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Serious Adverse Events Associated with Anti-Tumor Necrosis Factor Alpha Agents in Pediatric-Onset Inflammatory Bowel Disease and Juvenile Idiopathic Arthritis in A Real-Life Setting

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Abstract

Objectives

Anti-tumor necrosis factor alpha (anti-TNF-α) agents are generally well tolerated, yet they can be associated with serious adverse events (SAEs) in a minority of patients. We examined the incidence of SAEs in a pediatric referral center for chronic rheumatologic and gastroenterological inflammatory disorders.

Methods

Retrospective analysis of SAEs occurring during treatment with anti-TNF-α agents in patients with juvenile idiopathic arthritis (JIA) (n = 78)  or pediatric-onset inflammatory bowel disease (IBD) (n = 105) seen at the Institute for Maternal and Child Health IRCCS “Burlo Garofolo” in Trieste, Italy, between June 2001 and February 2016. Only SAEs grade 3–5 according to the Common Terminology Criteria for Adverse Events version 4.03 and/or requiring definitive therapy discontinuation were reported.

Results

Total anti-TNF-α exposure was 390.5 patient-years (PYs). The overall incidence rate of SAEs for etanercept was 4.14/100 PYs. Four patients developed uveitis, two had anxiety disorders, one had a serious zoster infection, and one developed TNF-α antagonist–induced lupus-like syndrome (TAILS). The overall incidence rate of SAEs for infliximab was 22.49/100 PYs. The most common SAEs were anaphylactoid reactions (n = 18), followed by infectious events (n = 9) and TAILS (n = 3). The overall incidence rate of SAEs for adalimumab was 4.71/100 PYs (two infectious SAEs). No malignancies or deaths were observed. A greater incidence rate of infectious SAEs was observed in IBD patients receiving infliximab compared to JIA patients receiving etanercept (8.11 vs 0.52 per 100 PYs).

Conclusions

Anti-TNF-α therapy was generally well tolerated. SAEs leading to anti-TNF-α discontinuation were rare and non-fatal. Infliximab was associated with the highest incidence of SAEs. Infectious SAEs were more frequently observed in IBD patients treated with infliximab than in JIA patients receiving etanercept.

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References

  1. Zak M, Pedersen FK. Juvenile chronic arthritis into adulthood: a long-term follow-up study. Rheumatology (Oxford). 2000;39:198–204.

    Article  CAS  Google Scholar 

  2. Jakobsen C, Bartek J, Wewer V, Vind I, Munkholm P, Groen R, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease–a population-based study. Aliment Pharmacol Ther. 2011;34:1217–24.

    Article  CAS  PubMed  Google Scholar 

  3. Hyams J, Crandall W, Kugathasan S, Griffiths A, Olson A, Johanns J, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children. Gastroenterology. 2007;132:863–73.

    Article  CAS  PubMed  Google Scholar 

  4. Klotsche J, Minden K, Thon A, Ganser G, Urban A, Horneff G. Improvement in health-related quality of life for children with juvenile idiopathic arthritis after start of treatment with etanercept. Arthritis Care Res (Hoboken). 2014;66:253–62.

    Article  CAS  Google Scholar 

  5. Toussi SS, Pan N, Walters HM, Walsh TJ. Infections in children and adolescents with juvenile idiopathic arthritis and inflammatory bowel disease treated with tumor necrosis factor-inhibitors: systematic review of the literature. Clin Infect Dis. 2013;57:1318–30.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A. Tumor necrosis factor alpha blockers and malignancy in children: forty-eight cases reported to the Food and Drug Administration. Arthritis Rheum. 2010;62:2517–24.

    Article  PubMed  Google Scholar 

  7. Swart JF, de Roock S, Wulffraat NM. What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis? Arthritis Res. Ther. 2013;15:15.

    Article  Google Scholar 

  8. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) v4.03 [Internet]. Bethesda, MD. 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed 31 aug 2017

  9. Lepore L, Marchetti F, Facchini S, Leone V, Ventura A. Drug-induced systemic lupus erythematosus associated with etanercept therapy in a child with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2003;21:276–7.

    CAS  PubMed  Google Scholar 

  10. Pastore S, Londero M, Gortani G, Abate MV, Marchetti F, Di Leo G, et al. Infliximab-related vasculitis in patients affected by ulcerative colitis. J Pediatr Gastroenterol Nutr. 2010;51:226–8.

    Article  PubMed  Google Scholar 

  11. Horneff G, Schmeling H, Biedermann T, Foeldvari I, Ganser G, Girschick HJ, et al. The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis. 2004;63:1638–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gerloni V, Pontikaki I, Gattinara M, Fantini F. Focus on adverse events of tumour necrosis factor alpha blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann Rheum Dis. 2008;67:1145–52.

    Article  CAS  PubMed  Google Scholar 

  13. Prince FHM, Twilt M, Cate RT, van Rossum MAJ, Armbrust W, Hoppenreijs EPAH, et al. Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis. 2009;68:635–41.

    Article  CAS  PubMed  Google Scholar 

  14. Schmeling H, Minden K, Foeldvari I, Ganser G, Hospach T, Horneff G. Efficacy and safety of adalimumab as the first and second biologic agent in juvenile idiopathic arthritis: the German Biologics JIA Registry. Arthritis Rheumatol. 2014;66:2580–9.

