Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease

Background and aim-The immunosuppressive properties of B-mercaptopurine and its parent compound azathioprine are mediated by their intracellular metab olism into active B-thioguanine (6-TG) metabolites. Measurement of erythroc yte 6-TG metabolite levels has been proposed as a useful clinical tool for assessing treatment efficacy in patients with inflammatory bowel disease (I BD). Aim-The purpose of the study was to establish a therapeutic index of treatm ent efficacy based on measurement of erythrocyte 6-TG metabolite levels, an d apply it clinically to guide therapy. Methods-Heparinised blood was obtained from 82 adult patients with IBD on l ong term (more than three months) antimetabolite therapy (63 Crohn's diseas e; 19 ulcerative colitis). Erythrocyte 6-TG metabolite levels were measured using reverse phase high performance chromatography, and correlated with t reatment efficacy. In 22 patients with refractory Crohn's disease despite l ong term azathioprine therapy, their dosage was increased by 25 mg/day at e ight week intervals as needed. Serial erythrocyte 6-TG metabolite levels we re measured at each clinic visit and correlated with treatment efficacy. Results-Clinical remission, as defined by a low disease index score in pati ents weaned off or on a low alternate day dose (<20 mg on alternate days) o f corticosteroid, was achieved in 68% of patients on long term antimetaboli te therapy. Treatment efficacy correlated with erythrocyte 6-TG levels grea ter than 250 pmol/8x10(8) red blood cells in patients with colonic and fist ulising Crohn's disease (p<0.01) but not in patients with ileocolonic disea se. Eighteen of 22 patients with incompletely responsive Crohn's disease ac hieved disease remission by optimising their dose of azathioprine therapy. Median (range) erythrocyte 6-TG metabolite levels increased from 194 (67-68 8) 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)/<mu>l with adjustment in azathioprine dosage. No patient incurred azathioprine i nduced leucopenia. Conclusion-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 respons e without inducing leucopenia. Patients who are clinically refractory to az athioprine therapy despite achieving high erythrocyte 6-TG levels (>250) sh ould be considered for adjunct or alternative forms of immunosuppressive th erapy or surgery.