Natural history of azathioprine-associated lymphopenia in inflammatory bowel disease patients: a prospective observational study Ahmad Al Rifai a , Neeraj Prasad a , Elinor Shuttleworth c , Helen McBurney b , Sudeep Pushpakom b , Andrew Robinson c , William Newman b and Simon Campbell a Introduction Azathioprine (AZA) is commonly used in inflammatory bowel disease (IBD) patients. Lymphopenia is a recognized effect of this treatment, but lymphopenia-related complications in IBD patients have not been widely reported. The incidence and progression of AZA-induced lymphopenia in IBD patients is not well described. There is no consensus on its optimal management in this group. Aims and methods We assessed the incidence and progression of lymphopenia and its related complications in a cohort of IBD patients over a 14-month period in two large tertiary gastroenterology units. Analysis of prospectively collected data was performed. Results Fifty-two patients were studied prospectively with a median age of 34 years. Eighteen patients (34.6%) developed lymphopenia ( < 1.0 ¾ 10 9 /l) during the course of treatment and 10 of them had severe lymphopenia ( < 0.6 ¾ 10 9 /l). Lymphopenia lasted on average 85.4 days and spontaneously resolved in 13 patients. No lymphopenia related-complications were documented. Patients treated with steroids had a significantly higher rate of lymphopenia (83.3 vs. 44.1%, P = 0.0083). Conclusion Lymphopenia is common among IBD patients treated with AZA. However, it did not seem to be associated with a higher risk of opportunistic infections and spontaneously resolved in the majority of cases. Eur J Gastroenterol Hepatol 23:153–158  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2011, 23:153–158 Keywords: azathioprine, Crohn’s disease, glutathione-S-transferase M1, inflammatory bowel disease, leucopenia, lymphopenia, neutropenia, opportunistic infections, thiopurines, ulcerative colitis a Department of Gastroenterology, Central Manchester University Hospitals NHS Foundation Trust, b Academic Unit of Medical Genetics, University of Manchester, Manchester and c Department of Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK Correspondence to Neeraj Prasad, MBChB, Department of Gastroenterology, Central Manchester University Hospitals NHS Foundation Trust, Manchester Royal Infirmary, Oxford Road, Manchester, M13 9WL, UK Tel: +44 1942 778576; fax: +44 1942 778634; e-mail: neeraj_prasad@hotmail.com Received 30 July 2010 Accepted 29 October 2010 Introduction Immunomodulators are widely used in the treatment of inflammatory bowel disease (IBD). Thiopurines such as azathioprine (AZA) and 6-mercaptopurine are used for Crohn’s disease (CD) [1–3] and ulcerative colitis (UC) [4,5] as a steroid-sparing agent and for maintenance of remission. Despite the use of these drugs in IBD for over three decades, our understanding of the mechanisms of action remains limited, but there is evidence that they have an impact on lymphocytes. AZA and its metabolites suppress intracellular inosinic acid synthesis, which interferes with intracellular purine synthesis leading to a reduction in the number of circulating B and T lymphocytes. In addition, this results in reduced immunoglobulin production and decreases interleukin-2 secretion [6–8]. A more recently described interaction of thiopurine metabolites with the Rac1 GTP-binding protein has been shown to induce apoptosis of T lymphocytes by blocking CD28 signalling [9,10]. It is well recognized that AZA and its metabolites can cause lymphopenia in IBD patients, but there is a lack of literature on its natural history and its clinical signifi- cance. Lymphopenia is not a normal endpoint to AZA dose titration, unlike neutropenia. Patients with reduced thiopurine methyltransferase activ- ity are susceptible to bone marrow suppression because of accumulation of metabolites and to potentially fatal complications of neutropenia [11]. Lymphopenia has been shown to be more prevalent in patients with the wildtype glutathione-S-transferase (GST) gene, GST-M1 [12]. Immunosuppressive therapies are used in a variety of medi- cal conditions and earlier studies have shown an increased risk of opportunistic infections [13,14]. Population-based cohort studies of IBD patients have also suggested an increased risk of serious infection [14–17], but whether treatment with AZA confers additional risk is conten- tious. In a large series of 622 patients treated at an IBD clinic with AZA, there were only five viral infections over Original article 153 0954-691X  c 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/MEG.0b013e32834233a2 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.