Maarten Cozijnsen

22 Treatment side effects and risk of malignancy Anti-TNF antibodies are in use for about two decades and most adverse effects are well established. Serious side-effects include acute and delayed infusion reactions, serious infections and opportunistic infections. 8,11,12,68,69 More uncertainty remains for rare but serious adverse events. These include rare cases of malignancies and mortality. Mortality in IBD patients is primarily linked to serious infections, followed by malignancy or uncontrolled disease. 70 The risk of malignancies was thought to be increased by anti-TNF treatment, as cases of lymphoma and hepato-splenic T-cell lymphomas (HSTCLs) were being reported in CD patients treated with both anti-TNF antibodies and immunomodulators. 71,72 This was one of the reasons why, next to the increased serious infection risk, anti-TNF antibodies were only approved for therapy refractory CD patients, because of a presumed lower benefit-risk ratio in this population. 73 Recently, new evidence suggests that the risk of lymphoma seems more linked to thiopurine use (+/- in combination with anti-TNF) than anti-TNF treatment in itself. A large industry- sponsored long-term observational registry of pediatric patients with IBD (DEVELOP; NCT00606346) was initiated in 2007 to evaluate the long-term safety profile of IFX and other therapies prescribed to pediatric IBD patients. In their first publication, using data from 5766 patients with a median follow-up of 4.7 years and a total of 18 malignancy events, the authors report that they did not find an increased risk of malignancy and hemophagocytic lympho-histiocytosis (HLH) in IFX treated patients compared to a non-CD control population. Instead these risks were increased in thiopurine treated patients—with or without biologic exposure. 74 Notably, all (5) HLH cases were patients exposed to thiopurine and either a primary Epstein Barr virus infection (4/5) or a cytomegalovirus infection (1/5)–none had been exposed to anti-TNF antibodies. For malignancies, 4 out of 15 cases were thiopurine related, and without anti-TNF antibodies exposure, in the remaining 11 malignancy cases patients were exposed to both thiopurines as anti-TNF antibodies. Note that these conclusions were based on exposure defined as ‘ever exposed’, and in their discussion the authors acknowledged that, based on their data, cessation of thiopurine treatment for more than 1 year reduced the malignancy risk approaching the baseline risk. Nevertheless, infliximab alone did not significantly increase the malignancy risk, this was only the case when patients were also—previously or currently—exposed to thiopurine. This was also the conclusion of a case-control study on the risk of lymphomas, which reported an increased risk of T-cell lymphoma for combination therapy (anti-TNF treatment plus thiopurines), but not for anti- TNF treatment alone. 75 These findings imply a somewhat more favorable benefit-risk ratio of anti-TNF treatment than previously assumed, especially when given as monotherapy— without thiopurines.