Tuesday, January 24, 2017

Methotrexate as the Anchor Drug for Rheumatoid Arthritis

Methotrexate (MTX) had been developed in 1951, but only in 1985 MTX had been introduced into rheumatology. MTX soon became an anchor drug in the treatment of rheumatoid arthritis. Still there are other indications, in which we aren’t so sure if it is as successful as in rheumatoid arthritis. If you look at effectiveness, tolerability, and cost, you will have a hard time finding an equal drug. EULAR and ACR guidelines have MTX as first line therapy (without the need of combination – combination comes later and MTX is very useful in any combination). An article by Walter Alexander: „Methotrexate Underutilized in RA“ stimulated this blogpost.

Oral MTX is widely used, but subcutaneous MTX offers advantages. Yet even oral MTX is underutilized. J.R. O’Dell, who introduced triple combination therapy (MTX + SSZ + HCQ), and colleagues looked at different strategies using MTX (2). They concluded, that “initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy”.

How does MTX work? Good question! There are five proposed mechanisms of action: anti-inflammatory, apoptosis, cytokines, cytostatic, and immunosuppressive – please have a look at the link for details (3).
There’s a study by G.S. Hazlewood and colleagues addressing the issue of subcutaneous vs. oral MTX (4). They looked at 666 patients (417 oral MTX, 249 subcutaneous MTX) [OT: N=666 – honi soit qui mal y pense. Rev. 13:18]. They concluded: “nitial treatment with subcutaneous MTX was associated with lower rates of treatment changes, no difference in toxicity and some improvements in disease control versus oral MTX over the first year in patients with ERA [Early Rheumatoid Arthritis].”

M.H. Schiff and colleagues published a head-to-head study on oral and SC MTX (5): “Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥15 mg may be overcome with subcutaneous administration.” Their conclusions: “Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ≥15 mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX.” The article can be freely accessed, so you should have a look at the graph. But I think that SC MTX also plateaus but only at doses above 30 mg per week, which is supported by the slower ascend of the curve between 20 and 25 mg per week.

Take home messages:
·         MTX is a drug with excellent effectiveness and tolerability
·         About the mode of action quite a lot, but not all is known
·         Oral MTX works good till 15 mg per week, but has no advantage above this dosage
·         SC MTX works better and the dosage might be increased up to 25 mg per week
·         MTX is good combination partner
·         It remains unclear, why this anchor drug still is underutilized



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