title: Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, Connecticut.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Hyams
authors.affiliation: Department of Pediatrics and Medicine, The Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Baldassano
authors.affiliation: Department of Pediatrics, University of Vermont Children's Hospital, Burlington, Vermont.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Colletti
authors.affiliation: Department of Pediatrics, Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome/University Hospital, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cucchiara
authors.affiliation: Department of Paediatric Gastroenterology, Erasmus Mc-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Johanna
authors.initials: J
authors.lastname: Escher
authors.affiliation: Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: William
authors.initials: W
authors.lastname: Faubion
authors.affiliation: Department of Paediatric Gastroenterology, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Fell
authors.affiliation: GI Care for Kids, Children's Center for Digestive Health Care, LLC, Atlanta, Georgia.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Gold
authors.affiliation: Department of Paediatrics, Hospital For Sick Children, Toronto, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Griffiths
authors.affiliation: Department of Gastroenterology and Hepatology, Dr von Hauner Children's Hospital, Ludwig Maximilians University München, Munich, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.affiliation: Department of Gastroenterology & Nutrition, Emory University, Atlanta, Georgia.
authors.forename: Subra
authors.initials: S
authors.lastname: Kugathasan
authors.affiliation: Department of Pediatric Gastroenterology, Cohen Children's Medical Center of New York, New York.
authors.forename: James
authors.initials: J
authors.lastname: Markowitz
authors.affiliation: 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.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Ruemmele
authors.affiliation: Department of Pediatrics, Universitair Ziekenhuis, Vrije Uniuversiteit Brussel, Brussels, Belgium.
authors.forename: Gigi
authors.initials: G
authors.lastname: Veereman
authors.affiliation: Department of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts.
authors.forename: Harland
authors.initials: H
authors.lastname: Winter
authors.affiliation: Biostatistics, DOCS, Durham, North Carolina.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Masel
authors.affiliation: Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, Pennsylvania.
authors.forename: Chu Ri
authors.initials: CR
authors.lastname: Shin
authors.affiliation: Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, Pennsylvania.
authors.forename: Kezhen L
authors.initials: KL
authors.lastname: Tang
authors.affiliation: Medical Affairs, Janssen Scientific Affairs, LLC, Horsham, Pennsylvania. Electronic address: mthayu@its.jnj.com.
authors.forename: Meena
authors.initials: M
authors.lastname: Thayu
mesh_terms: D000293:Adolescent; D017677:Age Distribution; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001688:Biological Products / Q000009:adverse effects*; D002648:Child; D003093:Colitis, Ulcerative / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D005060:Europe / Q000453:epidemiology; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D000069285:Infliximab / Q000009:adverse effects*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology*; D008297:Male; D009369:Neoplasms / Q000139:chemically induced / Q000175:diagnosis / Q000453:epidemiology*; D009656:North America / Q000453:epidemiology; D011446:Prospective Studies; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D018426:SEER Program; D017678:Sex Distribution; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D001688:Biological Products; D005765:Gastrointestinal Agents; D000069285:Infliximab
keywords: Anti-TNF; Cancer Risk; DEVELOP Registry; Tumor Necrosis Factor Antagonist