Efficacy of Tumour Necrosis Factor-alpha therapy in paediatric Crohn’s disease patients with perianal lesions: a systematic review

ABSTRACT

Introduction: Anti-Tumor Necrosis Factor-alpha (TNF-α) therapy, primarily infliximab and adalimumab, are now increasingly used to induce and maintain disease remission in the pediatric perianal Crohn’s disease (CD) population, however, their optimal use has not yet been defined in the pediatric setting.

Areas covered: In accordance with a published protocol (PROSPERO no. CRD42019118838), we systematically and critically evaluated all published evidence on the efficacy and safety of anti-TNF-α in children with perianal CD, in the PubMed, MEDLINE, Embase, Cochrane and clinicalTrials.gov databases until October, 18^th, 2018. We included in our systematic review 29 articles yielding a total of 565 perianal CD patients aged between 9 months to 18 years.

Expert opinion: According to low-quality evidence from small, uncontrolled and heterogeneous descriptive studies, and very few randomized controlled trial, nearly three-fifths children with perianal CD achieved remission with anti-TNF-α treatment and in approximately 40% remission was maintained after 12 months, with practically low discontinuation rate due to serious adverse events. More than half of the patients achieved complete fistula closure. There is still a need for more robust evidence adequately assessing the efficacy and safety of anti-TNF-α therapy in pediatric perianal CD, as well as in comparison with other therapies.

KEYWORDS:

• Biologic drugs
• Crohn’s disease
• drug safety
• pediatrics
• Tumor Necrosis Factor

Article highlights

• Therapy with biologic drugs inhibiting Tumor Necrosis Factor-alpha (TNF-α), primarily infliximab and adalimumab, are now increasingly used to induce and maintain disease remission in Crohn’s disease (CD); however, the efficacy in CD with perianal lesions is still debated, especially in children and young adults. A significant number of children fail to achieve disease remission or recurrence of their fistulae despite initial success with an anti-TNF-α therapy. The management of pediatric perianal CD remains thus challenging and frequently relying on surgical resection of the diseased bowel.

• A systematic review was conducted of 29 studies (yielding a total of 565 perianal CD patients aged between 9 months to 18 years), showing that the majority of pediatric data on the efficacy and safety of anti-TNF-α agents for perianal fistulising CD treatment are of a descriptive nature: only two RCTs were identified; the remaining 28 studies were either post-hoc analysis of RCTs, retrospective or prospective observational, case series or case report, reflecting the practical situation in pediatric settings where treatment is often based on expert opinion, and whose assumed benefits are extrapolated from studies conducted in adults and from descriptive studies rather than prospective controlled trials.

• Overall, the pooled remission rates following the different follow-up time points between 2 weeks and 34 months of therapy occur in approximately 60% of patients, whereas in 55% a clinical response was observed. Infants with severe fistulising perianal CD seems to achieve remission with complete fistula closure during the induction therapy with anti-TNF-α agents. This evidence, however, has to be considered of low-quality as it emerged only from sporadic clinical case reports. Although this treatment showed promising results in the short-term, long-term studies are thus needed to confirm these initial findings

• Safety issues of long-term use of anti-TNF therapies represent a significant concern. Acute infusion reactions were the most prevalent side effects. Serious adverse events leading to drug suspension seem relatively low (serious infection was the most frequent cause of drug withdrawal).

• Combination of different medical and surgical strategies along with anti-TNF-α therapy results in better clinical outcomes and quality of life in these patients. Further well-designed, prospective trials are needed to determine how anti-TNF- α treatment can be best optimized for the management of CD with perianal lesions in young patients.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was supported by the Agenzia Italiana del Farmaco (AIFA, to EC), by the Centre of Pharmacovigilance of Regione Lombardia (MEAP project, Monitoraggio degli Eventi Avversi nelle Popolazioni a Rischio, to EC).