Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease

Gastroenterology. 2017 Jun;152(8):1901-1914.e3. doi: 10.1053/j.gastro.2017.02.004. Epub 2017 Feb 11.

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.

Keywords: Anti-TNF; Cancer Risk; DEVELOP Registry; Tumor Necrosis Factor Antagonist.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Age Distribution
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / therapeutic use*
  • Biological Products / adverse effects*
  • Child
  • Colitis, Ulcerative / diagnosis
  • Colitis, Ulcerative / drug therapy*
  • Colitis, Ulcerative / immunology
  • Crohn Disease / diagnosis
  • Crohn Disease / drug therapy*
  • Crohn Disease / immunology
  • Europe / epidemiology
  • Female
  • Gastrointestinal Agents / adverse effects
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Immunocompromised Host
  • Incidence
  • Infliximab / adverse effects*
  • Lymphohistiocytosis, Hemophagocytic / chemically induced
  • Lymphohistiocytosis, Hemophagocytic / diagnosis
  • Lymphohistiocytosis, Hemophagocytic / epidemiology*
  • Male
  • Neoplasms / chemically induced
  • Neoplasms / diagnosis
  • Neoplasms / epidemiology*
  • North America / epidemiology
  • Prospective Studies
  • Registries
  • Risk Assessment
  • Risk Factors
  • SEER Program
  • Sex Distribution
  • Time Factors
  • Treatment Outcome

Substances

  • Anti-Inflammatory Agents
  • Biological Products
  • Gastrointestinal Agents
  • Infliximab

Supplementary concepts

  • Pediatric Crohn's disease
  • Pediatric ulcerative colitis