Genes tied to methotrexate response.

ZURICH -- The goal of individualized methotrexate therapy for psoriasis has drawn a big step closer as a consequence of a large pharmacogenetic study that identified polymorphisms in key genes in the drug's metabolic pathway that are associated with increased likelihood of favorable response or toxicity.

"Potentially, by combining screening for some of these polymorphisms in the pathway we may get a sort of pharmacogenetic index--a simple number that conveys the likelihood of efficacy or toxicity," Dr. Richard B. Warren explained at the annual meeting of the European Society for Dermatological Research.

The ability to predict a patient's likely response to methotrexate (MTX) would breathe new life into an old but still useful drug, noted Dr. Warren of the University of Manchester (England). In general, 20%-30% of psoriasis patients have moderate to severe disease. Many of these patients will require systemic therapy, and MTX will remain a first-line option for the foreseeable future. But the drug's utility has been limited until now by a less than stellar risk-benefit ratio. MTX is effective in about 60% of treated patients, while 30% develop significant toxicities. There has been no way to predict who would benefit or be harmed.

Dr. Warren presented retrospective data on 378 chronic plaque psoriasis patients treated with MTX. He and his coworkers analyzed single-nucleotide polymorphisms in enzymes coded by nine genes prominent in the MTX metabolic pathway. MTX was considered effective in a patient who achieved a psoriasis area severity index (PASI) 75 score. Patients on at least 15 mg/week for 3 months without attaining PASI 50 were considered nonresponders.

Only a single polymorphism was strongly associated with MTX efficacy. It was located on ABCC1, the efflux carrier gene, which codes for a protein serving as a pump that removes MTX from the cell. Carriage of two copies of the most common genotype of the polymorphism was associated with a 2.2-fold increased likelihood of a positive response to MTX, probably because it codes for a less active pump and consequently higher intracellular drug levels.

Three polymorphisms located elsewhere on ABCC1 were associated with MTX toxicity. The most potent of the three, known as rs246240, conferred a 2.2-fold higher risk of MTX-related adverse events and was strongly associated with GI toxicity.

BY BRUCE JANCIN

Denver Bureau