Su1416 Thiopurines in the Management of Crohn's Disease: Safety and Efficacy Profile in Patients With Intermediate and Normal Thiopurine Methyltransferase Activity, a Retrospective Study

Abstract

Introduction Thiopurines are important agents in the management of Crohn's Disease (CD). Thiopurine Methyltransferase (TPMT) levels may help guide initial dose of thiopurines. Aims To compare the efficacy and safety profile of thiopurines started at therapeutic versus low dose in the management of adults with CD and measured TPMT>25pmol/mg Hb/hr. Methods Adult CD patients with TPMT > 25 (including intermediate and normal metabolizers) and 1-year follow-up were included in our retrospective cohort study. Patients who were initiated on therapeutic dose (therapy group) of Azathioprine (2-2.5mg/kg) or 6-Mercatopurine (1- 1.5mg/kg) were compared to patients started at low dose with gradual increase (control group). Adverse events (AE) including gastrointestinal intolerance, myelosuppression, hepatitis, pancreatitis and others were recorded. Harvey-Bradshaw index (HBi), steroid doses, treatment failure (abscess, surgery, hospitalization, fistulizing disease, and initiation of anti- TNFalpha) and endoscopic findings were collected at baseline, 3, 6, 9 and 12 months when available. Results 134 patients were included, 85(63%) in the therapy group and 49(37%) in the control group of which 24 patients in the therapy group and 21 patients in the control group were excluded from the efficacy analysis due to lack of data (28% vs 21%, p=NS). Both groups were similar except for a marginally lower TPMT level in the control group (58 vs 61, p=0.01). AE were similar in both groups and occurred in 49% of patients. A trend for higher risk of pancreatitis in the control group was observed (2% vs 10%, p= 0.099). Increasing age significantly correlated with increasing adverse events regardless of treatment group (p=0.0002). Treatment failure occurred in 22(26%) patients in the therapy group and 12(24%) patients in the control group (p=NS). Younger age was significantly associated with treatment failure regardless of treatment group (p=0.009). Patients in therapy group had a statistically significant decrease in HBi at 3mo (p=0.034), 6mo (p=0.027) and 9mo (p=0.005) compared with baseline HBi, while this was observed only at 9mo (p=0.035) for control group. Patients in the therapy group achieved remission or maintained remission more often than the control group; respectively, 21% vs 10%, and 52% vs 40% at 3 months and 29% vs 17% and 54% vs 39% at 6 months. The therapy group had improved outcomes compared to the control group at 3mo and 6mo (Fisher's exact test p=0.076 at 3mo, p= 0.022 at 6mo). After adjusting covariates using multivariate logistic regression, this was statistically significant only at 6mo. There was no difference in remission rates at 9 or 12mo. Conclusion Adult CD patients with TPMT > 25 who received therapeutic dose thiopurine have similar rates of AE as opposed to those started on low dose. They also achieve improved clinical efficacy outcomes earlier. (Table Presented).