Elsevier

Pharmacological Research

Volume 161, November 2020, 105120
Pharmacological Research

Biological therapy in pediatric age

https://doi.org/10.1016/j.phrs.2020.105120Get rights and content

Abstract

Biological therapies, especially blocking tumor necrosis factor-α (TNFα) agents have radically changed the therapeutic approach and disease course of pediatric inflammatory bowel disease (IBD). In particular, drugs such as infliximab (IFX) and adalimumab (ADA) have been demonstrated to be effective in inducing and maintaining corticosteroid-free remission in both adult and pediatric patients with Crohns Disease (CD) and Ulcerative colitis (UC). Biosimilar biological (BioS) therapy is increasingly being used in pediatric age even though most knowledge on the safety and efficacy of these agents is based on IFX in adult IBD data. Studies show high rates of clinical response and remission in both IFX naïve patients and in patients switched from originator to BioS with similar risks of adverse events (AEs) as those reported with IFX originator. In the present review indications, efficacy and AEs of biological therapy in pediatric IBD will be discussed, as well as the role of other biological agents such as Golimumab, Vedolizumab and Ustekinumab, the role of BioS biological therapy and utility of therapeutic drug monitoring in clinical practice.

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.

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