Optimizing thiopurine therapy in autoimmune hepatitis: A multicenter study on monitoring metabolite profiles and co-therapy with allopurinol.

Abstract

In autoimmune hepatitis, achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response. The relation between metabolites and treatment response was assessed in 337 individuals from 4 European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanine nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N = 146) revealed higher average 6TGN levels in those with stable CBR (260pmol/0.2mL) compared to those failing to maintain CBR (181pmol/0.2mL; p = 0.0014) or never achieving CBR (153pmol/0.2mL; p < 0.0001), with an optimal 6TGN cutoff of ≥223pmol/0.2mL (sensitivity: 76% and specificity: 78%). Only 42% exhibited 6TGN ≥223pmol/0.2mL following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%; p < 0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N = 36) raised 6TGN (168→321pmol/0.2mL; p < 0.0001) and lowered 6MMP (2125→184pmol/0.2mL; p < 0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%. Maintaining CBR in autoimmune hepatitis was associated with 6TGN ≥223pmol/0.2mL. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, comedication of allopurinol alongside low-dose thiopurines represents an efficient alternative.