Biomarkers Predictive of Response to Thiopurine Therapy in Inflammatory Bowel Disease

Abstract

The complex nature of inflammatory bowel disease (IBD) often results in treatment failure for many patients. With some patients cycling through multiple therapies before achieving a sustained period of remission, the ability to predict a patient's response to therapeutics could decrease the time from active disease to clinical remission and mucosal healing. The prospect of such individualized treatment of IBD would be aided by accurate biomarkers, both fecal and serological, which have to date shown value as indicators of IBD activity. Here we review the utility of generic biomarkers for inflammation or mucosal healing, such as calprotectin, C-reactive protein (CRP), and fecal hemoglobin (fHb) as predictors of response to treatment of IBD. We further provide a deeper insight into the utility of monitoring the thiopurine treatment by thiopurine metabolites or alternative hematologic parameters. In light of multiple recent publications of biomarkers and biological therapy, our focus in this review is predicting response to thiopurine treatment only, that is, Azathioprine and 6-Mercaptopurine.

Keywords: 6-mercaptopurine; Crohn's disease; azathioprine; intestinal inflammation; outcome; predictors; thiopurine; ulcerative colitis.

Figure 1

Simplified metabolism of thiopurines and modes of action according to (–21). As a prodrug, AZA is converted to 6-MP upon reaching the systemic circulation. Following the uptake by transporter molecules, 6-MP is metabolized by three competing pathways either in the liver or gut resulting in immunosuppressive effects. Importantly, 6-TGNs serve as the active metabolites of thiopurine therapy, incorporating into lymphocyte DNA and thereby inducing apoptosis of activated T-lymphocytes as well as exerting direct cytotoxic effects at higher doses. In addition, 6-TGTP inhibits the activity of the GTPase Rac1 resulting in suppression of T cell-dependent immune response. The thiopurine metabolites 6-MeMP and MeTIMP inhibit the enzyme PPAT which catalyzes the first step of de novo purine synthesis; resulting in inhibition of DNA synthesis and cell proliferation along with cytotoxic effects. AZA, Azathioprine; 6-MP, 6-mercaptopurine; TPMT, thiopurine S-methyltransferase; TUA, thiouric acid; HPRT, hypoxanthine phosphoribosyltransferase; MeMP, methylmercaptopurine; TIMP, thioinosine monophosphate; TGNs, thioguanine nucleotides; XO, xanthine oxidase; AO, aldehyde oxidase; TGMP, guanosine monophosphate; TGDP, guanosine diphosphate; TGTP, guanosine triphosphate, NUDT15, nudix hydrolase 15; PPAT, phosphoribosyl pyrophosphate aminotransferase; Rac1, Rac family small GTPase 1. ^*Associated with variability in tolerance to thiopurines. ^#XO inhibitor allopurinol, applied to induce a switch toward 6-TGN production in patients who do not adequately respond to thiopurine treatment.

Figure 2

Prediction of treatment responses in inflammatory bowel diseases. An outline of disease activity, from preclinical symptoms through to remission as indicated by a clinical manifestation threshold. At a predefined stage of the induction therapy (e.g., after 1–3 months according to the treat to target strategy), biomarkers, such as C-reactive protein (CRP), hemoglobin (Hb), fecal hemoglobin (fHb), or neutrophile count (NC) correlate with intestinal inflammation and can predict the response to treatment. Early assessment of treatment efficacy using such surrogate markers, and in conjunction with other biochemical tests, clinical signs, and/or imaging studies, can help to adjust treatment in case of persistent inflammatory disease activity. Such an individualized approach/algorithm can help to achieve mucosal healing and thus to avoid long-term bowel damage and subsequent disability.