Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative

Annals of the Rheumatic Diseases

Volumn 68, Issue 7, 2009, Pages 1086-1093

  Visser, K ^a   Katchamart, W ^b   Loza, E ^c   Martinez Lopez, J A ^d   Salliot, C ^e   Trudeau, J ^f   Bombardier, C ^b,g   Carmona, L ^d   Van Der Heijde, D ^a   Bijlsma, J W J ^h   Boumpas, D T ⁱ   Canhao, H ^j,x   Edwards, C J ^k   Hamuryudan, V ^l   Kvien, T K ^m   Leeb, B F ⁿ   Martin Mola E M ^o   Mielants, H ^p   Muller Ladner U ^q   Murphy, G ^r   Ostergaard M ^s   Pereira, I A ^t   Ramos Remus, C ^u   Valentini, G ^v   Zochling, J ^w   Dougados, M ^e   more..

^a LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF TORONTO   (Canada)

^c HOSPITAL CLÍNICO SAN CARLOS   (Spain)

^d UNIDAD DE INVESTIGACIÓN   (Spain)

^e UNIVERSITÉ PARIS DESCARTES   (France)

^f NOTRE DAME HOSPITAL   (Canada)

^g Division of Clinical Decision Making and Health Care Research   (Canada)

^h UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

ⁱ UNIVERSITY OF CRETE   (Greece)

^j INSTITUTO DE MEDICINA MOLECULAR   (Portugal)

^k UNIVERSITY HOSPITAL SOUTHAMPTON NHS FOUNDATION TRUST   (United Kingdom)

^l ISTANBUL UNIVERSITY   (Turkey)

^m DIAKONHJEMMET HOSPITAL   (Norway)

ⁿ State Hospital Stockerau   (Austria)

^o HOSPITAL UNIVERSITARIO LA PAZ   (Spain)

^p GHENT UNIVERSITY   (Belgium)

^q JUSTUS LIEBIG UNIVERSITY   (Germany)

^r University College Cork and INFANT Centre   (Ireland)

^s Mental Health Services CPH   (Denmark)

^t FEDERAL UNIVERSITY OF SANTA CATARINA   (Brazil)

^u Unidad de Investigacion en Enfermedades Cronico Degenerativas   (Mexico)

^v UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^w UNIVERSITY OF TASMANIA   (Australia)

^x HOSPITAL DE SANTA MARIA   (Portugal)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ALBUMIN; ASPARTATE AMINOTRANSFERASE; CREATININE; DISEASE MODIFYING ANTIRHEUMATIC DRUG; FOLIC ACID; GLUCOSE; HYDROXYCHLOROQUINE; LEFLUNOMIDE; LIPID; METHOTREXATE; PREDNISONE; SALAZOSULFAPYRIDINE; ANTIRHEUMATIC AGENT;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALBUMIN BLOOD LEVEL; ALCOHOL CONSUMPTION; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BLOOD CELL COUNT; CLINICAL ASSESSMENT; CLINICAL PRACTICE; COCHRANE LIBRARY; CONGENITAL MALFORMATION; CREATININE BLOOD LEVEL; DERMATOMYOSITIS; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG MEGADOSE; DRUG MONITORING; DRUG SAFETY; EMBASE; EVIDENCE BASED PRACTICE; GASTROINTESTINAL SYMPTOM; GASTROINTESTINAL TOXICITY; GIANT CELL ARTERITIS; GLUCOSE BLOOD LEVEL; HEALTH CARE ORGANIZATION; HEPATITIS B; HEPATITIS C; HUMAN; LIPID BLOOD LEVEL; LIVER TOXICITY; MEDLINE; MONOTHERAPY; MORTALITY; ORTHOPEDIC SURGERY; PATIENT EDUCATION; PERIOPERATIVE PERIOD; PRACTICE GUIDELINE; PREGNANCY; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; REVIEW; RHEUMATIC POLYMYALGIA; RHEUMATOID ARTHRITIS; SEROLOGY; SIDE EFFECT; SPONTANEOUS ABORTION; SYSTEMATIC REVIEW; SYSTEMIC LUPUS ERYTHEMATOSUS; THORAX RADIOGRAPHY; UNSPECIFIED SIDE EFFECT; VALIDITY; CLINICAL TRIAL; CONFERENCE PAPER; CONSENSUS DEVELOPMENT; DRUG COMBINATION; EVIDENCE BASED MEDICINE; FEMALE; LONG TERM CARE; MALE; MATERNAL CARE; MULTICENTER STUDY; ORAL DRUG ADMINISTRATION; RHEUMATIC DISEASE; RISK FACTOR;

