart  1 , Judith Trudeau, Veerapong Phumethum, Claire Bombardier
Affiliations
Meta-Analysis

Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis

Wanruchada Katchamart et al. Cochrane Database Syst Rev. .

Abstract

Background: Methotrexate (MTX) is among the most effective disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) with less toxicity and better tolerability.

Objectives: To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA.

Search strategy: Trials were identified in MEDLINE (1950 to 2009), EMBASE (1980 to 2009), the Cochrane Controlled trials Registry (CENTRAL) (up to 2009), the American and European scientific meeting abstracts 2005-9, the reference lists of all relevant studies, letters, and review articles.

Selection criteria: Randomized controlled trials comparing MTX monotherapy versus MTX combined with other non-biologic DMARDs of at least 12 weeks of trial duration in adult RA patients.

Data collection and analysis: Two reviewers independently identified eligible studies,extracted the data, and assessed the risk of bias of relevant studies.The efficacy analysis was stratified into 3 groups based on previous DMARDs use: DMARD naive, MTX inadequate response, and non-MTX DMARDs inadequate response. The toxicity analysis was stratified by DMARD combination and pooled across trials for each combination. Our prespecified primary analysis was based on total withdrawal rates for efficacy or toxicity.

Main results: A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (risk ratio (RR) 1.16, 95% CI.0.70 to 1.93, absolute risk difference(ARD) 5%, 95%CI-3% to 13%). Trials in MTX or non-MTX DMARDs inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups with RR 0.86 95% CI 0.49 to1.51, ARD -2 %, 95% CI-13 % to 8 % and RR 0.75 95% CI 0.41 to 1.35, ARD -10%, 95% CI -31% to 11%, respectively. Significant reductions of pain and improvement in physical function (measured by Health Assessment Questionnaire or HAQ) were found in the MTX combination group, but only in MTX-inadequate responders (absolute risk difference -9.72%, 95%CI -14.7% to -4.75% for pain and mean difference (MD) -0.28, 95%CI -0.36 to -0.21 (0-3) for HAQ).

Authors' conclusions: When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy. Trials are needed that compare currently used MTX doses and combination therapies.

PubMed Disclaimer

Conflict of interest statement

None at present.

The original article published in the Annals for Rheumatic Diseases was supported by Abbott with an unrestricted educational grant. Abbott had no role in the study design, literature search, data collection, data analysis, data interpretation or writing of the report.

This current review was updated without the support of any industry sponsor.