    Article  CAS  PubMed  Google Scholar 

  15. Tarkiainen M, Tynjälä P, Vähäsalo P, Lahdenne P. Occurrence of adverse events in patients with JIA receiving biologic agents: long-term follow-up in a real-life setting. Rheumatology (Oxford). 2015;54:1170–6.

    Article  CAS  Google Scholar 

  16. Windschall D, Müller T, Becker I, Horneff G. Safety and efficacy of etanercept in children with the JIA categories extended oligoarthritis, enthesitis-related arthritis and psoriasis arthritis. Clin Rheumatol. 2015;34:61–9.

    Article  CAS  PubMed  Google Scholar 

  17. Klotsche J, Niewerth M, Haas J-P, Huppertz H-I, Zink A, Horneff G, et al. Long-term safety of etanercept and adalimumab compared to methotrexate in patients with juvenile idiopathic arthritis (JIA). Ann Rheum Dis. 2016;75:855–61.

    Article  CAS  PubMed  Google Scholar 

  18. Verazza S, Davì S, Consolaro A, Bovis F, Insalaco A, Magni-Manzoni S, et al. Disease status, reasons for discontinuation and adverse events in 1038 Italian children with juvenile idiopathic arthritis treated with etanercept. Pediatr Rheumatol Pediatric Rheumatol. 2016;14:68.

    Article  Google Scholar 

  19. Baldassano R, Colletti R, Cucchiara S, Dubinsky M, Escher J, Faubion W, et al. 15 Serious infections and associated risk factors in patients receiving infliximab and immunotherapies for children with inflammatory bowel disease: DEVELOP registry data. J Crohn’s Colitis. 2013;7:S7–8.

    Article  Google Scholar 

  20. Colletti R, Cucchiara S, Dubinsky M, Escher J, Faubion W, Fell J, et al. P436 Malignancies in children receiving infliximab and other inflammatory bowel disease therapies: an inflammatory bowel disease multicenter, prospective, long-term registry of pediatric patients (DEVELOP) registry data. J Crohn’s Colitis. 2013;7:S184–5.

    Article  Google Scholar 

  21. Vahabnezhad E, Rabizadeh S, Dubinsky MC. A 10-year, single tertiary care center experience on the durability of infliximab in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:606–13.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cameron FL, Wilson ML, Basheer N, Jamison A, McGrogan P, Bisset WM, et al. Anti-TNF therapy for paediatric IBD: the Scottish national experience. Arch Dis Child. 2015;100:399–405.

    Article  CAS  PubMed  Google Scholar 

  23. Hyams JS, Dubinsky MC, Baldassano RN, Colletti RB, Cucchiara S, Escher J, et al. Infliximab is not associated with increased risk of malignancy or hemophagocytic lymphohistiocytosis in pediatric patients with inflammatory bowel disease. Gastroenterology. 2017;152(1901–1914):e3.

    Google Scholar 

  24. Wang F, Wang N-S. Etanercept therapy-associated acute uveitis: a case report and literature review. Clin Exp Rheumatol. 2009;27:838–9.

    CAS  PubMed  Google Scholar 

  25. Horneff G. Biologic-associated infections in pediatric rheumatology. Curr Rheumatol Rep. 2015;17:66.

    Article  PubMed  Google Scholar 

  26. Dulai PS, Thompson KD, Blunt HB, Dubinsky MC, Siegel CA. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol. 2014;12:1443–51.

    Article  PubMed  Google Scholar 

  27. Van den Brande JMH, Braat H, van den Brink GR, Versteeg HH, Bauer CA, Hoedemaeker I, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology. 2003;124:1774–85.

    Article  PubMed  Google Scholar 

  28. Wetter DA, Davis MDP. Lupus-like syndrome attributable to anti-tumor necrosis factor alpha therapy in 14 patients during an 8-year period at Mayo Clinic. Mayo Clin Proc. 2009;84:979–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Williams EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus. Rheumatology (Oxford). 2009;48:716–20.

    Article  CAS  Google Scholar 

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Author notes

  1. Serena Pastore and Samuele Naviglio contributed equally to this work.

Authors and Affiliations

  1. Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy

    Serena Pastore, Samuele Naviglio, Stefano Martelossi, Alessandro Ventura & Andrea Taddio

  2. University of Trieste, Via dell’Istria 65/1, 34137, Trieste, Italy

    Samuele Naviglio, Arianna Canuto, Loredana Lepore, Alessandro Ventura & Andrea Taddio

Authors
  1. Serena Pastore
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  2. Samuele Naviglio
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  3. Arianna Canuto
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  4. Loredana Lepore
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Corresponding author

Correspondence to Arianna Canuto.

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Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Serena Pastore, Samuele Naviglio, Arianna Canuto, Loredana Lepore, Stefano Martelossi, Alessandro Ventura and Andrea Taddio declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. As this is a retrospective study, formal consent is not required.

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Pastore, S., Naviglio, S., Canuto, A. et al. Serious Adverse Events Associated with Anti-Tumor Necrosis Factor Alpha Agents in Pediatric-Onset Inflammatory Bowel Disease and Juvenile Idiopathic Arthritis in A Real-Life Setting. Pediatr Drugs 20, 165–171 (2018). https://doi.org/10.1007/s40272-017-0267-8

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  • DOI: https://doi.org/10.1007/s40272-017-0267-8

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