An unprecedented confluence of events has led to insight into how methotrexate (MTX) exerts its therapeutic and toxic effects in patients receiving the low weekly doses used in rheumatic diseases. Because of the prevalence of genetic variations (single-nucleotide polymorphisms (SNPs)) in enzymes associated with the metabolism of MTX and regeneration of reduced folate, some SNPs may be associated with clinical variations in patients receiving the drug.

MTX is one of the best-studied drugs,¹ and there exists an unusually rich opportunity to explore and understand a large variety of well-described enzyme pathways, each with a variety of SNPs that may be relevant to the effects of MTX. There has recently been an interest in the association of folate pathway SNPs with the clinical effects of MTX. Observations of the clinical effects of MTX in patients with known enzyme SNPs will help clinicians derive practical insights that can help with patient management decisions. All that is needed then to determine whether certain folate enzyme pathway SNPs were associated with clinical, laboratory or toxic effects is the ability to document what these SNPs were in different populations and closely observe patients who were receiving the drug.

In this issue of Annals of the Rheumatic Diseases, Hughes et al² report on racial differences in certain SNPs of the methylene tetrahydrofolate reductase (MTHFR) enzyme, and its effect on certain side effects of MTX. Of the many enzyme systems …