Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis

Abstract

Background: Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. Aims:To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response.Methods: English abstracts were identified in PubMed by multiple search terms. Fulllength articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. Conclusions:The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis

“…Current management strategies for autoimmune hepatitis are based mainly on administering prednisone or prednisolone alone or in combination with azathioprine [9,31,32]. The glucocorticoids and thiopurines have multiple redundant immunosuppressive mechanisms that inhibit transcription of pro-inflammatory cytokines [33,34], interrupt T cell antigen receptor (TCR) binding and signaling [35,36], decrease expression of pro-inflammatory genes [32,34,36,37], and reduce inflammatory cell migration and adhesion [38][39][40]. These broad anti-inflammatory and immunosuppressive actions alter the subsets of activated T cells in favor of those that produce anti-inflammatory cytokines, such as IL-10, and that proliferate as Tregs [41][42][43][44][45].…”