Management of Anti‐drug Antibodies to Biologic Medications in Children With Inflammatory Bowel Disease

Abstract

Background: Treatment of pediatric inflammatory bowel disease (IBD) with monoclonal anti- tumor necrosis factor-alpha (TNFα) can result in immunogenicity and formation of anti-drug antibodies (ADAs). ADAs are associated with loss of clinical response and worsening disease progression. Data examining treatment interventions to overcome ADA in pediatric patients with IBD are lacking. Results: Medical records were reviewed from 234 children and adolescents with IBD treated with infliximab or adalimumab who underwent therapeutic drug monitoring (626 tests). All patients who had detectable antibodies were further analyzed. A total 58 patients (24.8%) developed ADA while being treated with infliximab or adalimumab. The incidence of antibody development was 12.9 per 100 person-years of anti-TNF treatment. Twenty-eight patients underwent dose optimization and 54% had undetectable ADA on follow-up monitoring. The mean duration of antibody suppression was 16.8 ± 10.9 months in those who were successfully suppressed with optimization. Patients who switched to a second anti-TNF medication were not more likely to develop antibodies to the second agent. Conclusions: With limited therapies for IBD and the chronicity of the disease, we advocate salvage of the current anti-TNF through dose optimization in pediatric patients with antibody level <10 U/mL.

Pharmacogenetic variants of infliximab response in young patients with inflammatory bowel disease

“…15 The production of antibodies against anti-TNFα agents is an important cause of loss of response in patients with IBD. 31 ADA production is associated with worse treatment response, due to a lower bioavailability caused by higher anti-TNFα clearance. Indeed, the generation of ADAs facilitates the opsonization and phagocytosis of anti-TNFα agents.…”

“…The proinflammatory TNFα cytokine plays an important role in the pathogenesis of IBD and it is possible that different levels of this cytokine may affect the response to therapy. Many variants in the untranslated region of the human TNFα gene have also been described and seem to alter the transcriptional process, increasing TNFα production 31 . Several studies concerning the association of TNFα rs1800629 polymorphism and response to anti‐TNFα agents in inflammatory disorders have been performed 23,28,33 .…”

“…Many variants in the untranslated region of the human TNFα gene have also been described and seem to alter the transcriptional process, increasing TNFα production. 31 Several studies concerning the association of TNFα rs1800629 polymorphism and response to anti‐TNFα agents in inflammatory disorders have been performed. 23 , 28 , 33 A meta‐analysis of nine studies concludes that rs1800629 A allele carriers respond less to TNFα inhibitors when used in the treatment of rheumatoid arthritis, probably due to higher TNFα levels.…”

Therapeutic Drug Monitoring and Outcome of Infliximab Therapy in Pediatric Onset Inflammatory Bowel Disease

“…Notably, drug antibodies may appear already during induction (18, 46) although in most cases they are detected during maintenance at the time of secondary loss of response (32). In the single-center report by Cohen and coauthors, drug antibodies with a detection limit of 3.1 U/mL for infliximab were present in one fourth of the anti-TNFα treated patients (47). They concluded that therapy optimization rather than switching to another therapeutic agent is advisable with antibody level < 10 U/mL.…”

Biomarkers for Optimization and Personalization of Anti-TNFs in Pediatric Inflammatory Bowel Disease

“…ADAs bind to the anti-TNF drug, thus reducing free functional drug levels, neutralizing the therapeutic effect, and resulting in a loss of response [64]. ADA levels inversely correlate with drug levels and treatment response in adults [45,65], as well as in children [66][67][68][69].…”