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.
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.
von Ahsen
Nicolas
N
Department of Clinical Chemistry, University of Göttingen, Göttingen, Germany.
Armstrong
Victor W
VW
Behrens
Christoph
C
von Tirpitz
Christian
C
Stallmach
Andreas
A
Herfarth
Hans
H
Stein
Jürgen
J
Bias
Peter
P
Adler
Guido
G
Shipkova
Maria
M
Oellerich
Michael
M
Kruis
Wolfgang
W
Reinshagen
Max
M
Schütz
Ekkehard
E
D000328:Adult; D000409:Alanine / Q000235:genetics; D001379:Azathioprine / Q000009:adverse effects* / Q000627:therapeutic use; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000172:deficiency* / Q000378:metabolism; D010352:Patient Dropouts; D011446:Prospective Studies; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000097630:Inosine Triphosphatase
D000409:Alanine; D001379:Azathioprine; D003545:Cysteine; D008780:Methyltransferases; D011755:Pyrophosphatases; D000097630:Inosine Triphosphatase; C022745:thiopurine methyltransferase