Biological therapy in pediatric age
Graphical abstract
Introduction
Inflammatory bowel diseases (IBD) are multifactorial disorders characterized by chronic relapsing intestinal inflammation. The main subtypes of pediatric IBD are Crohn’s disease (CD), ulcerative colitis (UC), and IBD unclassified (IBDU). Approximately 25 % of IBD patients are diagnosed before the age of 18, particularly during puberty. The natural history of pediatric IBD is characterized by a more severe phenotype compared with adult IBD.
For many years corticosteroids (CS), have been the main agents for induction of remission in IBD patients with consequent serious adverse events, especially on growth and development. However, CS-free remission and reduced CS dosing are important targets of quality of care in IBD. Moreover, immunosuppressive (IM) agents such as azathioprine (AZA) and methotrexate (MTX) have been utilized for many years to maintain remission in IBD but are often associated with suboptimal efficacy and potential adverse events.
Biological therapies, especially blocking tumor necrosis factor-α (TNFα) agents, have radically changed the therapeutic approach and disease course of IBD. In particular, drugs such as infliximab (IFX) and adalimumab (ADA) have been demonstrated to be effective in inducing and maintaining CS-free remission in both adult and pediatric patients with CD and UC.
The aim of the present review is to present an update on indications, efficacy and adverse events of biological therapy in pediatric IBD.
A systematic search was carried out between December 2019 and January 2020 through Medline via PubMed to identify all articles published in English on the basis of the following keywords: “pediatric inflammatory bowel disease”, “ulcerative colitis”, “crohns disease”, “infliximab”, “adalimumab”, “ustekinumab”, “vedolizumab”, “golimumab”.
Section snippets
Infliximab
Infliximab (IFX) is a purified, recombinant DNA-derived chimeric human-mouse IgG monoclonal antibody. which has an anti-inflammatory effect due to neutralization of biological activity of TNFα; it binds with high affinity to the soluble and transmembrane forms of TNFα, preventing the binding with its receptors.
Biosimilar biological therapy
Biosimilar (BioS) is defined by the EMA as “biological medicinal product containing a version of the active substance of an already authorized original biological product”. The FDA defines BioS as a “biological product that is highly similar to the reference product with respect to safety, purity and potency”. Because of the structure of the biological molecules and trade secrets of the companies producing the original products (originators), the BioSs are very similar but not exactly identical
Combination immunosoppression
Approximately one third of pediatric patients receiving monotherapy with anti-TNFα agents lose response over time [[156], [157], [158]]. Development of neutralizing antibodies against the drug appears to be the main responsible of treatment failure to anti-TNFα [159,160].
A combination of biologic agents and IMM have been proposed to increase efficacy of biologic monotherapy. Indeed, combination therapy seems to be related to the decreased immunogenicity (i.e. preventing and/or reversing
Therapeutic drug monitoring
The use of biologics blocking TNFα have revolutionized the treatment outcomes, possibly modifying the natural history of these diseases [[197], [198], [199]]. However, lack of response (primary failure) and LOR during treatment (secondary failure) including patients requiring therapy intensification are quite common problems, involving up to 40 % and 60 % of patients respectively [200,201] and reported LOR up to 13 % annually [58,202,203]. In addition, a substantial proportion of patients need
Treatment discontinuation with anti-TNFα agents
Prior to withdrawal or reduction of any maintenance treatment for IBD, it is considered appropriate to re-evaluate disease activity using a combination of clinical, biochemical, endoscopic/histological, and/or radiological techniques, in order to evaluate the risks and benefits of stopping. It is important to take into account disease history, severity, and extent.
A systematic review conducted by Gisbert et al. [227] evaluated in 27 studies the factors associated with relapse of IBD after
Conclusions
Efficacy of anti-TNFα agents in children with IBD in particular IFX and ADA is well established and supported by RCTs and observational studies. Utilization of these agents has been rising and recently the use early in the course of disease has increased, especially in those with severe and extensive disease at onset. Physicians are gradually adopting a “step-down” approach which permits a reduction in CS exposure and a reduction of CS related AEs.
