APPENDIX 1
Systematic search strategy Medline
APPENDIX 2
Oxford Centre for Evidence-based Medicine Levels of Evidence
Level / Evidence (Therapeutic studies)1 /
- Systematic review of RCTs
- Individual RCT (high quality)
2 /
- Systematic review of cohort studies
- Individual cohort study or lower quality RCT*
3 /
- Systematic review of case-control studies
- Individual case-control study
4 / Case-series and poor quality cohort and case-control studies
5 / Expert opinion
*e.g. <80% follow-up, no double-blind design.
APPENDIX 3
Flowchart results systematic literature search
EXCLUDED REFERENCES
After full text review with reason for exclusion (n=41)
1Bathon JM, Genovese MC. The Early Rheumatoid Arthritis (ERA) trial comparing the efficacy and safety of etanercept and methotrexate. Clin Exp Rheumatol 2003;21:S195-S197. Original publication is included in the review.
2Boerbooms AM, Kerstens PJ, van Loenhout JW, Mulder J, van de Putte LB. Infections during low-dose methotrexate treatment in rheumatoid arthritis. Semin Arthritis Rheum 1995;24:411-21. Original publication is included in the review.
3Burgardt C. [Drug therapy and malpractice exemplified by combination leflunomide and methotrexate therapy]. Z Rheumatol 2002;61:189-90. No RCT.
4Cohen S, Cannon GW, Schiff M, Weaver A, Fox R, Olsen N et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001;44:1984-92. Original publication is included in the review.
5Drosos AA, Voulgari PV, Papadopoulos IA, Politi EN, Georgiou PE, Zikou AK. Cyclosporine A in the treatment of early rheumatoid arthritis. A prospective, randomized 24-month study. Clin Exp Rheumatol 1998;16:695-701. No MTX monotherapy, but combination with prednison.
6Fiehn C, Jacki S, Heilig B, Lampe M, Wiesmuller G, Richter C et al. Eight versus 16-week re-evaluation period in rheumatoid arthritis patients treated with leflunomide or methotrexate accompanied by moderate dose prednisone. Rheumatol Int 2007;27:975-9. No MTX monotherapy, but combination with prednison.
7Furst DE. Clinical pharmacology of very low dose methotrexate for use on the rheumatoid arthritis. J Rheumatol 1985;12 (suppl):11-4. No RCT.
8Ganguly S. Use of methotrexate in rheumatoid arthritis. Bull Rgkmc 2000;5:16-8. Article not retrieved.
9Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH et al.Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum 2002;46:1443-50. Original publication is included in the review.
10Haagsma CJ, Blom HJ, van Riel PL, van't Hof MA, Giesendorf BA, van Oppenraaij-Emmerzaal D et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis 1999;58:79-84. Original publication is included in the review.
11Haagsma CJ, Van Riel PLCM, De Rooij DJRA, Vree TB, Russel FJM, van't Hof MA 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;33:1049-55. MTX in comparator arm.
12Hall GH, Jones BJ, Head AC, Jones VE. Intra-articular methotrexate. Clinical and laboratory study in rheumatoid and psoriatic arthritis. Ann Rheum Dis 1978;37:351-6. Wrong population and insufficient outcomes.
13Herborn G, Rau R, Menninger H, Elhardt D, Schmitt J. [Data of two years of the comparative study methotrexate/aurothiomalate in 102 patients]. Z Rheumatol 1992;51:163-71. Original publication is included in the review.
14Kavuncu V, Sahin S, Kamanli A, Ardicoglu O. The comparison of the efficiency of methotrexate and sulphasalazine treatments in patients with rheumatoid arthritis. Journal of Rheumatology & Medical Rehabilitation 2002;13:2-6. Insufficient data for analysis.
15Kosinski M, Kujawski SC, Martin R, Wanke LA, Buatti MC, Ware Jr JE et al. Health-related quality of life in early rheumatoid arthritis: Impact of disease and treatment response. Am J Manag Care 2002;8:231-40. Original publication is included in the review.
16Krause D. [Long-term combination therapy of chronic polyarthritis: methotrexate and parenteral gold]. Z Rheumatol 1998;57:37-40. No RCT.
17Mateo L, Romera M, Rozadilla A, Cintero MI. Evaluating the safety of self-injection of gold and methotrexate in patients with inflammatory arthritis. J Rheumatol 2000;27:818. No RCT.
