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Abstract

Effect of the 34C>T variant in the AMPD1 gene on the clinical response to methotrexate in patients with rheumatoid arthritis: comment on the article by Wessels et al To the Editor:We read with interest the pharmacogenetics study by Wessels et al, in which they explored the effect of polymorphisms in genes involved in the metabolism of adenosine on the clinical response to methotrexate (MTX) in patients with rheumatoid arthritis (1). Patients carrying at least 1 allele with the 34CϾT variant in AMPD1 were more likely to have a good clinical response. This finding is relevant, because it offers the possibility to tailor antiinflammatory therapy in individual patients. Unfortunately, the authors do not speculate about the possible underlying mechanism of action.AMPD1 encodes the muscle isoform of adenosine monophospate deaminase (AMPD), which catalyzes the intracellular conversion of AMP to IMP. The 34CϾT variant encodes a truncated protein with loss of function (2). As a consequence, AMP is preferentially converted into adenosine. Endogenous adenosine has potent antiinflammatory properties. Evidence is accumulating that the antiinflammatory effects of MTX are mediated by increased adenosine receptor stimulation (3). Polyglutamated MTX inhibits the enzyme 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which will increase the intracellular AICAR concentration. Subsequently, AICAR itself inhibits AMPD and adenosine deaminase, which will increase the AMP and adenosine concentrations (3). As such, it is expected that in patients with the 34CϾT variant, the antiinflammatory potential of MTX is reduced rather than increased, because the deficient AMPD enzyme prevents further inhibition by MTX.Moreover, we would like to comment on the use of the European League Against Rheumatism (EULAR) response criteria in the study by Wessels et al, because this may have contributed to a suboptimal interpretation of the data. The authors' primary cutoff point is a Disease Activity Score (DAS) of Յ2.4 at 6 months: they considered patients with a DAS of Յ2.4 to be responders and the rest to be nonresponders. One of the secondary end points is good or moderate improvement, which they define as a decrease of Ͼ1.2 or Ͼ0.6, respectively, in the DAS. The EULAR response criteria, however, define good response as an end DAS of Յ2.4 and a decrease in the DAS of Ͼ1.2. A bad response is defined as a decrease in the DAS of Յ0.6 regardless of the end DAS or a decrease in the DAS of Ͼ0.6 to Յ1.2 if the end DAS remains Ͼ3.7 (4). The use of the EULAR criteria as postulated in the Wessels study leads to pooling of good responders, moderate responders, and nonresponders in the so-called responder group and of moderate responders and nonresponders in the so-called nonresponder group. This can lead to serious confounding.In conclusion, the association between the 34CϾT variant of AMPD1 and the increased likelihood of a good response to MTX cannot be explained with the current paradigm of the mechanism of action of MTX and may be conf...