This work was performed as part of the Portuguese participation in the 3E Initiative 2007–2008, dedicated to the use of methotrexate (MTX) in rheumatic conditions. Three questions raised by Portuguese rheumatologists and considered relevant to clinical practice remained out of the selection of a set of ten key questions formulated to further establish multinational recommendations on the use of MTX in rheumatic diseases. The authors collected and analyzed all the evidence available by using a systematic literature search methodology and selection criteria concerning the following issues in rheumatoid arthritis (RA): (1) the management of MTX after clinical remission; (2) the management of MTX during infections and (3) the screening and treatment of tuberculosis in patients on MTX treatment. A total of 1,862 references were identified, of which 163 were selected for detailed analysis and 12 included in the final review. The evidence was appraised according to the Oxford Centre for Evidence-based Medicine (EBM) levels of evidence. Although with limited evidence, the authors concluded that: (1) extending the interval for MTX therapy may be a valid alternative regimen in a subset of RA patients in clinical remission (EBM level 2b); (2) MTX may be safe during some common infections in RA patients (EBM level 3b/4); (3) screening and treatment of TB in patients on MTX should be similar to the general population (EBM level 4). The evidence available to support clinical decisions in this area is very limited in number and quality. There is a need for further research and while that is unavailable, practical decisions have to rely on experience and expert opinion.
Infection Methotrexate Remission Rheumatoid arthritis Systematic literature review Tuberculosis
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We wish to thank the librarian, Helena Donato, and the epidemiologists, Paulo Nicola and Nuno Lunet, for their collaboration and support in the search and in the methodology used. We also thank Prof Maxime Dougados and the members of the 3E Initiative International Scientific Committees for their encouragement and guidance.
This work has been supported by an unrestricted grant from Abbott Immunology. Abbott had no role in the study design, literature search, data collection, analysis, and writing of this report.
Conflicts of interest
Aletaha D, Smolen JS (2002) The rheumatoid arthritis patient in the clinic: comparing more than 1, 300 consecutive DMARD courses. Rheumatology 41:1367–1374CrossRefPubMedGoogle Scholar
Borchers AT, Keen CL, Cheema GS, Gershwin ME (2004) The use of methotrexate in rheumatoid arthritis. Semin Arthritis Rheum 34:465–483CrossRefPubMedGoogle Scholar
Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS (2003) Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol 21:179–185Google Scholar
Visser K, Katchamart W, Loza E, Martinez-Lopez JA et al (2009) 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. Ann Rheum Dis 68:1086–1093CrossRefPubMedGoogle Scholar
Saleem B, Nizam S, Emery P (2006) Can remission be maintained with or without further drug therapy in rheumatoid arthritis? Clin Exp Rheumatol 24:37–40Google Scholar
Mierau M, Schoels M, Gonda G, Fuchs J, Aletaha D, Smolen JS (2007) Assessing remission in clinical practice. Rheumatology 46:975–979CrossRefPubMedGoogle Scholar
Koivuniemi R, Leirisalo-Repo M, Suomalainen R, Piirainen H, Paimela L (2006) Infectious causes of death in patients with rheumatoid arthritis: an autopsy study. Scand J Rheumatol 35:273–276CrossRefPubMedGoogle Scholar
Naz SM, Symmons DP (2007) Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 21:871–883CrossRefPubMedGoogle Scholar
Blöndal K (2007) Barriers to reaching the targets for tuberculosis control: multidrug-resistant tuberculosis. Bull World Health Organ 85:387–390CrossRefPubMedGoogle Scholar
Vadillo Font C, Hernández-García C, Pato E et al (2003) Incidencia y características de la tuberculosis en pacientes con enfermedades reumáticas autoinmunes. Rev Clin Esp 203:178–182CrossRefPubMedGoogle Scholar
Carmona L, Hernández-García C, Vadillo C et al (2003) EMECAR Study. Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 30:1436–1439PubMedGoogle Scholar
Gomez-Reino JJ, Carmona L, Valverde VR, Mola EM, BIOBADASER GROUP (2003) Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: a multicenter active-surveillance report. Arthritis Rheum 48:2122–2127CrossRefPubMedGoogle Scholar
van Tulder M, Furlan A, Bombardier C, Bouter L (2003) Updated method guidelines for systematic reviews in the Cochrane Collaboration Back Review Group. Spine 28:1290–1299CrossRefPubMedGoogle Scholar
Luis M, Pacheco-Tena C, Cazarín-Barrientos J et al (1999) Comparision 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 42:2160–2165CrossRefPubMedGoogle Scholar
van der Veen MJ, van der Heide A, Kruize AA, Bijlsma JW (1994) Infection rate and use of antibiotics in patients with rheumatoid arthritis treated with methotrexate. Ann Rheum Dis 53:224–228CrossRefPubMedGoogle Scholar
Furst DE, Erikson N, Clute L, Koehnke R, Burmeister LF, Kohler JA (1990) Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis. J Rheumatol 17:1628–1635PubMedGoogle Scholar
Schnabel A, Herlyn K, Burchardi C, Reinhold-Keller E, Gross WL (1996) Long-term tolerability of methotrexate at doses exceeding 15 mg per week in rheumatoid arthritis. Rheumatol Int 15:195–200CrossRefPubMedGoogle Scholar
Wolfe F, Caplan L, Michaud K (2006) Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum 54:628–634CrossRefPubMedGoogle Scholar
Antonelli MA, Moreland LW, Brick JE (1991) Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Am J Med 90:295–298PubMedGoogle Scholar
Mok MY, Ng WL, Yuen MF, Wong RW, Lau CS (2000) Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 18:363–368PubMedGoogle Scholar
Nissen MJ, Fontanges E, Allam Y, Zoulim F, Trépo C, Miossec P (2005) Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon. Rheumatology 44:1016–1020CrossRefPubMedGoogle Scholar
Kujawska A, Clements M, Wise CM, Roberts WN (2003) Hepatitis C and methotrexate. Arthritis Rheum 15:843–845CrossRefGoogle Scholar
Iikuni N, Kitahama M, Ohta S, Okamoto H, Kamatani N, Nishinarita M (2006) Evaluation of Pneumocystis pneumonia infection risk factors in patients with connective tissue disease. Mod Rheumatol 16:282–288CrossRefPubMedGoogle Scholar
Perhala RS, Wilke WS, Clough JD, Segal AM (1991) Local infectious complications following large joint replacement in rheumatoid arthritis patients treated with methotrexate versus those not treated with methotrexate. Arthritis Rheum 34:146–152CrossRefPubMedGoogle Scholar
Jain A, Witbreuk M, Ball C, Nanchahal J (2002) Influence of steroids and methotrexate on wound complications after elective rheumatoid hand and wrist surgery. J Hand Surg [Am] 27:449–455CrossRefGoogle Scholar