18McKendry RJR. Azathioprine and methotrexate as combination chemotherapy in rheumatoid arthritis. Journal of Rheumatology Vol 17(SUPPL )()(pp 28-33), 1990 1990;28-33. Insufficient data for analysis.
19Michaels RM, Nashel DJ, Leonard A, Sliwinski AJ, Derbes SJ. Weekly intravenous methotrexate in the treatment of rheumatoid arthritis. Arthritis Rheum 1982;25:339-41. No RCT.
20Rau R, Herborn G, Karger T, Menninger H, Elhardt D, Schmitt J. A double blind randomized parallel trial of intramuscular methotrexate and gold sodium thiomalate in early erosive rheumatoid arthritis. J Rheumatol 1991;18:328-33. Original publication is included in the review.
21Rau R, Herborn G, Karger T, Menninger H, Elhardt D, Schmitt J. A double-blind comparison of parenteral methotrexate and parenteral gold in the treatment of early erosive rheumatoid arthritis: an interim report on 102 patients after 12 months. Semin Arthritis Rheum 1991;21:13-20. Original publication is included in the review.
22Schiff MH. Leflunomide versus methotrexate: a comparison of the European and American experience. Scand J Rheumatol 1999;112 (suppl):31-5. Original publication is included in the review.
23Schnabel A, Herlyn K, Burchardi C, Reinhold-Keller E, Gross WL. Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis. Rheumatol Int 1996;15:195-200. Original publication is included in the review.
24Seideman P. Better effect of methotrexate on C-reactive protein during daily compared to weekly treatment in rheumatoid arthritis. Clin Rheumatol 1993;12:210-3. Patients not in remission or stable on MTX, therefore not included for the frequency analysis.
25Seideman P. Methotrexate--the relationship between dose and clinical effect. Br J Rheumatol 1993;32:751-3. Insufficient data for analysis.
26Sigidin YA and Usova SB. Comparative study of cyclosporin A in systemic rheumatoid arthritis. Int J Immunother 1994;10:61-5. Insufficient data for analysis.
27Solomon SD. Methotrexate for rheumatoid arthritis. New Engl J Med 1985;313:639-40. No RCT.
28Strand V, Tugwell P, Bombardier C, Maetzel A, Crawford B, Dorrier C et al.Function and health-related quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum 1999;42:1870-8. Original publication is included in the review.
29Szanto E. Low-dose methotrexate in rheumatoid arthritis: effect and tolerance. An open trial and a double-blind randomized study. Scand J Rheumatol 1986;15:97-102. Insufficient data for analysis.
30Tascioglu F, Oner C, Armagan O. The effect of low-dose methotrexate on bone mineral density in patients with early rheumatoid arthritis. Rheumatol Int 2003;23:231-5. Insufficient data for analysis.
31Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 1984;11:760-3. Insufficient data for analysis.
32Tugwell P, Bombardier C, Buchanan WW, Goldsmith C, Grace E, Bennett KJ et al. Methotrexate in rheumatoid arthritis. Impact on quality of life assessed by traditional standard-item and individualized patient preference health status questionnaires. Arch Intern Med 1990;150:59-62. Wrong outcome.
33Tugwell P, Wells G, Strand V, Maetzel A, Bombardier C, Crawford B et al. Clinical improvement as reflected in measures of function and health- related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: Sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial. Arthritis Rheum 2000;43:506-14. Original publication is included in the review.
34van der Heijde D, Klareskog L, Rodriguez-Valverde V, Codreanu C, Bolosiu H, Melo-Gomes J et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a double-blind, randomized trial. Arthritis Rheum 2006;54:1063-74. Original publication is included in the review.
35van Jaarsveld CH, Jahangier ZN, Jacobs JW, Blaauw AA, van Albada-Kuipers GA, Ter Borg EJ et al. Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis. Rheumatology (Oxford) 2000;39:1374-82. Original publication is included in the review.
36Verstappen SM, Jacobs JW, Bijlsma JW. The Utrecht experience with different treatment strategies in early rheumatoid arthritis. Clin Exp Rheumatol 2003;21:S165-S168. No RCT.