ABNORMALITIES, DRUG-INDUCED; ADMINISTRATION, ORAL; ANTIRHEUMATIC AGENTS; DRUG THERAPY, COMBINATION; EVIDENCE-BASED MEDICINE; FEMALE; FOLIC ACID; HUMANS; LONG-TERM CARE; MALE; METHOTREXATE; PRECONCEPTION CARE; RHEUMATIC DISEASES; RISK FACTORS;

EID: 67549096874     PISSN: 00034967     EISSN: 14682060     Source Type: Journal    
DOI: 10.1136/ard.2008.094474     Document Type: Review

References (110)

1. Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol 2003;21:S179-85.
2. Wong JM, Esdaile JM. Methotrexate in systemic lupus erythematosus. Lupus 2005;14:101-5.
3. Pope JE, Hong P, Koehler BE. Prescribing trends in disease modifying antirheumatic drugs for rheumatoid arthritis: a survey of practicing Canadian rheumatologists. J Rheumatol 2002;29:255-60.
4. Criswell LA, Henke CJ. What explains the variation among rheumatologists in their use of prednisone and second line agents for the treatment of rheumatoid arthritis? J Rheumatol 1995;22:829-35.
5. Combe B, Landewe R, Lukas C, Bolosiu HD, Breedveld F, Dougados M, et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66:34-45.
6. Sidiropoulos PI, Hatemi G, Song IH, Avouac J, Collantes E, Hamuryudan V, et al. Evidence-based recommendations for the management of ankylosing spondylitis: systematic literature search of the 3E Initiative in Rheumatology involving a broad panel of experts and practising rheumatologists. Rheumatology (Oxford) 2008;47:355-61.
7. van Tulder M, Furlan A, Bombardier C, Bouter L. Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine 2003;28:1290-9.
8. Sackett DL, Richardson WS, Rosenberg WM, Haynes RB. Evidence-based medicine: how to practice and teach EBM. London, UK: Churchill Livingstone, 1997.
9. Oxford Centre for Evidence-Based Medicine. Levels of evidence. 1995. http:// www.cebm.net/index.aspx?o=1025 (accessed March 2008).
10. Roddy E, Zhang W, Doherty M, Arden NK, Barlow J, Birrell F, et al. Evidence-based clinical guidelines: a new system to better determine true strength of recommendation. J Eval Clin Pract 2006;12:347-52.
11. Rheumatoid Arthritis Clinical Trial Archive Group. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 1995;22:218-23.
12. Alarcon GS, Kremer JM, Macaluso M, Weinblatt ME, Cannon GW, Palmer WR, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med 1997;127:356-64.
13. Kent PD, Luthra HS, Michet C Jr. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. J Rheumatol 2004;31:1727-31.
14. Kremer JM, Kaye GI, Kaye NW, Ishak KG, Axiotis CA. Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Followup over long treatment intervals and correlation with clinical and laboratory variables. Arthritis Rheum 1995;38:1194-203.
15. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, Alarcon GS, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993;36:329-35.
16. Golden MR, Katz RS, Balk RA, Golden HE. The relationship of preexisting lung disease to the development of methotrexate pneumonitis in patients with rheumatoid arthritis. J Rheumatol 1995;22:1043-7.
17. Cottin V, Tebib J, Massonnet B, Souquet PJ, Bernard JP. Pulmonary function in patients receiving long-term low-dose methotrexate. Chest 1996;109:933-8.
18. Beyeler C, Jordi B, Gerber NJ, Im Hof V. Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. Br J Rheumatol 1996;35:446-52.
19. Ito S, Nakazono K, Murasawa A, Mita Y, Hata K, Saito N, et al. Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of lowdose methotrexate therapy in a rheumatoid arthritis patient. Arthritis Rheum 2001;44:339-42.
20. Hagiyama H, Kubota T, Komano Y, Kurosaki M, Watanabe M, Miyasaka N. Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol 2004;22:375-6.
21. Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. Am J Med 1988;85:771-4.
22. Phillips CA, Cera PJ, Mangan TF, Newman ED. Clinical liver disease in patients with rheumatoid arthritis taking methotrexate. J Rheumatol 1992;19:229-33.
23. Minocha A, Dean HA, Pittsley RA. Liver cirrhosis in rheumatoid arthritis patients treated with long-term methotrexate. Vet Hum Toxicol 1993;35:45-8.
24. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Guidelines for monitoring drug therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:723-31.
25. Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol 1989;16:313-20.
26. Schnabel A, Reinhold-Keller E, Willmann V, Gross WL. Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. Rheumatol Int 1994;14:33-8.
27. Verstappen SM, Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, Ter Borg EJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2007;66:1443-9.
28. Wegrzyn J, Adeleine P, Miossec P. Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis. Ann Rheum Dis 2004;63:1232-4.
29. Rozin A, Schapira D, Balbir-Gurman A, Braun-Moscovici Y, Markovits D, Militianu D, et al. Relapse of rheumatoid arthritis after substitution of oral for parenteral administration of methotrexate. Ann Rheum Dis 2002;61:756-7.
30. Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D. A comparison of low dose methotrexate bioavailability: oral solution, oral tablet, subcutaneous and intramuscular dosing. J Rheumatol 1993;20:1845-9.
31. Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 2004;31:645-8.
32. Braun J, Kaestner P, Flaxenberg P, Waehrisch J, Hanke P, Demary W, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis. Arthritis Rheum 2008;58:73-81.
33. Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V. Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: a randomized, controlled trial. Arthritis Rheum 2004;50:364-71.
34. Katchamart W, Ortiz Z, Shea B, Tugwell P, Bombardier C. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis (an update systematic review and metaanalysis). Arthritis Rheum 2008;58(suppl):S473.
35. van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderen CJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001;44:1515-24.
36. Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 1990;33:9-18.
37. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994;121:833-41.
38. Griffith SM, Fisher J, Clarke S, Montgomery B, Jones PW, Saklatvala J, et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology (Oxford) 2000;39:1102-9.
39. Buckley LM, Vacek PM, Cooper SM. Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis. J Rheumatol 1990;17:1158-61.
40. Shiroky JB, Neville C, Esdaile JM, Choquette D, Zummer M, Hazeltine M, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebocontrolled trial. Arthritis Rheum 1993;36:795-803.
41. Weinblatt ME, Maier AL, Coblyn JS. Low dose leucovorin does not interfere with the efficacy of methotrexate in rheumatoid arthritis: an 8 week randomized placebo controlled trial. J Rheumatol 1993;20:950-2.
42. Hanrahan PS, Russell AS. Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. J Rheumatol 1988;15:1078-80.
43. Joyce DA, Will RK, Hoffman DM, Laing B, Blackbourn SJ. Exacerbation of rheumatoid arthritis in patients treated with methotrexate after administration of folinic acid. Ann Rheum Dis 1991;50:913-14.
44. Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy. A prospective study with baseline and sequential biopsy samples. Arthritis Rheum 1989;32:121-7.
45. Kremer JM, Furst DE, Weinblatt ME, Blotner SD. Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis. J Rheumatol 1996;23:459-61.
46. Tolman KG, Clegg DO, Lee RG, Ward JR. Methotrexate and the liver. J Rheumatol 1985;12(suppl 12):29-34.
47. Willkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, et al. Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis. Ann Rheum Dis 1990;49:591-3.
48. Kremer JM, Alarcon GS, Lightfoot RW Jr, Willkens RF, Furst DE, Williams HJ, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994;37:316-28.
49. Erickson AR, Reddy V, Vogelgesang SA, West SG. Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis patients. Arthritis Rheum 1995;38:1115-19.
50. Mckendry RJ, Freeman C, Dale P. Ast and/or Alt for methotrexate monitoring. Arthritis Rheum 1995;38:9(suppl):680.
51. Gutierrez-Urena S, Molina JF, Garcia CO, Cuellar ML, Espinoza LR. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis. Arthritis Rheum 1996;39:272-6.
52. Rau R, Karger T, Herborn G, Frenzel H. Liver biopsy findings in patients with rheumatoid arthritis undergoing longterm treatment with methotrexate. J Rheumatol 1989;16:489-93.
