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Re: Methotrexate, the gold standard?

Dear editor,

The editorial of colleagues Kay and Westhovens on the 3 E project about use of methotrexate makes some excellent points on the position of methotrexate in our daily practice, especially in the first 2 paragraphs.
The fact that apparently methotrexate remains the initial preferred antirheumatic drug rests on perceived efficacy, an acceptable safety profile, and maybe predominantly on low costs. Our subanalysis of the BeSt trial has shown that, when aiming at low disease activity as preferred treatment outcome, only 1/3 of patients continue to benefit from initial treatment with methotrexate in the first 2 years [1], and this proportion drops to ¼ after 5 years. The majority of the patients have to switch to or add other drugs because of lack of efficacy of MTX, not because of toxicity.

Many trials, including the BeSt trial, have shown that at the group level, initial treatment with a combination of MTX and either prednisone or a TNF-blocking agent [2-7], is superior to treatment with MTX alone.
Disease activity decreases more rapidly in the groups treated with combination therapy, which results in less radiological damage progression. Many follow up studies have shown that the toxicity of these drugs is low or manageable.

From a theoretical point of view, it may be interesting to know what length of delay, while trying out initial treatment with methotrexate monotherapy, would not result in more damage progression. For individual patients there is more at stake than that. Most have already suffered for some time from the symptoms of (developing) rheumatoid arthritis before they came to the rheumatologist’s office. The impact on their daily life, and that of their family members, is not to be underestimated. We have an obligation to our patients to try to aim at clinical improvement as early as possible, which in general is best achieved with combination therapy.
In case of a good response, we can taper to monotherapy. For some this strategy will mean temporary overtreatment. For most, it will mean the best chance on early and prolonged benefit of our initial treatment choice.

References

1. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YPM, van Zeben D, Kerstens PJSM, Gerards AH, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis 2007;66:1356-1362.

2. 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(9074):309-18.

3. Möttönen T, Hannonen P, Leirisalo-Repo M, Nissilä M, Kautiainen H, Korpela M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999;353(9164):1568-73.

4. Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al. TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. 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(9410):675-81.

5. 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(1):26-37.

6. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146(6):406-15.