37Verstappen SM, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, Borg EJ et al.Five-year followup of rheumatoid arthritis patients after early treatment with disease-modifying antirheumatic drugs versus treatment according to the pyramid approach in the first year. Arthritis Rheum 2003;48:1797-807. Insufficient data for analysis.
38Westedt ML, Dijkmans BA, Hermans J. [Comparison of azathioprine and methotrexate in rheumatoid arthritis: an open-randomized clinical study]. Rev Rhum Ed Fr 1994;61:591-7. Original publication is included in the review.
39Willkens RF, Sharp JT, Stablein D, Marks C, Wortmann R. 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;38:1799-806. Insufficient data for analysis.
40Willkens RF and Stablein D. Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheumatol 1996;44 (suppl):64-8. Original publication is included in the review.
41Woodruff TG, Hill W, Geddes R, Weatherall M, Bertouch J, Brooks PM. Clinical trials of methotrexate in rheumatoid arthritis. [abstract]. Aust NZ J Med 1984;14 (suppl):344. Article not retrieved.
APPENDIX 4
Indirect comparisons MTX dosage/route
The MTX arms of 22 out of the 30 trials grouped per comparator drug could not be indirectly compared, as the dosage and route of MTX were not different. Mean oral MTX dose was around 10mg/wk in the trials versus azathioprine[1-5] or im auranofin[6,7]; 12-15mg/wk in the trials versus placebo[8-12] or leflunomide[10,13-16]; 17-19mg/wk versus anti-TNF[17-19]; and 20mg/wk versus cyclosporine[20,21]. Nevertheless, in the remaining 8 studies oral MTX 10, 15 or 20mg/wk was evaluated versus sulphasalazine (SSZ)[20,22-24] and oral/im MTX 10 or 15mg/wk was evaluated versus im gold[25-28]. However, due to large heterogeneity of the clinical responses in the comparator arms and the lack of uniformly reported outcome measures, a comparison of the MTX arms was not possible (data not shown). Interestingly, however, the studies using MTX 10 or 15mg/wk versus SSZ all reported equal efficacy of both compounds, while the study using 20mg/wk showed significantly more ACR50 responses in the MTX group (OR=2.67 [1.10-6.47]).[20]
REFERENCES
1Arnold MH, O'Callaghan J, McCredie M, Beller EM, Kelly DE, Brooks PM. Comparative controlled trial of low-dose weekly methotrexate versus azathioprine in rheumatoid arthritis: 3-year prospective study. Br J Rheumatol 1990;29:120-5.
2Hamdy H, McKendry RJ, Mierins E, Liver JA. Low-dose methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A twenty-four-week controlled clinical trial. Arthritis Rheum 1987;30:361-8.
3Jeurissen ME, Boerbooms AM, van de Putte LB, Doesburg WH, Mulder J, Rasker JJ et al. Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial. Arthritis Rheum 1991;34:961-72.
4Westedt ML, Dijkmans BAC, Hermans J. Azathioprine compared with methotrexate for rheumatoid arthritis: An open randomized clinical trial. Rev Rhum Engl Ed1994;61(9):523-9.
5Willkens RF, Urowitz MB, Stablein DM, McKendry RJ, Jr., Berger RG, Box JH et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1992;35:849-56.
6Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon SD, Wall B et al. Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirty-six-week, double-blind trial. Arthritis Rheum 1990;33:330-8.
7Williams HJ, Ward JR, Reading JC, Brooks RH, Clegg DO, Skosey JL et al. Comparison of auranofin, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: A controlled clinical trial. Arthritis Rheum1992;35(3):259-69.
8Andersen PA, West SG, O'Dell JR, Via CS, Claypool RG, Kotzin BL. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study. Ann Intern Med 1985;103:489-96.
9Pinheiro GR, Helfenstein JM, Ferraz MB, Atra E. [A short-term randomized controlled study with methotrexate in rheumatoid arthritis]. Rev Assoc Med Bras 1993;39:91-4.
10Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med 1999;159(21):2542-50.
11Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985;312:818-22.
12Williams HJ, Willkens RF, Samuelson CO, Jr., Alarcon GS, Guttadauria M, Yarboro C et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 1985;28:721-30.
13Bao C, Chen S, Gu Y, Lao Z, Ni L, Yu Q et al. Leflunomide, a new disease-modifying drug for treating active rheumatoid arthritis in methotrexate-controlled phase II clinical trial. Chin Med J (Engl)2003;116(8):1228-34.
14Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gomor B et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000;39:655-65.
15Hu Y, Tu S, Liu P. A randomized, controlled, single-blind trial of leflunomide in the treatment of rheumatoid arthritis. J Tongji Med Univ 2001;21:72-4.
16Kraan MC, Reece RJ, Barg EC, Smeets TJ, Farnell J, Rosenburg R et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum 2000;43:1820-30.
17Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93.
18Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R 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. Arthritis Rheum 2006;54:26-37.
19Klareskog L, van der HD, de Jager JP, Gough A, Kalden J, Malaise M 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. Lancet 2004;363:675-81.
20Ferraccioli GF, Gremese E, Tomietto P, Favret G, Damato R, Di PE. Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Rheumatology 2002;41(8):892-8.
21Singh CP, Kaur BG, Singh G, Singh N, Singh J. The open randomised trial of cyclosporine vs methotrexate in refractory rheumatoid arthritis. Journal of Internal Medicine of India 2000;3(1):19-25.
22Capell HA, Madhok R, Porter DR, Munro RA, McInnes IB, Hunter JA et al. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis 2007;66:235-41.
23Dougados M, Combe B, Cantagrel A, Goupille P, Olive P, Schattenkirchner M 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. Ann Rheum Dis 1999;58:220-5.
24Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB. 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;36:1082-8.
25Hamilton J, McInnes IB, Thomson EA, Porter D, Hunter JA, Madhok R et al. Comparative study of intramuscular gold and methotrexate in a rheumatoid arthritis population from a socially deprived area. Ann Rheum Dis 2001;60:566-72.
26Morassut P, Goldstein R, Cyr M, Karsh J, McKendry RJ. Gold sodium thiomalate compared to low dose methotrexate in the treatment of rheumatoid arthritis--a randomized, double blind 26-week trial. J Rheumatol 1989;16:302-6.
27Rau R, Herborn G, Menninger H, Blechschmidt J. Comparison of intramuscular methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis: 12 month data of a double-blind parallel study of 174 patients. Br J Rheumatol 1997;36:345-52.
28Suarez-Almazor ME, Fitzgerald A, Grace M, Russell AS. A randomized controlled trial of parenteral methotrexate compared with sodium aurothiomalate (Myochrysine) in the treatment of rheumatoid arthritis. J Rheumatol 1988;15:753-6.
APPENDIX 5
Direct comparisons MTX frequencies
In addition to the primary research question, 3 RCTs directly comparing oral MTX weekly versus non-weekly were identified and included.[29,30,31] Pandya et al. evaluated MTX 10mg once weekly versus 5mg twice weekly, in a double-blind RCT.[31] Results showed equally large ES after 16 weeks for SJC, TJC, HAQ and ESR (range 1.03-1.99 and 0.88-1.95 for the twice versus the once weekly schedule, respectively), without a difference in hepatotoxicity (OR=0.9 [0.3-3.6]).
Luis et al. evaluated 7mg MTX weekly versus every other week (eow) in a single-blind trial in RA patients in remission on MTX.[30] SRM for SJC, TJC, VAS, HAQ and ESR for MTX eow (range -0.40; 0.26) versus weekly (range -0.40; 0.56) did not differ and remission percentages were equal in both groups (OR=0.5 [0.04-5.4]), although the negative values indicate worsening in a subset of the patients. Kremer et al. showed similar results in a double-blind trial with 15mg MTX weekly versus eow in patients stable on MTX, showing more flares in the eow group (OR=6.3 [1.5-25]).[29]
REFERENCES
1Kremer JM, Davies JM, Rynes RI, Fink S, Lawrence DA, Petrillo GF et al. Every-other-week methotrexate in patients with rheumatoid arthritis. A double-blind, placebo-controlled prospective study. Arthritis Rheum 1995;38:601-7.
2Luis M, Pacheco-Tena C, Cazarin-Barrientos J, Lino-Perez L, Goycochea MV, Vazquez-Mellado J et al. Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: a twenty-four week, single blind, randomized study. Arthritis Rheum 1999;42:2160-5.
3Pandya S, Aggarwal A, Misra R. Methotrexate twice weekly vs once weekly in rheumatoid arthritis: a pilot double-blind, controlled study. Rheumatol Int 2002;22:1-4.
1