Figures

1
1
Results of the literature search and disposition of the potentially relevant studies * Number is not equal to the sum of number from each database due to duplication among databases Abbreviations :‐ CENTRAL = Cochrane Central Register of Controlled Trials, ACR = American College of rheumatology, EULAR =European League Against Rheumatism, RA = Rheumatoid arthritis, MTX =Methotrexate, RCT = Randomised controlled trial
2
2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
3
3
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
1.1
1.1. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 1 ACR response of DMARD naive.
1.2
1.2. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 2 ACR response of MTX inadequate response.
1.3
1.3. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 3 ACR response of non‐MTX DMARDs inadequate response.
1.4
1.4. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 4 EULAR response of DMARD naive.
1.5
1.5. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 5 EULAR response of non‐MTX DMARDs inadequate response.
1.6
1.6. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 6 Withdrawal due to lack of efficacy (stratified by DMARDs use before randomisation).
1.7
1.7. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 7 Withdrawal due to lack of efficacy (by regimen).
1.8
1.8. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 8 Combined withdrawal due to lack of efficacy or toxicity (stratified by DMARDs use before randomisation).
1.9
1.9. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 9 Combined withdrawal due to lack of efficacy or toxicity (stratified by regimen).
1.10
1.10. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 10 Combined withdrawal due to lack of efficacy or toxicity at 6 months.
1.11
1.11. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 11 Combined withdrawal due to lack of efficacy or toxicity at 12 months.
1.12
1.12. Analysis
Comparison 1 MTX combo vs mono therapy (Efficacy), Outcome 12 Combined withdrawal due to lack of efficacy or toxicity at 24 months.
2.1
2.1. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 1 Total adverse events.
2.2
2.2. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 2 GI side effects.
2.3
2.3. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 3 Abnormal liver function (Transaminitis).
2.4
2.4. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 4 Mucositis.
2.5
2.5. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 5 Haematological side effects.
2.6
2.6. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 6 Infection.
2.7
2.7. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 7 Withdrawal due to adverse reaction (by regimen).
2.8
2.8. Analysis
Comparison 2 MTX combo vs MTX monotherapy (Toxicity), Outcome 8 Withdrawal due to adverse events (stratified by DMARDs use before randomisation).
3.1
3.1. Analysis
Comparison 3 Swollen joint count, Outcome 1 Swollen joint count: MTX inadequate response.
3.2
3.2. Analysis
Comparison 3 Swollen joint count, Outcome 2 Swollen joint count: Non‐MTX DMARDs inadequate response.
4.1
4.1. Analysis
Comparison 4 Tender joint count, Outcome 1 Tender joint count: DMARD naive.
4.2
4.2. Analysis
Comparison 4 Tender joint count, Outcome 2 Tender joint count: MTX inadequate response.
4.3
4.3. Analysis
Comparison 4 Tender joint count, Outcome 3 Tender joint count: Non‐MTX DMARDs inadequate response.
5.1
5.1. Analysis
Comparison 5 Pain, Outcome 1 Pain: DMARD naive.
5.2
5.2. Analysis
Comparison 5 Pain, Outcome 2 Pain: MTX inadequate response.
5.3
5.3. Analysis
Comparison 5 Pain, Outcome 3 Pain: Non‐MTX DMARDs inadequate response.
6.1
6.1. Analysis
Comparison 6 Patient global assessment, Outcome 1 Patient global assessment: DMARD naive.
6.2
6.2. Analysis
Comparison 6 Patient global assessment, Outcome 2 Patient global assessment: MTX inadequate response.
6.3
6.3. Analysis
Comparison 6 Patient global assessment, Outcome 3 Patient global assessment: Non‐MTX DMARDs inadequate response.
7.1
7.1. Analysis
Comparison 7 Physician global assessment, Outcome 1 Physician global asessment: MTX inadequate response.
7.2
7.2. Analysis
Comparison 7 Physician global assessment, Outcome 2 Physician global assessment: Non‐MTX inadequate response.
8.1
8.1. Analysis
Comparison 8 HAQ, Outcome 1 HAQ: DMARD naive.
8.2
8.2. Analysis
Comparison 8 HAQ, Outcome 2 HAQ: MTX inadequate response.
8.3
8.3. Analysis
Comparison 8 HAQ, Outcome 3 HAQ: Non‐MTX DMARDs inadequate response.
9.1
9.1. Analysis
Comparison 9 ESR, Outcome 1 ESR: DMARD naive.
9.2
9.2. Analysis
Comparison 9 ESR, Outcome 2 ESR: MTX inadequate response.
9.3
9.3. Analysis
Comparison 9 ESR, Outcome 3 ESR: Non‐MTX DMARDs inadequate response.
10.1
10.1. Analysis
Comparison 10 CRP, Outcome 1 CRP: DMARD naive.
10.2
10.2. Analysis
Comparison 10 CRP, Outcome 2 CRP: MTX inadequate response.
10.3
10.3. Analysis
Comparison 10 CRP, Outcome 3 CRP: Non‐MTX DMARDs inadequate response.
11.1
11.1. Analysis
Comparison 11 DAS, Outcome 1 DAS: DMARD naive.
11.2
11.2. Analysis
Comparison 11 DAS, Outcome 2 DAS: Non‐MTX DMARDs inadequate response.
12.1
12.1. Analysis
Comparison 12 Modified Sharp's score, Outcome 1 Modified Sharp's score: DMARD naive.
12.2
12.2. Analysis
Comparison 12 Modified Sharp's score, Outcome 2 Modified Sharp's score: MTX inadequate response.
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References

