P450 Thioguanine and low dose thiopurines and allopurinol are both safe options after failure of conventional thiopurines: a comparative analysis of two multicentre cohorts

Abstract

Abstract Background Both thioguanine (TG) and low dose thiopurines and allopurinol (LDTA) can be considered for the treatment of inflammatory bowel disease (IBD) when conventional thiopurines fail due to intolerance or adverse events (AE). However, head-to-head trials are currently not available. The aim of this study was to compare the safety of TG and LDTA in IBD patients. Methods Adult IBD patients who failed conventional thiopurines and initiated LDTA in standard care were identified in the observational prospective multicentre ICC Registry. IBD patients who failed conventional thiopurines and initiated TG were retrospectively enrolled in three university hospitals. Patients with concomitant treatment with biologicals were excluded. The primary outcome was discontinuation of therapy due to AE. Secondary outcomes included: medication-related AE, infections (moderate: oral medication, severe: intravenously administrated medication), hospitalisations, and biological- and corticosteroid-free clinical remission (i.e. physician global assessment = 0) after 104 weeks of treatment. To adjust for confounding and selection bias, both multiple logistic regression and propensity score matching (PSM) were used to correct for baseline characteristics associated with disease severity or therapy refractoriness. Results In total, 182 IBD patients treated with TG (n = 94) or LDTA (n = 88) were included with a median follow-up of 104 weeks (IQR 91–104). The median dose of TG was 0.27 mg/kg (IQR 0.22–0.32), for LDTA: 100 mg allopurinol with either 0.67 mg/kg (IQR 0.54–0.75) azathioprine (n = 45) or 0.35 mg/kg (IQR 0.28–0.38) mercaptopurine (n = 41) (n = 2 unknown). By PSM, 64 TG patients were strictly matched with 64 LDTA patients with comparable baseline characteristics. In total, 19% (TG: 20%, LDTA: 18%) of patients discontinued therapy due AE. After adjusting for confounders, there were no significant differences in terms of discontinuation rate due to AE (TG: n = 19, LDTA = 16, OR 0.50 95% CI 0.15–1.68 p = 0.26), other AE (TG: n = 46, LDTA: n = 44, OR 0.89 95% CI 0.44–1.81 p = 0.75) (no cases of nodular regenerative hyperplasia of the liver were reported), infections (TG: n = 13, LDTA: n = 18, OR 1.05 95% CI 0.40–2.73 p = 0.93), hospitalisations (TG: n = 5, LDTA: n = 9, OR 2.00, 95% CI 0.64–6.23 p = 0.23), or biological- and corticosteroid-free clinical remission (OR 0.74 95% CI 0.33–1.68 p = 0.48). Escalation to biological treatment was comparable (TG 21% vs. LDTA 24% p = 0.68). All these results were in line with the PSM cohort. Conclusion A relative low percentage of patients with prior failure to conventional thiopurines discontinued therapy with TG or LDTA due to AE. Both maintenance therapies may be considered after failure of conventional thiopurines before escalating to biological therapy.