Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease.
OBJECTIVE
The immunosuppressive properties of 6-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metabolism into active 6-thioguanine (6-TG) metabolites. Measurement of erythrocyte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (IBD).


OBJECTIVE
The purpose of the study was to establish a therapeutic index of treatment efficacy based on measurement of erythrocyte 6-TG metabolite levels, and apply it clinically to guide therapy.


METHODS
Heparinised blood was obtained from 82 adult patients with IBD on long term (more than three months) antimetabolite therapy (63 Crohn's disease; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with treatment efficacy. In 22 patients with refractory Crohn's disease despite long term azathioprine therapy, their dosage was increased by 25 mg/day at eight week intervals as needed. Serial erythrocyte 6-TG metabolite levels were measured at each clinic visit and correlated with treatment efficacy.


RESULTS
Clinical remission, as defined by a low disease index score in patients weaned off or on a low alternate day dose (<20 mg on alternate days) of corticosteroid, was achieved in 68% of patients on long term antimetabolite therapy. Treatment efficacy correlated with erythrocyte 6-TG levels greater than 250 pmol/8x10(8) red blood cells in patients with colonic and fistulising Crohn's disease (p<0.01) but not in patients with ileocolonic disease. Eighteen of 22 patients with incompletely responsive Crohn's disease achieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-688) to 303 (67-737) pmol/8x10(8) red blood cells (p<0.05). Clinical response associated well with a reduction in corticosteroid requirements. Mean (SEM) white blood cell count decreased from 8.6 (0.9) to 6.9 (0.6) x10(3)/microl with adjustment in azathioprine dosage. No patient incurred azathioprine induced leucopenia.


CONCLUSIONS
Measurement of erythrocyte 6-TG metabolite levels is helpful in determining the adequacy of azathioprine dosage and can be used to optimise the dose of antimetabolite therapy to achieve an improved clinical response without inducing leucopenia. Patients who are clinically refractory to azathioprine therapy despite achieving high erythrocyte 6-TG levels (>250) should be considered for adjunct or alternative forms of immunosuppressive therapy or surgery.
Cuffari
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C
Division of Gastroenterology, Department of Paediatrics, The Johns Hopkins Hospital, Baltimore, MD 21287, USA. ccuffari@jhmi.edu
Hunt
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S
Bayless
T
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012074:Remission Induction; D013866:Thioguanine / Q000097:blood*; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D013866:Thioguanine; D001379:Azathioprine