References to studies included in this review

Capell 2007 {published data only}
    1. Capell HA, Madhok R, Porter DR, et al. Combiantion therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with suboptimal response to sulfasalazine:results from double‐blind placebo‐controlled MASCOT study. Ann Rheum Dis 2007;66:235‐41. - PMC - PubMed
Dougados 1999 {published data only}
    1. Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early rheumatoid arthritis:a randomised, controlled, double blind 52 week clinical trial of sulfasalazine and methotrexate compared with single components. Ann Rheum Dis 1999;58:220‐5. - PMC - PubMed
Ferraz 1994 {published data only}
    1. Ferraz MB, Pinheiro GR, Helfenstein M, et al. Combination therapy with methotrexate and chloroquine in rheumatoid arthritis. A multicenter randomized placebo‐controlled trial. Scand J Rheum 1994;23(5):231‐6. - PubMed
Haagsma 1994 {published data only}
    1. Haagsma CJ, Van RielP, Rooij D, et al. Combination of methotrexate and sulphasalazine vs methotrexate alone: A randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol 1994;33(11):1049‐51. - PubMed
Haagsma 1997 {published data only}
    1. Haagsma CJ, Riel PL, Jong A.J, et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double‐blind, 52 week clinical trial. Br J Rheumatol 1997;36(10):1082‐8. - PubMed
Hanyu 1999 {published data only}
    1. Hanyu T, Arai K, Ichikawa H, et al. Long‐term methotrexate (MTX) combination therapy versus MTX alone for active rheumatoid arthritis. Japanease J Rheumatol 1999;9(1):31‐44.
Hetland 2006 {published data only}
    1. Hetland ML, Stengaard‐Pedersen K, Junker P, et al. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: An investigator‐initiated, multicenter, randomized, double‐blind, parallel‐group, placebo‐controlled study. Arthritis Rheum 2006;54(5):1401‐9. - PubMed
Ichikawa 2005 {published data only}
    1. Ichikawa Y, Saito T, Yamanaka H at al. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: A multicenter, double‐blind, randomized controlled study. Mod Rheumatol 2005;15:323‐8. - PubMed
Islam 2000 {published data only}
    1. Islam MN, Alam MN, Haq SA, et al. Efficacy of sulphasalazine plus methotrexate in rheumatoid arthritis. Bangladesh Med Res Counc Bull 2000;25(1):1‐7. - PubMed
Jarette 2006 {published data only}
    1. Jarrett SJ, Conaghan PG, Sloan VS, et al. Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis. Arthritis Rheum 2006;54(5):1410‐4. - PubMed
Kremer 2002 {published data only}
    1. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: A randomized, double‐blind, placebo‐controlled trial. Ann Int Med 2002;137:726‐33. - PubMed
Lehman 2005 {published data only}
    1. Lehman AJ, Esdaile JM, Kinkhoff AV, et al. A 48‐week, randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study. Arthritis Rheum 2005;52(5):1360‐70. - PubMed
Marchesoni 2003 {published data only}
    1. Marchesoni A, Battafarano N, Arreghini M, et al. Radiographic progression in early rheumatoid arthritis: a 12‐month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology 2003;42:1545‐9. - PubMed
O'Dell 1996 {published data only}
    1. O'Dell JR, Haire C, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996;334(20):1287‐91. - PubMed
O'Dell 2006 {published data only}
    1. O'Dell JR, Elliott JR, Mallek JA, et al. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 2006;54(2):621‐7. - PubMed
Ogrendik 2007 {published data only}
    1. Ogrendik M. Levofloxacin treatment in patients with rheumatoid arthritis receiving methotrexate. Southern Med J 2007;100(2):135‐9. - PubMed
Taschioglu 2003 {published data only}
    1. Tascioglu F, Oner C, Armagan O. Comparison of low dose methotrexate and combination therapy with methotrexate and sulphasalazine in the treatment of early rheumatoid arthritis. J Rheum Med Rehab 2003;14(3):142‐9.
Tugwell 1995 {published data only}
    1. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate‐Cyclosporine Combination Study Group.. N Engl J Med 1995;333(3):137‐41. - PubMed
Willkins 1992 {published data only}
    1. Williams HJ, Ward JR, Reading J, et al. Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1992;35(8):849‐56. - PubMed
Willkins 1995 {published data only}
    1. Willkens RF, Sharp JT, Stablein D, et al. Comparison of azathioprine, methotrexate, and the combination of the two in the treatment of rheumatoid arthritis. A forty‐eight‐week controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 1995;38(12):1799‐806. - PubMed

References to studies excluded from this review

Calguneri 1999 {published data only}
    1. Calguneri M, Pay S, Calikaner Z. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheum 1999;17:699‐704. - PubMed
Clegg 1997 {published data only}
    1. Clegg DO, Frederick D, Duffy J, et al. Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. J Rheum 1997;24(10):1896‐902. - PubMed
Haagsma 1995 {published data only}
    1. Haagsma CJ, Riel PLCM, Putte LBA. Combination sulfasalazine and methotrexate in rheumatoid arthritis:early clinical impressions. Br J Rheum 1995;34(suppl 2):104‐8. - PubMed
Kremer 2004 {published data only}
    1. Kremer J, Genovese M, Cannon GW. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open‐label extension of a randomised, double‐blind, placebo controlled trial. J Rheum 2004;31:1521‐31. - PubMed
Maillefert 2003 {published data only}
    1. Maillefert JF, Combe B, Goupille P. Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study. Ann Rheum Dis 2003;62:764‐6. - PMC - PubMed
Matucci‐Cerinic 2003 {published data only}
    1. Matucci‐Cerinic M. Leflunomide improves the clinical response in patients iwth active rheumatoid arthritis treated with methotrexate. Clin Exp Rheum 2003;21(6):695‐6. - PubMed
Mottaghi 2005 {published data only}
    1. Mottaghi P, Karimzade H. Does chloroquine decrease liver enzyme abnormalities induced by methotrexate in patients with rheumatoid arthritis?. J Res Med Science 2005;10(3):135‐8.
Mroczkowski 1999 {published data only}
    1. Mroczkowski PJ, Weinblatt ME, Kremer JM. Methotrexate and leflunomide combination therapy for patients with active rheumatoid arthritis. Clin Exp Rheum 1999;17(suppl18):S66‐8. - PubMed
Nagashima 2006 {published data only}
    1. Nagashima M, Matsuoka T, Saitoh K. Treatment continuation rate in relation to efficacy and toxicity in long‐term therapy with low‐dose methotrexate, sulfasalazine, and bucillamine in 1,358 Japanese patients with rheumatoid arthritis. Clin Exp Rheum 2006;24:260‐7. - PubMed
Nisar 1994 {published data only}
    1. Nisar M, Carlisle L, Amos RS. Methotrexate and sulfasalazine as combination therapy in rheumatoid arthritis. Br J Rheum 1994;33:651‐4. - PubMed
O'Dell 1996 {published data only}
    1. O'Dell JR, Haire C, Erison N, et al. Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. J Rheum 1996;23(suppl44):72‐4. - PubMed
Rou 1998 {published data only}
    1. Rau R, Schleusser B, Herborn G. Longterm combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. J Rheum 1998;25(8):1485‐92. - PubMed
Stein 1997 {published data only}
    1. Stein MC, Pincus T, Yocum D. Combination treatment of severe rheumatoid arthritis with cyclosporin and methotrexate for forty‐eight weeks: an open‐label extension study. Arthritis Rheum 1997;40(10):1843‐51. - PubMed
Trnavsky 1993 {published data only}
    1. Trnavsky K, Batterova J, Linduskova M, et al. Combination therapy with hydroxychloroquine and methotrexate in rheumatoid arthritis. Z Rheum 1993;52:292‐6. - PubMed
Willkins 1996 {published data only}
    1. Willkens RF, Stablein D. Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheum 1996;44(suppl):64‐8. - PubMed

