Letter: metabolite monitoring for thiopurines in Crohn's disease – still not fully understood

Abstract

We read with great interest the study by Dassopoulos et al. comparing individualised vs. weight-based dosing of azathioprine in Crohn's disease.1 Publication of such negative results is welcome, as it avoids publication bias and provides independent data. Great interest has been focused on the metabolism of thiopurines, related to a supposed capability to predict, monitor, individualise and optimise azathioprine treatment as it represents a pharmacogenetic model that seems to be a matter of therapeutic intervention. However, we are still far from fully understanding the metabolism of thiopurines, and this randomised trial is another example of that. The observed results cannot be fully explained by current knowledge. Surprisingly, and despite very different azathioprine doses, both groups (individualised and weight-based) achieved similar 6-tioguanine-nucleotide (6TGN) levels. Regardless of that, the proportion of patients who achieved clinical remission in each arm was different, although this was not statistically significant. As 6TGN levels were similar in both groups, it is difficult to understand whether these differences, if true, could be related to the azathioprine dose adjustments based on 6TGN levels. The authors, however, found a trend favouring the individualised strategy. Some important limitations of the study, pointed out by the authors themselves, should also question this finding.1 Despite this, the trial confirms the results of a prior meta-analysis showing a relationship between 6TGN levels and clinical remission.2, 3 Previous attempts to develop a tailored thiopurine treatment were also unsuccessful. Reinshagen et al. failed to demonstrate the usefulness of 6TGN-adapted azathioprine therapy.4 A Spanish study, including 113 steroid-refractory patients whose 6TGN blood levels were periodically determined during 6 months of follow-up after steroid withdrawal, also failed to identify therapeutic threshold levels of 6TGN.5 Systematic determinations of thiopurine methyltransferase or 6TGN levels are expensive and not always available. Strong evidence of their usefulness is still needed before recommending such an individualised approach. Declaration of personal and funding interests: None.