Received on July 5, 2005
Accepted on September 13, 2005

Drug Monitoring and Toxicology

Association of Inosine Triphosphatase 94C>A and Thiopurine S-Methyltransferase Deficiency with Adverse Events and Study Drop-Outs under Azathioprine Therapy in a Prospective Crohn Disease Study

¹ Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany
² Clinical Research & Development, Merckle GmbH, Ulm, Germany
³ Department of Medicine I, University of Ulm, Ulm, Germany
⁴ Department of Internal Medicine II, Saarland University, Homburg, Germany
⁵ Department of Medicine I, University of Regensburg, Regensburg, Germany
⁶ Department of Medicine I, ZAFES, University of Frankfurt, Frankfurt, Germany
⁷ Institute for Clinical Chemistry and Laboratory Medicine, Katharinenhospital, Stuttgart, Germany
⁸ Evangelisches Krankenhaus Kalk, University of Cologne, Cologne, Germany
⁹ Department of Medicine I, Klinikum Braunschweig, Brauschweig, Germany

^* To whom correspondence should be addressed. E-mail: nahsen{at}gwdg.de.

Background: Azathioprine (aza) therapy is beneficial in the treatment of inflammatory bowel disease, but 10%-30% of patients cannot tolerate aza therapy because of adverse drug reactions. Thiopurine S-methyltransferase (TPMT) deficiency predisposes to myelotoxicity, but its association with other side effects is less clear. Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance.

Methods: We analyzed data from a 6-month prospective study including 71 patients with Crohn disease undergoing first-time aza treatment with respect to aza intolerance. Patients were genotyped for common TPMT and ITPA mutations and had pretherapy TPMT activity measured.

Results: Early drop-out (within 2 weeks) from aza therapy was associated with ITPA 94C>A [P = 0.020; odds ratio (OR), 4.6; 95% confidence interval (95% CI), 1.2-17.4] and low TPMT activity [<10 nmol/(mL erythrocytes · h); P = 0.007; OR = 5.5; 95% CI, 1.6-19.2]. A high-risk group defined by ITPA 94C>A or TPMT <10 nmol/(mL erythrocytes · h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3). For only drop-outs attributable to aza-related side effects (n = 16), there was a significant association with ITPA 94C>A (P = 0.002; OR = 7.8; 95% CI, 2.1-29.1). Time-to-event analysis over the 24-week study period revealed a significant association (P = 0.031) between the time to drop-out and ITPA 94C>A mutant allele carrier status.

Conclusions: Patients with ITPA 94C>A mutations or low TPMT activity constitute a pharmacogenetic high-risk group for drop-out from aza therapy. ITPA 94C>A appears to be a promising marker indicating predisposition to aza intolerance.