53. Visser K, van der Heijde D. Incidence of liver enzyme elevations and liver biopsy abnormalities during methotrexate treatment in rheumatoid arthritis: a systematic review of the literature. Arthritis Rheum 2008;58(suppl):S557.
54. Espinoza LR, Zakraoui L, Espinoza CG, Gutierrez F, Jara LJ, Silveira LH, et al. Psoriatic arthritis: clinical response and side effects to methotrexate therapy. J Rheumatol 1992;19:872-7.
55. Grismer LE, Gill SA, Harris MD. Liver biopsy in psoriatic arthritis to detect methotrexate hepatotoxicity. J Clin Rheumatol 2001;7:224-7.
56. Tilling L, Townsend S, David J. Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. Clin Drug Invest 2006;26:55-62.
57. Ujfalussy I, Koo E, Sesztak M, Gergely P. Termination of disease-modifying antirheumatic drugs in rheumatoid arthritis and in psoriatic arthritis. A comparative study of 270 cases. Z Rheumatol 2003;62:155-60.
58. Ros S, Juanola X, Condom E, Canas C, Riera J, Guardiola J, et al. Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Scand J Rheumatol 2002;31:330-6.
59. Alarcon GS, Tracy IC, Strand GM, Singh K, Macaluso M. Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Ann Rheum Dis 1995;54:708-12.
60. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173-7.
61. Assous N, Touze E, Meune C, Kahan A, Allanore Y. Cardiovascular disease in rheumatoid arthritis: single-center hospital-based cohort study in France. Joint Bone Spine 2007;74:66-72.
62. van Halm VP, Nurmohamed MT, Twisk JW, Dijkmans BA, Voskuyl AE. Disease-modifying antirheumatic drugs are associated with a reduced risk for cardiovascular disease in patients with rheumatoid arthritis: a case control study. Arthritis Res Ther 2006;8:R151.
63. Maetzel A, Wong A, Strand V, Tugwell P, Wells G, Bombardier C. Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs. Rheumatology (Oxford) 2000;39:975-81.
64. Salliot C, van der Heijde D. Long term safety of methotrexate monotherapy in rheumatoid arthritis patients: a systematic literature research. Ann Rheum Dis 2009;68:1100-4.
65. Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002;46:2294-300.
66. Wolfe F, Michaud K, Chakravarty EF. Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology (Oxford) 2006;45:1370-5.
67. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004;50:1740-51.
68. Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002;99:3909-15.
69. Hoshida Y, Xu JX, Fujita S, Nakamichi I, Ikeda JI, Tomita Y, et al. Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication. J Rheumatol 2007;34:322-31.
70. Kojima M, Itoh H, Hirabayashi K, Igarashi S, Tamaki Y, Murayama K, et al. Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases. Pathol Res Pract 2006;202:679-85.
71. Kamel OW, Weiss LM, van de Rijn M, Colby TV, Kingma DW, Jaffe ES. Hodgkin's disease and lymphoproliferations resembling Hodgkin's disease in patients receiving long-term low-dose methotrexate therapy. Am J Surg Pathol 1996;20:1279-87.
72. Kamel OW, van de Rijn M, Lebrun DP, Weiss LM, Warnke RA, Dorfman RF. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol 1994;25:638-43.
73. Tutor-Ureta P, Yebra-Bango M, Salas-Anton C, Andreu JL. Rheumatoid arthritis, methotrexate and non-Hodgkin's lymphoma. A report of 3 patients. Medicina Clinica 2005;125:637.
74. 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 metaanalysis. Ann Rheum Dis 2009;68:1105-12.
75. Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 1995;333:137-41.
76. Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002;137:726-33.
77. Lehman AJ, Esdaile JM, Klinkhoff AV, Grant E, Fitzgerald A, Canvin J. 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;52:1360-70.
78. Ogrendik M. Levofloxacin treatment in patients with rheumatoid arthritis receiving methotrexate. South Med J 2007;100:135-9.
79. Capell 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.
80. Ichikawa Y, Saito T, Yamanaka H, Akizuki M, Kondo H, Kobayashi S, et 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.
81. Haagsma 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.
