Objective: to compare the incidence of malignancy in patients with inflammatory bowel disease (IBD) exposed and not exposed to biologic therapy (infliximab).
Design: multicentre prospective cohort study.
Setting: 82 paediatric gastroenterology units in the United States (56) and the European Union (EU) (26).
Study population: 5766 patients managed over a period of 9 years, with a confirmed diagnosis of IBD, aged less than 17 years in the United States and between 6 and 17 years in the EU. Patients were compared with a United States population database (SEER). The planned duration of followup is 20 years.
Risk factor assessment: the study population was divided in three cohorts: 2824 patients exposed to biologic therapy (anti-tumour necrosis factor [anti-TNF] or other), 2396 exposed to infliximab (IFX) (a subset of the biologics cohort) and 2942 exposed to non-biologic agents (aminosalicylates, corticosteroids, thiopurines [TP], methotrexate or antibiotics). All study cohorts were stratified by TP or methotrexate exposure.
Outcome measurement: the authors calculated the rates of malignancy and haemophagocytic lymphohistiocytosis (HLH) per 1000 patient-years of followup for each cohort, as the quotient of the total number of malignancy events and cumulative patient-years of exposure multiplied by 1000. Results were expressed with the corresponding 95% confidence intervals (95 CI). The rates were stratified by TP or methotrexate exposure, so that single participants could contribute to more than one cohort in patient-years of followup based on the received treatments.
The authors assessed the risk relative to that of the general population by means of the standardised incidence ratio (SIR), calculated as the quotient of the number of events observed in each cohort and the expected number of events in the reference population. The SIRs and their corresponding 95 CIs were adjusted for sex, age and race.
Main results: the mean duration of followup was 4.7 years, with a total of 24 543 patient-years of followup. Fifteen tumours were detected (8 of them leukaemia/lymphoma), 10 in patients exposed to IFX (9 of who were also exposed to a TP). In all, 13 de los 15 tumours were associated with exposure to TP.
There were 5 cases of HLH, all in patients exposed to TP and none in those exposed to anti-TNF. Four were associated with primary infection by Epstein-Barr virus and one with infection by cytomegalovirus.
The unadjusted incidence rates in the cohort exposed to IFX showed no increase in the risk of malignancy (0.46/1000 patients-year) or of HLH (0/1000 patient-years) compared to patients not exposed to biologics (malignancy, 0.56/1000 patient-years, HLH 0.2/1000 patient-years).
The comparison with the reference population did not show any increase in the risk of malignancy in patients exposed to IFX (SIR: 1.69, 95 CI: 0.46 to 4.32) compared to patients not exposed to it (SIR: 2.17, 95 CI: 0.59 to 5.56), even in the analysis in which the data were stratified by TP exposure.
Conclusion: exposure to IFX is not associated with an increased risk of malignancy or HLH in children with IBD, while TP exposure is an important risk factor for the development of these complications.
Conflicts of interest: the study sponsor was involved in the study design, analysis and interpretation of results, and writing the primary manuscript.
Funding source: Janssen Scientific Affairs.