62 The main enzyme involved in generation of the active metabolite 6-thioguanin is thiopurine methyltransferase
(TPMT). Genetic typing of this enzyme may aid in identifying patients at risk to develop early neutropenia.63 An increased risk of cancer is a major concern in thiopurine-treated patients. In a landmark study Beaugerie et al. assessed the risk of lymphoproliferative disorders according to Inhibitors,research,lifescience,medical thiopurine exposure. The median follow-up was 35 months. The study population consisted of 5867 patients receiving thiopurines, 2809 who discontinued therapy, and 10,810 controls who never received thiopurines. A total of 23 new cases of lymphoproliferative disorder were diagnosed, of which one was a Hodgkin’s lymphoma, and 22 were non-Hodgkin lymphomas. The incidence of lymphoma was 0.90 per 1000 patient-years (95% CI 0.50–1.49) for thiopurine-treated
Inhibitors,research,lifescience,medical patients compared to 0.20 per 1000 (0.02–0.72) patient-years in those who discontinued treatment and 0.26 per 1000 (0.10–0.57) patient-years in those who had never received thiopurines (P = 0.0054). The hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received these drugs was 5.28 (2.01–13.9, P = 0.0007).64 Another risk of thiopurine HKI-272 molecular weight therapy is for young males (<35 years), Inhibitors,research,lifescience,medical who were reported to develop lymphoproliferative disorders after EBV infection in EBV-naïve patients.65 Hepatosplenic T cell lymphoma is also a risk, particularly when treatment Inhibitors,research,lifescience,medical is combined with anti-TNF agents for more than 2 years in young males.66 Another major risk is of bone-marrow suppression
Inhibitors,research,lifescience,medical which may occur already at the start of therapy in genetically susceptible hosts.63 Anti-TNF agents have revolutionized IBD therapy. Therapy with anti-TNF agents was shown to induce and maintain remission67 and was also shown to be effective for fistula closure,68,69 which is significantly superior to any other drug used for this purpose. Moreover, early treatment with anti-TNF agents TCL (top-down approach) was shown to be superior to conventional therapy for achieving long-term mucosal healing as compared to patients treated conventionally with steroids first and immunosuppressive later on (step-up approach).70 Finally, anti-TNF therapy was shown to reduce hospitalizations and surgery rates.67,71 These robust results raised the possibility of changing the natural disease course and were a main driver for the development of damage and disability measurement tools mentioned above. Recent data also demonstrated that the combination of immunosuppressive therapy with anti-TNF was superior to either agent alone.72 Optimizing anti-TNF treatment is an evolving effort.