current study since few of the included articles provided information on short-term side effects of the different MTX dosages. Earlier studies have suggested that higher MTX doses are associated with more (subjective) side effects, even though side effects appear to be less common when MTX is combined with glucocorticoids or bDMARDs [40, 41]. Only one study included in this review made a direct comparison between two MTX dosages in combination with a glucocorticoid[42]; therefore indirect comparisons between treatment groups of different studies had to be made, which have a higher risk of bias than direct treatment comparisons[43]. We have tried to reduce possible bias by adjusting for baseline disease activity and time of assessment, but we have insufficient data on -for instance- symptom duration at baseline, and presence or absence of autoantibodies and radiologic damage. We have to make a further reservation to extrapolate results of clinical trials with selected patients to daily practice with unselected patients.
To conclude, the results of this systematic review suggest that for DMARD naive RA patients who start on MTX either as monotherapy or in combination with glucocorticoids or bDMARDs, there is little if any additional benefit to be expected from starting with a high instead of a lower dose of MTX between 3 to 6 months from start of treatment. We therefore suggest that rheumatologists may consider to start MTX at a lower dose, in particular when prescribed in combination with a bDMARD or a glucocorticoid, and increase or change therapy in the setting of a treat-to-target protocol as recommended.
Acknowledgments
We thank Jan Schoones from the Walaeus Library for his help in conducting the systematic literature search.
REFERENCES
1. Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73:492-509.
2. Singh JA, Furst DE, Bharat Aet al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken ) 2012; 64:625-39.
3. Visser K, Katchamart W, Loza Eet al. 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 2009; 68:1086-93.
4. Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009; 68:1094-9.
5. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001; 60:729-35.
6. Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 1983; 75:69-73.
7. Black RL, O’Brien WM, Vanscotte EJ, Auerbach R, Eisen AZ, Bunim JJ. Methotrexate therapy in psoriatic arthritis; double-blind study on 21 patients. JAMA 1964; 189:743-7.
8. Lard LR, Visser H, Speyer Iet al. Early versus delayed treatment in patients with recent- onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 2001; 111:446-51. 9. Goekoop-Ruiterman YP, de Vries-Bouwstra
JK, Allaart CFet 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.
10. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with
rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009; 68:1100-4. 11. Wevers-de BK, Visser K, Heimans Let
al. Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study). Ann Rheum Dis 2012; 71:1472-7.
12. Verstappen SM, Jacobs JW, van der Veen MJ 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.
13. Aletaha D, Smolen JS. Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for rheumatoid arthritis. An observational study. J Rheumatol 2002;29:1631-8.
14. Breedveld FC, Weisman MH, Kavanaugh AF 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.
15. Boers M, Verhoeven AC, Markusse HMet al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350; 309-18.
16. Bakker MF, Jacobs JW, Welsing PMet al. Low- dose prednisone inclusion in a methotrexate- based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med 2012; 156:329-39.
17. Abasolo L, Leon L, Rodriguez-Rodriguez Let al. Safety of disease-modifying antirheumatic drugs and biologic agents for rheumatoid arthritis patients in real-life conditions. Semin Arthritis Rheum 2015; 44:506-13.
18. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2009; 68:1105-12.