82. Dougados 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.
83. Marchesoni A, Battafarano N, Arreghini M, Panni B, Gallazzi M, Tosi S. Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford) 2003;42:1545-9.
84. Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Andersen LS, 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;54:1401-9.
85. O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, et al. Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 2006;54:621-7.
86. Islam MN, Alam MN, Haq SA, Moyenuzzaman M, Patwary MI, Rahman MH. Efficacy of sulphasalazine plus methotrexate in rheumatoid arthritis. Bangladesh Medl Res CouncBull 2000;26:1-7.
87. Tascioglu FO, Oner C, Armagan O. Comparison of low dose methotrexate and combination therapy with methotrexate and sulphasalazine in the treatment of early rheumatoid arthritis. J Rheumatol Med Rehabil 2003;14:142-9.
88. O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996;334:1287-91.
89. Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.
90. Breedveld 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.
91. Genovese 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.
92. Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study) - a randomized, controlled trial. Arthritis Rheum 2005;52:3381-90.
93. Mahr AD, Jover JA, Spiera RF, Hernandez-Garcia C, Fernandez-Gutierrez B, Lavalley MP, et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum 2007;56:2789-97.
94. Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. J Rheumatol 1996;23:624-8.
95. Caporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, et al. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med 2004;141:493-500.
96. Fortin PR, Abrahamowicz M, Ferland D, Lacaille D, Smith CD, Zummer M. Study of methotrexate in lupus erythematosus (SMILE): significant decreased disease activity and steroid sparing effect in patients without damage. Arthritis Rheum 2001;44(suppl):S387.
97. Carneiro JR, Sato EI. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J Rheumatol 1999;26:1275-9.
98. Ramanan AV, Campbell-Webster N, Ota S, Parker S, Tran D, Tyrrell PN, et al. The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis Rheum 2005;52:3570-8.
99. Sany J, Anaya JM, Canovas F, Combe B, Jorgensen C, Saker S, et al. Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis. J Rheumatol 1993;20:1129-32.
100. Grennan DM, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis 2001;60:214-17.
101. Carpenter MT, West SG, Vogelgesang SA, Casey Jones DE. Postoperative joint infections in rheumatoid arthritis patients on methotrexate therapy. Orthopedics 1996;19:207-10.
102. Murata K, Yasuda T, Ito H, Yoshida M, Shimizu M, Nakamura T. Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery. Mod Rheumatol 2006;16:14-19.
103. Ostensen M, von Esebeck M, Villiger PM. Therapy with immunosuppressive drugs and biological agents and use of contraception in patients with rheumatic disease. J Rheumatol 2007;34:1266-9.
104. Ostensen M, Hartmann H, Salvesen K. Low dose weekly methotrexate in early pregnancy. A case series and review of the literature. J Rheumatol 2000;27:1872-5.
105. Lewden B, Vial T, Elefant E, Nelva A, Carlier P, Descotes J. Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. J Rheumatol 2004;31:2360-5.
106. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD, Wilke WS, Segal AM. Outcome of first-trimester exposure to low-dose methotrexate in eight patients with rheumatic disease. Am J Med 1990;88:589-92.
107. Donnenfeld AE, Pastuszak A, Noah JS, Schick B, Rose NC, Koren G. Methotrexate exposure prior to and during pregnancy. Teratology 1994;49:79-81.
108. Chakravarty EF, Sanchez-Yamamoto D, Bush TM. The use of disease modifying antirheumatic drugs in women with rheumatoid arthritis of childbearing age: a survey of practice patterns and pregnancy outcomes. J Rheumatol 2003;30:241-6.
109. Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:839-54.
110. Otis. Información para mujeres embarazadas y amamantando sobre el estrés. March 2006. http://www.otispregnancy.org/pdf/es-estres. pdf (accessed March 2008).