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

Jeffrey S. Hyams, Marla C. Dubinsky, Robert N. Baldassano, Richard B. Colletti, Salvatore Cucchiara, Johanna Escher, William Alvis Faubion, John Fell, Benjamin D. Gold, Anne Griffiths, Sibylle Koletzko, Subra Kugathasan, James Markowitz, Frank M. Ruemmele, Gigi Veereman, Harland Winter, Nicholas Masel, Chu Ri Shin, Kezhen L. Tang, Meena Thayu

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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.

Original languageEnglish (US)
Pages (from-to)1901-1914.e3
JournalGastroenterology
Volume152
Issue number8
DOIs
StatePublished - Jun 1 2017

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Hemophagocytic Lymphohistiocytosis
Inflammatory Bowel Diseases
Pediatrics
Neoplasms
Incidence
Infliximab
SEER Program
Biological Factors
Confidence Intervals
Biological Products
Databases

Keywords

  • Anti-TNF
  • Cancer Risk
  • DEVELOP Registry
  • Tumor Necrosis Factor Antagonist

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease. / Hyams, Jeffrey S.; Dubinsky, Marla C.; Baldassano, Robert N.; Colletti, Richard B.; Cucchiara, Salvatore; Escher, Johanna; Faubion, William Alvis; Fell, John; Gold, Benjamin D.; Griffiths, Anne; Koletzko, Sibylle; Kugathasan, Subra; Markowitz, James; Ruemmele, Frank M.; Veereman, Gigi; Winter, Harland; Masel, Nicholas; Shin, Chu Ri; Tang, Kezhen L.; Thayu, Meena.

In: Gastroenterology, Vol. 152, No. 8, 01.06.2017, p. 1901-1914.e3.

Research output: Contribution to journalArticle

Hyams, JS, Dubinsky, MC, Baldassano, RN, Colletti, RB, Cucchiara, S, Escher, J, Faubion, WA, Fell, J, Gold, BD, Griffiths, A, Koletzko, S, Kugathasan, S, Markowitz, J, Ruemmele, FM, Veereman, G, Winter, H, Masel, N, Shin, CR, Tang, KL & Thayu, M 2017, 'Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease', Gastroenterology, vol. 152, no. 8, pp. 1901-1914.e3. https://doi.org/10.1053/j.gastro.2017.02.004
Hyams, Jeffrey S. ; Dubinsky, Marla C. ; Baldassano, Robert N. ; Colletti, Richard B. ; Cucchiara, Salvatore ; Escher, Johanna ; Faubion, William Alvis ; Fell, John ; Gold, Benjamin D. ; Griffiths, Anne ; Koletzko, Sibylle ; Kugathasan, Subra ; Markowitz, James ; Ruemmele, Frank M. ; Veereman, Gigi ; Winter, Harland ; Masel, Nicholas ; Shin, Chu Ri ; Tang, Kezhen L. ; Thayu, Meena. / Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease. In: Gastroenterology. 2017 ; Vol. 152, No. 8. pp. 1901-1914.e3.
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title = "Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease",
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.",
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TY - JOUR

T1 - Infliximab Is Not Associated With Increased Risk of Malignancy or Hemophagocytic Lymphohistiocytosis in Pediatric Patients With Inflammatory Bowel Disease

AU - Hyams, Jeffrey S.

AU - Dubinsky, Marla C.

AU - Baldassano, Robert N.

AU - Colletti, Richard B.

AU - Cucchiara, Salvatore

AU - Escher, Johanna

AU - Faubion, William Alvis

AU - Fell, John

AU - Gold, Benjamin D.

AU - Griffiths, Anne

AU - Koletzko, Sibylle

AU - Kugathasan, Subra

AU - Markowitz, James

AU - Ruemmele, Frank M.

AU - Veereman, Gigi

AU - Winter, Harland

AU - Masel, Nicholas

AU - Shin, Chu Ri

AU - Tang, Kezhen L.

AU - Thayu, Meena

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

KW - Anti-TNF

KW - Cancer Risk

KW - DEVELOP Registry

KW - Tumor Necrosis Factor Antagonist

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