December 2017. Volume 13. Number 4

Biologics, thiopurines and risk of malignancy development: is it time to change our clinical practice?

 
 
 
 
 
 
 
 
 
 
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Author: Navas López VM1.
1Unidad de Gastroenterología y Nutrición Infantil. Hospital Materno-Infantil. Málaga. España.
Correspondence: Víctor Manuel Navas López. Email: victor.navas@gmail.com
Publication date: 18/10/2017

CA | Associated comment

Author: Navas López VM1.
1Unidad de Gastroenterología y Nutrición Infantil. Hospital Materno-Infantil. Málaga. España.
Correspondence: Víctor Manuel Navas López. Email: victor.navas@gmail.com
Publication date: 18/10/2017

The incidence of inflammatory bowel disease (IBD) has increased in recent decades in both adults and children. In the paediatric population, this increase has been marked and significant in children aged less than 10 years, who are characterised by presenting with more aggressive and extensive forms and a longer duration of disease. The goals of treatment in paediatric IBD are control of inflammation, mucosal healing, disease modification, prevention of adverse effects of treatment, and guaranteeing adequate growth and development.

The identification of factors predictive of a poor outcome at the time of diagnosis has become a priority of the initial evaluation of the patient.1 The addition of biologic agents to the therapeutic armamentarium of paediatric IBD has contributed to the modification of the course of disease and an improved prognosis in these patients. The recently published results of a multicentre study with early introduction (within 90 days from diagnosis) of anti-tumour necrosis factor (anti-TNF) showed that this was associated with a decreased incidence of fistulising complications in the subsequent 3 years of followup.2 A widespread approach is combination therapy with anti-TNF and azathioprine, which aims at improving remission rates and decreasing the formation of anti-TNF antibodies and the subsequent loss of response due to the immunogenicity of these components, especially in chimeric preparations.3

Before starting treatment, the benefits and risks of this therapeutic modality must be explained to the patient and the family, with particular emphasis on individual risk based on the characteristics of the patient. The potential consequences of not initiating the proposed treatment must also be explained.  The overall risk of developing malignant disease in patients with inflammatory bowel disease that can be attributed to the prescribed medication is low, although there is evidence of increased susceptibility in specific patient subsets.4 The article subject of this commentary concludes, within the methodological limitations already stated by the authors themselves as well as the reviewers, that exposure to infliximab is not associated with an increased risk of malignancy or haemophagocytic lymphohistiocytosis in children with inflammatory bowel disease, although such an association was found for thiopurines. These results do not support the current trend in some countries of not prescribing thiopurines in these patients, although it seems that the appropriateness of their use should be considered in patients without primary Epstein-Barr virus infection.1 Table 1 presents the types of lymphoma that may develop during treatment with thiopurines, their risk factors and possible preventive measures. 4,5

Table Risk factors for lymphoma and haemophagocytic lymphohistiocytosis during thiopurine treatment4,5.Show/hide

The chief conclusions are:

  1. The overall risk of malignant complications in children with inflammatory bowel disease receiving thiopurines ± anti-TNF is low.
  2. The use of thiopurines in patients without primary infection by Epstein-Barr virus has been associated with an increased risk of developing haemophagocytic lymphohistiocytosis, while no such case has been observed in patients treated with methotrexate, so the latter may be a valid and safe alternative in this subset of patients.
  3. Combined treatment must be used for the shortest possible time, and only in clinical situations in which it has been proven to be efficacious.
  4. These patients must be monitored closely for the early detection of these complications.
  5. Patients at risk of developing complications within the next few months must be identified for the early initiation of anti-TNF therapy.
  6. The risks and benefits of treatments must be explained in detail to the patient and his or her family.

References

  1. Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, et al. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn’s disease. J Crohns Colitis. 2014;8:1179-207.
  2. Kugathasan S, Denson LA, Walters TD, Kim M-O, Marigorta UM, Schirmer M, et al. Prediction of complicated disease course for children newly diagnosed with Crohn’s disease: a multicentre inception cohort study. Lancet. 2017;10080:1710-8.
  3. Cozijnsen MA, Escher JC, Griffiths A, Turner D, de Ridder L. Benefits and risks of combining anti-tumor necrosis factor with immunomodulator therapy in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:951–61.
  4. 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.
  5. Beaugerie L. Lymphoma: the bête noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterology. 2013;145:927-30.

How to cite this article

Navas López VM. Biologics, thiopurines and risk of malignancy development: is it time to change our clinical practice? Evid Pediatr. 2017;13:60.


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