Considering the available literature on
Declaration of Competing Interest
The authors report no declarations of interest.
References (203)
- et al.
Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children
Gastroenterology
(2007) - et al.
Efficacy of infliximab in pediatric Crohn’s disease: a randomized multicenter open-label trial comparing scheduled to on demand maintenance therapy
Inflamm. Bowel Dis.
(2009) - et al.
Use of infliximab in the treatment of Crohn’s disease in children and adolescents
J. Pediatr.
(2000) - et al.
Infliximab (REMICADE) therapy in the treatment of pediatric Crohn’s disease
Am. J. Gastroenterol.
(2003) - et al.
A prospective study of the efficacy and tolerance of a chimeric antibody to tumor necrosis factors (remicade) in severe pediatric Crohn disease
J. Pediatr. Gastroenterol. Nutr.
(2003) - et al.
Mucosal healing in pediatric Crohn’s disease after anti-TNF therapy: a long-term experience at a single center
Eur. J. Gastroenterol. Hepatol.
(2014) - et al.
Predictors of response to Infliximab in children with luminal Crohn’s disease
J. Crohns Colitis
(2014) - et al.
Infliximab maintains durable response and facilitates catch-up growth in luminal pediatric Crohn’s disease
Inflamm. Bowel Dis.
(2014) - et al.
Infliximab therapy in children with concurrent perianal crohn disease: observations from REACH
J. Pediatr. Gastroenterol. Nutr.
(2009) - et al.
Predictors of response to infliximab in paediatric perianal Crohn’s disease
Aliment. Pharmacol. Ther.
(2014)
Higher postinduction infliximab serum trough levels are associated with healing of fistulizing perianal Crohn’s disease in children
Inflamm. Bowel Dis.
Infliximab in pediatric Crohn disease patients with enterovesicular fistulas
J. Pediatr. Gastroenterol. Nutr.
Recognition and treatment of genitourinary complications in paediatric Crohn’s disease using Infliximab
Acta Paediatr. Int. J. Paediatr.
Infliximab therapy in pediatric patients 7 years of age and younger
J. Pediatr. Gastroenterol. Nutr.
Causes of treatment failure in children with inflammatory bowel disease treated with infliximab: a pharmacokinetic study
J. Pediatr. Gastroenterol. Nutr.
Induction and maintenance therapy with infliximab for children with moderate to severe ulcerative colitis
Clin. Gastroenterol. Hepatol.
Acute severe ulcerative colitis in children: a systematic review
Inflamm. Bowel Dis.
Outcome following infliximab therapy in children with ulcerative colitis
Am. J. Gastroenterol.
Infliximab efficacy in pediatric ulcerative colitis
Inflamm. Bowel Dis.
Infliximab in pediatric ulcerative colitis: two-year follow-up
J. Pediatr. Gastroenterol. Nutr.
Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response
Gastroenterology
Severe attack of ulcerative colitis in children: retrospective clinical survey
Dig. Liver Dis.
Managing paediatric acute severe ulcerative colitis according to the 2011 ECCO-ESPGHAN guidelines: efficacy of infliximab as a rescue therapy
Dig. Liver Dis.
Contemporary outcomes for ulcerative colitis inpatients admitted to pediatric hospitals in the United Kingdom
Inflamm. Bowel Dis.
The availability of calcineurin inhibitors and infliximab in acute severe colitis have reduced colectomy rates in 283 children admitted during 1990-2012
J. Pediatr. Gastroenterol. Nutr.
Induction & maintenance infliximab therapy in children with moderate to severe ulcerative colitis: retrospective, multicenter study
Adv. Clin. Exp. Med.
Review article: dose optimisation of infliximab for acute severe ulcerative colitis
Aliment. Pharmacol. Ther.
Fecal infliximab loss
Gastroenterology
Review article: applying pharmacokinetics to optimise dosing of anti-TNF biologics in acute severe ulcerative colitis
Aliment. Pharmacol. Ther.
Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis
Aliment. Pharmacol. Ther.
The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study
Gut
Loss of infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis
Gastroenterology
An accelerated infliximab induction regimen reduces the need for early colectomy in patients with acute severe ulcerative colitis
Clin. Gastroenterol. Hepatol.
Accelerated infliximab dosing increases 30-day colectomy in hospitalized ulcerative colitis patients: a propensity score analysis
Inflamm. Bowel Dis.
Predicting response after infliximab salvage in acute severe ulcerative colitis
J. Gastroenterol. Hepatol.
Intensified infliximab induction is associated with improved response and decreased colectomy in steroid-refractory paediatric ulcerative colitis
J. Crohn’s Colitis
Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease
N. Engl. J. Med.
Human antichimeric antibody in children and young adults with inflammatory bowel disease receiving infliximab
J. Pediatr. Gastroenterol. Nutr.
Clinical and biological consequences of immunization to infliximab in pediatric Crohn’s disease
Clin. Immunol.
Premedication and infusion reactions with infliximab: results from a pediatric inflammatory bowel disease consortium
Inflamm. Bowel Dis.
Prevention of acute adverse events related to infliximab infusions in pediatric patients
Arthritis Care Res. (Hoboken)
Severe adverse reactions to infliximab therapy are common in young children with inflammatory bowel disease
Acta Paediatr. Int. J. Paediatr.
Prevention of infusion reactions to infliximab in paediatric patients with oral acetylsalicylic acid
Clin. Exp. Rheumatol.
Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model
Aliment. Pharmacol. Ther.
Antitumor necrosis factor treatment for pediatric inflammatory bowel disease
Inflamm. Bowel Dis.
European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease
J. Crohns Colitis
Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update
J. Pediatr. Gastroenterol. Nutr.
T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-α) inhibitors: results of the REFURBISH study
Am. J. Gastroenterol.
Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial
Gastroenterology
Efficacy and safety of adalimumab after infliximab failure in pediatric Crohn disease
J. Pediatr. Gastroenterol. Nutr.
Cited by (8)
The novel role of glucocorticoid-induced leucine zipper as a marker of mucosal healing in inflammatory bowel diseases
2022, Pharmacological ResearchCitation Excerpt :Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD) are relapsing and remitting chronic diseases that affect the patient’s quality of life [1,2]. Clinical management is focused on the achievement of symptomatic relief by using several drug classes, including 5-aminosalicylates (5-ASA), glucocorticoids (GCs), immune suppressors (e.g methotrexate) and biological drugs, such as monoclonal antibodies against tumor necrosis factor (TNF) (e.g., infliximab and adalimumab), interleukin (IL)− 12, and IL-23 (ustekinumab), and gut-selective blockers of lymphocyte trafficking (e.g., vedolizumab) [3–5]. Both UC and CD require hospitalization and surgery within the first 10 years of disease [6].
Vedolizumab as the First-Line of Biologicals for Pediatric Patients With Ulcerative Colitis
2022, Clinical TherapeuticsCitation Excerpt :In induction studies, the therapeutic effect of VDZ was second to that of IFX, but it was the highest in maintenance studies. According to the pediatric IBD guideline,5,6 VDZ should be considered in patients with chronically active or CS-dependent UC as second-line biological therapy after failure of anti-TNF therapy; however, VDZ as the first-line biological for pediatric patients with UC may also be considered. In addition, one report suggested that biological-naive patients with UC initially treated with VDZ may be successfully treated with IFX, which allows the clinician to choose between VDZ and IFX as first-line treatment.14
Direct transition from rapid-infusion originator to rapid-infusion biosimilar tumor necrosis factor inhibitor in children with inflammatory bowel disease: A case series
2024, American Journal of Health-System PharmacyAdalimumab vs Infliximab in Pediatric Patients With Crohn’s Disease: A Propensity Score Analysis and Predictors of Treatment Escalation
2022, Clinical and Translational Gastroenterology