Additional references

Bukhari 2003
    1. Bukhari M, Wiles M, Lunt M, et al. Influence of disease‐modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: Results from a large observational inception study [Influence of disease‐modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: Results from a large observational inception study]. Arthritis Rheum 2003;48(1):46‐53. - PubMed
Bykerk 2005
    1. Bykerk V, Keystone E. What are the goals and principles of management in the early treatment of rheumatoid arthritis? [What are the goals and principles of management in the early treatment of rheumatoid arthritis?]. Best Pract Res Clin Rheumatol 2005;19(1):147‐61. - PubMed
Choy 2005
    1. Choy EHS, Smith C, Dore CJ, Scott DL. A meta‐analysis of the efficacy and toxicity of combining disease‐modifying anti‐rheumatic drugs in rheumatoid arthritis based on patient withdrawal. Rheumatology 2005;44(11):1414‐21. - PubMed
Donahue 2008
    1. Donahue KE, Gartlehner G, Jonas DE, Lux LJ, Thieda P, Jonas BL, et al. Systematic Review: Comparative Effectiveness and Harms of Disease‐Modifying Medications for Rheumatoid Arthritis.. Ann Intern Med 2008;148(2):124‐34. - PubMed
Felson 1993
    1. Felson D, Anderson JJ, Boers M, Bombardier C, et al. The American college of rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials [The American college of rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials]. Arthritis Rheum 1993;36(6):729‐40. - PubMed
Felson 1994
    1. Felson DT, Anderson JJ, Meenan RF. The efficacy and toxicity of combination therapy in rheumatoid arthritis: A meta‐analysis. Arthritis Rheum 1994;37(10):1487‐91. - PubMed
Felson 1995
    1. Felson D, Anderson J, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American college of rheumatology preliminary definition of improvement in rheumatoid arthritis [American college of rheumatology preliminary definition of improvement in rheumatoid arthritis]. Arthritis Rheum 1995;38(6):727‐35. - PubMed
Goekoop YPM 2005
    1. Goekoop‐Ruiterman YPM, Vries‐Bouwstra J, Allaart C, Zeben D, Kerstens PJSM, Hazes J, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomised, controlled trial.. Arthritis Rheum 2005;52(11):3381‐90. - PubMed
Goekoop YPM 2007
    1. Goekoop‐Ruiterman YPM, Vries‐Bouwstra J, Allaart C, Zeben D, Kerstens PJSM, Hazes J, et al. Comparison of treatment strategies in early rheumatoid arthritis: A randomised Trial. Ann Intern Med 2007;146(6):406‐15. - PubMed
Heath 1992
    1. Heath CJ, Fortin P. Epidemiologic studies of rheumatoid arthritis: future directions [Epidemiologic studies of rheumatoid arthritis: future directions]. J Rheum 1992;32(Suppl):74‐7. - PubMed
Hochberg 2001
    1. Hochberg MC, Tracy JK, Flores RH. 'Stepping‐up' from methotrexate: A systematic review of randomised placebo controlled trials in patients with rheumatoid arthritis with an incomplete response to methotrexate. Ann Rheum Dis 2001;60(SUPPL. 3):iii51‐iii4. - PMC - PubMed
Makinen 2007
    1. Makinen H, Kautiainen H, Hannonen P, et al. Sustained Remission and Reduced Radiographic Progression with Combination Disease Modifying Antirheumatic Drugs in Early Rheumatoid Arthritis [Sustained Remission and Reduced Radiographic Progression with Combination Disease Modifying Antirheumatic Drugs in Early Rheumatoid Arthritis]. J Rheumatology 2007;34(2):316‐21. - PubMed
Möttönen 1999
    1. Möttönen T, Hannonen P, Leirisalo‐RepoM, Nissilä M, Kautiainen H, Korpela M. Comparison of combination therapy with single‐drug therapy in early rheumatoid arthritis: a randomised trial. Lancet 1999;353(9164):1568‐73. - PubMed
OMERACT 1993
    1. OMERACT. Outcome measures in rheumatoid arthritis clinical trials. J Rheumatol 1993 1993;20(3):526‐91. - PubMed
Pinals 1981
    1. Pinals R, Alfonse T, Larsen R. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 1981;24(10):1308‐15. - PubMed
Prevoo 1995
    1. Prevoo MLL, Van't Hof MA, Kuper HH, Leeuwen MA, Putte LB, Riel PLCM. 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 1995;38(1):44‐8. - PubMed
van der Heijde 1992
    1. Heijde DM, van't Hof MA, Riel PL, Leeuwen MA, Rijswijk MH, Putte LB. Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis 1992;51(2):177‐81. - PMC - PubMed
van der Heijde1996
    1. Heijde A, Jacobs JWG, Bijlsma JWJ. The Effectiveness of Early Treatment with "Second‐Line" Antirheumatic Drugs: A Randomized, Controlled Trial. Ann Intern Med 1996;124(8):699‐707. - PubMed
Van Gestel 1996
    1. Gestel AM, Prevoo MLL, Van't Hof MA, Rijswijk MH, Putte LBA, Riel PLCM. Development and validation of the European league against rheumatism response criteria for rheumatoid arthritis: Comparison with the preliminary American College of Rheumatology and the world health organization/international league against rheumatism criteria. ArthritisRheum 1996;39(1):34‐40. - PubMed
Verhoeven 1998
    1. Verhoeven AC, Boers M, Tugwell P. Combination therapy in rheumatoid arthritis: updated systematic review. Br Rheumatol 1998;37(6):612‐9. - PubMed

References to other published versions of this review

Katchamart 2009
    1. Katchamart W, Trudeau J, Phumethum V, Bombardier C. The efficacy and toxicity of methotrexate (MTX) monotherapy vs. MTX combination therapy with non‐biologic disease‐modifying anti‐rheumatic drugs in rheumatoid arthritis: A systematic review and meta‐analysis. Ann Rheum Dis 2009;68(7):1105‐12. - PMC - PubMed

MeSH terms