A 6-thioguanine nucleotide threshold level of 400 pmol/8 x 10(8) erythrocytes predicts azathioprine refractoriness in patients with inflammatory bowel disease and normal TPMT activity.
OBJECTIVE
A therapeutic level of 6-thioguanine nucleotides (6-TGN) has been reported in inflammatory bowel disease (IBD) patients under azathioprine (AZA). We investigated the threshold value of 6-TGN that may be predictive of AZA refractoriness and its impact on safety profile.


METHODS
Patients with normal thiopurine methyltransferase (TPMT) activity (7.5-14 U/mL erythrocytes), suffering from steroid-dependent or active IBD despite AZA use for at least 6 months, were prospectively included. Clinical efficacy, adverse events, and thiopurine metabolite levels were recorded at baseline, 1 month after each dose escalation, and thereafter every 3 months.


RESULTS
Fifty-five patients were included (43 with Crohn's disease, 12 with ulcerative colitis). After a mean follow-up of 12 months, 31 patients (56.3%) did not reach clinical remission despite a gradual increase in AZA dose and 6-TGN level of >400 pmol/8 x 10(8) erythrocytes, and were considered refractory to AZA (sensitivity 45%, specificity 100%). Adverse events occurred more frequently in these patients than in responders (42%vs 25%, respectively, P= 0.02). Among 55 patients, 15 cases of myelotoxicity associated with elevated levels of total methylated metabolites (14,500 pmol/8 x 10(8) erythrocytes vs 5,230 pmol/8 x 10(8) erythrocytes in patients without myelotoxicity, P= 0.03) were observed. Patients with total methylated metabolites of >11,100 pmol/8 x 10(8) erythrocytes had an increased risk of developing myelotoxicity (odds ratio [OR] 11.0, 95% confidence interval [CI] 1.1-250, P= 0.05).


CONCLUSIONS
A 6-TGN level of >400 pmol/8 x 10(8) erythrocytes in IBD patients with normal TPMT activity and steroid-dependent or active disease despite an optimal AZA regimen may predict refractoriness to this drug. Furthermore, high levels of methylated derivatives are associated with an increased risk of myelotoxicity.
Roblin
Xavier
X
Department of Gastroenterology, CHU Grenoble, Grenoble, France.
Peyrin-Biroulet
Laurent
L
Biroulet
Laurent P
LP
Phelip
Jean M
JM
Nancey
Stéphane
S
Flourie
Bernard
B
D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use*; D004351:Drug Resistance; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D011446:Prospective Studies; D013866:Thioguanine / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism*; D016896:Treatment Outcome
D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine