AB0464 Azathioprione metabolites in connective tissue disease
Authors: P Pentony, TY-E Tsai
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Azathioprine (AZA) is a common treatment for connective tissue diseases (CTD). AZA is a pro-drug which is metabolised to active moieties of 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP). These metabolites, rather than the absolute dose of AZA, are associated with clinical efficacy and toxicity. An idiosyncratic skewed metabolism towards 6-MMP in some patients ("shunters") increases the risk of hepatotoxicity and treatment failure. Allopurinol can correct such shunts<sup>1</sup>. Therapeutic protocols using metabolite concentrations have been shown to be cost effective, improve efficacy, and decrease treatment morbidity in IBD<sup>1</sup>. Only one small study estimated a therapeutic 6-TGN level for SLE patients<sup>2</sup>. There are scant data on AZA shunters in connective tissue disease<sup>3</sup>. <h3>Objectives</h3> Explore the proportion of AZA therapeutic failure, toxicity, and shunters in CTD patients. <h3>Methods</h3> Retrospective, multicentre audit of AZA metabolite levels in CTD patients from 2012–2016. Patient demographics, treatments, disease activity and drug toxicity were also extracted. <h3>Results</h3> 61 testing episodes occurred in 34 patients whose mean age was 55 (32–79) years; predominantly female (N=26, 77%), with SLE (N=19, 56%). Active disease was present in 15/61 (25%) episodes. 20/34 (60%) patients were on HCQ + AZA. 25/34 (76%) of patients were either on no or &lt;10mg/day of prednisone. 22/61 (36%) episodes had bone marrow suppression, and 8/61 (13%) had moderate liver function derangement. 12/35 (34%) patients were AZA shunters. Based on AZA metabolite levels, patients were classified into four categories: SLE patients were over-represented in the underdosed/non-compliant category (7/9). Patients in underdosed and 6-MMP shunter categories had more active disease (44% &amp; 31%), compared with appropriate and overdosed (17% and 19% p=0.24). Surprisingly, patients who were overdosed by 6TGN levels had the lowest mean AZA dose. 6-MMP shunters had significantly lower median 6TGN levels (147pmol/8x10<sup>8</sup> RBC), yet toxic MMP levels (9630pmol/8x10<sup>8</sup> RBC) that was associated with worst LFT derangement prevalence (4/13, 31% vs &lt;13%, p=0.16). <h3>Conclusions</h3> AZA dose is poorly predictive of 6-TGN and 6-MMP levels. Overall, one third of CTD patients were shunters, with lower 6-TGN levels and more hepatotoxicity. Only 40% of test episodes were appropriately dosed. Patients with low disease activity are more likely to have adequate 6TGN levels, however, 40% of patients with CTD won9t have adequate disease control despite therapeutic 6-TGN levels. AZA metabolites can identify the multiple causes for therapeutic failure (under dosing, shunter, or true non-response), and enable early detection of shunters to avoid liver toxicity. <h3>References</h3> Croyle, L., &amp; Morand, E. F. (2015). Optimizing the use of existing therapies in lupus. Int J Rheum Dis 18(2), 129–37. Askanase, AD et al (2009). Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus. J Rheum, 36(1), 89–95. Haines, ML et al (2011). Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflam Bowel Dis, 17(6), 1301–7. <h3>Disclosure of Interest</h3> None declared