Jeffrey S Hyams1, Marla C Dubinsky2, Robert N Baldassano3, Richard B Colletti4, Salvatore Cucchiara5, Johanna Escher6, William Faubion7, John Fell8, Benjamin D Gold9, Anne Griffiths10, Sibylle Koletzko11, Subra Kugathasan12, James Markowitz13, Frank M Ruemmele14, Gigi Veereman15, Harland Winter16, Nicholas Masel17, Chu Ri Shin18, Kezhen L Tang18, Meena Thayu19. 1. Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut. 2. Department of Pediatrics and Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 4. Department of Pediatrics, University of Vermont Children's Hospital, Burlington, Vermont. 5. Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome/University Hospital, Rome, Italy. 6. Department of Paediatric Gastroenterology, Erasmus Mc-Sophia Children's Hospital, Rotterdam, The Netherlands. 7. Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. 8. Department of Paediatric Gastroenterology, Chelsea and Westminster Hospital, London, United Kingdom. 9. GI Care for Kids, Children's Center for Digestive Health Care, LLC, Atlanta, Georgia. 10. Department of Paediatrics, Hospital For Sick Children, Toronto, Canada. 11. Department of Gastroenterology and Hepatology, Dr von Hauner Children's Hospital, Ludwig Maximilians University München, Munich, Germany. 12. Department of Gastroenterology & Nutrition, Emory University, Atlanta, Georgia. 13. Department of Pediatric Gastroenterology, Cohen Children's Medical Center of New York, New York. 14. Department of Pediatric Gastroenterology, Assistance-Publique, Hôpitaux de Paris (APHP), Hôpital Necker-Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France; Department of Pediatric Gastroenterology, Université Paris Descartes-Sorbonne Paris Cité, Faculté de Médecine, Paris, France. 15. Department of Pediatrics, Universitair Ziekenhuis, Vrije Uniuversiteit Brussel, Brussels, Belgium. 16. Department of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts. 17. Biostatistics, DOCS, Durham, North Carolina. 18. Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, Pennsylvania. 19. Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, Pennsylvania. Electronic address: mthayu@its.jnj.com.
Abstract
BACKGROUND AND AIMS: Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase the risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates of malignancy and HLH in pediatric patients with IBD exposed to infliximab (IFX) with patients not exposed to biologics and calculated standardized incidence ratios (SIRs). METHODS: We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from May 31, 2007 through June 30, 2016. Patients were 17 years old or younger and had Crohn's disease, ulcerative colitis, or IBD-unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% confidence intervals (CIs), using the Surveillance, Epidemiology, and End Results Program (SEER) database. RESULTS: Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurines; 10 patients with malignancy had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to IFX as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to IFX (SIR, 1.69; 95% CI, 0.46-4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59-5.56), even when patients were stratified by thiopurine exposure. CONCLUSIONS: In determination of age-, sex-, and race-adjusted SIRs using data from a large clinical study and the SEER database, we found that IFX exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.
BACKGROUND AND AIMS: Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase the risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates of malignancy and HLH in pediatric patients with IBD exposed to infliximab (IFX) with patients not exposed to biologics and calculated standardized incidence ratios (SIRs). METHODS: We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from May 31, 2007 through June 30, 2016. Patients were 17 years old or younger and had Crohn's disease, ulcerative colitis, or IBD-unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% confidence intervals (CIs), using the Surveillance, Epidemiology, and End Results Program (SEER) database. RESULTS: Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurines; 10 patients with malignancy had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to IFX as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to IFX (SIR, 1.69; 95% CI, 0.46-4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59-5.56), even when patients were stratified by thiopurine exposure. CONCLUSIONS: In determination of age-, sex-, and race-adjusted SIRs using data from a large clinical study and the SEER database, we found that IFX exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.
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