Crohn's disease affects increasing numbers of children worldwide. Generally, childhood-onset disease runs a more severe course than in adults and has a greater impact on quality of life. Therapy in children must take account of a different set of risks for toxicity compared to adults, but also to their longevity. Biologic drugs present remarkable advantages in terms of disease control for children, especially in those whose disease cannot be controlled with conventional therapies, but their long-term risks are still being assessed. Data regarding biologic use in children is limited and mostly amounts to case series, but results have been promising, both in terms of controlling disease activity and improving growth parameters. Adverse reactions are infrequent in the short term, but loss of response is a long-term problem, particularly in children. More information is needed about very long term risks. Infliximab and adalimumab are the most studied agents in children, while there is relatively limited data on certolizumab and natalizumab. Further collection of data on these agents is still needed, but this should not restrict access to these agents for children in whom no other agent is effective.
The last 20 years have seen an evolution in the approach to therapy of Crohn’s disease in both children and adults. The further development of ASA-based drugs, introduction of immunomodulators, and adoption of a “top-down” approach to early disease have brought substantial therapeutic benefit. However, persisting treatment failures lead to the development of a new class of drugs—biologicals—which have been used to target specific cytokines and receptors thought to be pivotal in the perpetuation of intestinal inflammation. Although a number have been developed, only a few have proven efficacy and entered standard clinical practice. A substantial proportion of patients develop Crohn’s disease in childhood, but there are few studies of efficacy or safety of these new biologicals in this vulnerable population. The purpose of this paper is to summarise the information available on the efficacy and risks of available biologicals in childhood Crohn’s disease.
The incidence of childhood Crohn’s disease appears to be increasing globally [
Childhood-onset Crohn’s disease tends to be characterized by ileocolonic or colonic involvement at outset [
The genetics of paediatric CD has specific differences, mirroring its phenotypic distinctions. While there are many susceptibility loci common to adults and children, five new loci associated with childhood-onset disease have recently been identified through genome-wide association studies [
A growing pharmacopoeia of biologic drugs has broadened the treatment arsenal in the last fifteen years. In children, the two phases of treatment are induction and maintenance of remission. In the past, medical treatment options were limited. Induction mainstays have been corticosteroids and enteral nutrition [
Biologic drugs leverage components of the human immune system to target molecules implicated in the pathogenesis of Crohn’s [
Most trial evidence for the use of biologics comes from adults, and while there is more similarity than difference between adults and children, this literature must be interpreted with caution [
Disease activity indices used in children are different from those used in adults, adding a further layer of complexity. Since Crohn’s disease can have a substantial impact on growth, the Paediatric Crohn’s Disease Activity Index (PCDAI) includes height and weight criteria [
There is a paucity of authoritative evidence regarding the use of biologics in paediatric CD. Infliximab is the main agent used, with other biologics used mostly in the event of lost response to infliximab therapy. There are no trials comparing the relative efficacy of one biologic with another. Paediatric evidence regarding the use of biologics in the management of fistulising and postsurgical patients is scant.
Randomised controlled trial evidence regarding the use of infliximab is confined to adults. Here, infliximab has proven efficacy for induction, maintenance, and for the treatment of fistulae [
For maintenance, the REACH study also provides the best support for the use of infliximab in children [
At ten weeks, 88.4% had responded and 58.9% entered remission. At fifty-four weeks, in those receiving infliximab every eight or twelve weeks, respectively, 55.8% and 23.5% remained in remission. These data suggest that infliximab does have some efficacy in children. However, the REACH study has significant limitations, including the lack of a control group during induction, the universal use of concurrent immunomodulators, the unblinded nature of the study, randomization of participants to a dose frequency which was almost certain to be inferior, and, extensive involvement of the manufacturer in the design, data acquisition, and authorship of the study. These limitations obfuscate the true size of the treatment effect. They also add further difficulty when making comparisons with adult data. The only therapeutic property of infliximab that this study proves beyond contention is that it should be given every eight weeks for maintenance in children.
The possibility of using infliximab only in episodes of exacerbated disease was raised due to concerns about minimising exposure to biologics in children. The study by Ruemmele and colleagues confirms that scheduled doses are superior to episodic therapy in children, at least in terms of treatment effect [
Secondary loss of response to infliximab is a major limiting factor in maintenance therapy. It may require dose escalation or the cessation of infliximab therapy. Within the first year, in adults with luminal disease, approximately 30% will lose response [
There appears to be some correlation between the rates of secondary loss of response and the acquisition of antibodies to infliximab, in both adults and children [
The early and aggressive use of infliximab in selected paediatric patients is a nascent area of research. The top-down approach to therapy supposes that early disease (commonly possessing inflammatory behaviour) is the most amenable to early aggressive therapy such as with immunosuppressants or biologicals, given that infliximab, for instance, targets the inflammatory cascade [
In children, Kim and colleagues address the issue of top-down therapy with infliximab in a case series [
The key issues in top down therapy, which remain unresolved, are to reliably indentify those patients who will go on to experience complications, so warranting the risks of aggressive therapy [
Again, randomised controlled trial evidence for the efficacy of adalimumab is confined to adults. Here it has been proven effective in both the induction and maintenance of remission [
In children, limited prospective evidence comes from the study by Viola and colleagues [
There is retrospective evidence that supports the use of adalimumab in children. The RESEAT cohort reports outcomes in 115 children (mean age at diagnosis: 11 years) who had almost all previously received infliximab [
Certolizumab shows evidence of moderate efficacy in adults with CD [
Natalizumab was first developed for use in multiple sclerosis. The ENCORE trial demonstrated moderate efficacy in the induction of remission in adult Crohn’s [
Families and children with CD are often concerned about the physical and psychosocial impact of impaired growth. While growth arrest may be a central feature early in the course of disease, it appears that most children will go on to achieve an adult height that is within normal limits [
Growth failure mostly appears to be due to disease activity, with smaller nutritional and iatrogenic components [
By targeting TNF
Three retrospective studies have since provided limited, yet more compelling, evidence of infliximab’s efficacy in growth. The first describes twenty-seven children (18 male) with otherwise refractory Crohn’s who received maintenance infliximab [
Quite apart from the effect of Crohn’s disease on growth, bone health is impaired, with bone deficits being well documented in children [
The use of biologics in growth impairment warrants further investigation. There are no published data regarding the growth properties of the other anti-TNF
There are a number of toxicities that may occur in anti-TNF
Infusion reactions occur commonly with the use of infliximab and may be severe in some cases. In REACH, 17-18% of children had infusion reactions, while only one infusion reaction was severe enough to warrant cessation of infliximab [
A large number of children develop antinuclear antibodies (ANAs) after infliximab exposure [
Serious and/or opportunistic infections are unusual, but do occur. Adult studies demonstrate similar rates between placebo and treatment groups, and this is compatible with the available uncontrolled paediatric data [
As with adults [
An additional risk for infants is the biological impact of placenta-fetal passage of anti-TNF therapies. A death after vaccination from disseminated
A paradoxical dermatological effect is infliximab-induced psoriasis (IIP). IIP appears to occur in children of both sexes at a rate of 8–10% and to be primarily of the non-pustular subtypes [
Malignancy can be considered a rare occurrence with the use of biologics at this stage. Any discussion of malignancy must be prefaced with mention of the high rate of malignancy in poorly controlled CD; for example, intestinal malignancy occurs at a rate of approximately 0.8 cases/1000 person years [
There is some evidence that treatment with anti-TNF agents may increase the general risk for malignancy [
Hepatosplenic T-cell lymphoma (HSTCL) is an extremely rare but mostly fatal malignancy occurring almost exclusively in young males receiving thiopurines [
There is only one study regarding the safety of natalizumab in children [
Progressive multifocal leukoencephalopathy (PML) is associated with polyomavirus JC reactivation in patients receiving natalizumab [
Regulatory and funding arrangements constrain the use of biologicals in children. Here we consider the United States (US), European Union (EU), and Australian jurisdictions. Infliximab is the only drug with an explicit licence for use in children around the world. Adalimumab is approved for use in adults but not approved for use in children. In the United States, somewhat more permissive licensing has allowed for the use of certolizumab and natalizumab in adult CD. Approval has either been refused or not sought in the EU and Australia. Compassionate funding arrangements have permitted the off-label use of drugs other than infliximab in children.
There is a need for higher-quality evidence to inform decision making when using biologics in paediatric Crohn’s. While it may be argued that children and their families will not accept the risks involved in such research, on the contrary there is no reason to accept that treatment is currently guided by little or no rigorous evidence specific to children [