Immunogenicity of biologic agents in juvenile idiopathic arthritis: a systematic review and meta-analysis

Abstract

Objective The clinical impact of anti-drug antibodies (ADAbs) in paediatric patients with JIA remains unknown. This systematic review and meta-analysis aimed to summarize the prevalence of ADAbs in JIA studies; investigate the effect of ADAbs on treatment efficacy and adverse events; and explore the effect of immunosuppressive therapy on antibody formation. Methods PubMed, Embase and the Cochrane Library were systematically searched to identify relevant clinical trials and observational studies that reported prevalence of ADAbs. Studies were systematically reviewed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses and appropriate proportional and pairwise meta-analyses were performed. Results A total of 5183 references were screened; 28 articles, involving 26 studies and 2354 JIA patients, met eligibility criteria. Prevalence of ADAbs ranged from 0% to 82% across nine biologic agents. Overall pooled prevalence of ADAbs was 16.9% (95% CI, 9.5, 25.9). Qualitative analysis of included studies indicated that antibodies to infliximab, adalimumab, anakinra and tocilizumab were associated with treatment failure and/or hypersensitivity reactions. Concomitant MTX uniformly reduced the risk of antibody formation during adalimumab treatment (risk ratio 0.33; 95% CI 0.21, 0.52). Conclusion The association of ADAbs with treatment failure and hypersensitivity reactions indicates their clinical relevance in paediatric patients with JIA. Based on our findings, we recommend a preliminary course of action regarding immunogenicity of biologic agents in patients with JIA. Further strategies to predict, prevent, detect and manage immunogenicity could optimize treatment outcomes and personalize treatment with biologic therapies.

Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients

“…ADA formation is a well-recognized impediment to mAbbased therapies in pediatric indications, such as juvenile idiopathic arthritis (JIA) [50]. The current literature suggests no significant difference in immunogenicity between adults and pediatric populations for most investigated mAbs, including etanercept, infliximab, and tocilizumab [3].…”

Hypersensitivity Reactions to Monoclonal Antibodies in Children

“…In adults, antibodies against mAb reduces the efficacy of treatment and increases the risk of HSR, especially for infliximab [39][40][41][42]. A meta-analysis [43] on the immunogenicity of mAbs used for JIA showed that all mAbs induced antibodies: abatacept in 2.3-23.3% of cases, adalimumab 10.9-37%, anakinra 81.8%, canakinumab 3.1%, etanercept 0-21.9%, golimumab 46.8%, infliximab 36.6%, tocilizumab 0.5-7.5%, with a total pooled prevalence of 16.9%. In 4 of 20 patients treated with infliximab who had antibodies to infliximab, a possible anaphylactic reaction was observed, while none occurred in those who had lacked infliximab antibodies.…”

Biomarkers of Response to Biologic Therapy in Juvenile Idiopathic Arthritis

“…The formation of ADA is documented with all the licensed biologic treatments in JIA. However, the relation between ADA and treatment failure or adverse effects, the persistent or transient nature of ADA, as well as their prevalence in relation to treatment duration, vary across the different biologics ( Doeleman et al, 2019 ). For instance, antibodies against etanercept, abatacept and canakinumab are non-neutralizing and are not linked with loss of efficacy ( Mori et al, 2012 ; Sun et al, 2016 ; Doeleman et al, 2019 ; Verstegen et al, 2020 ).…”

“…However, the relation between ADA and treatment failure or adverse effects, the persistent or transient nature of ADA, as well as their prevalence in relation to treatment duration, vary across the different biologics ( Doeleman et al, 2019 ). For instance, antibodies against etanercept, abatacept and canakinumab are non-neutralizing and are not linked with loss of efficacy ( Mori et al, 2012 ; Sun et al, 2016 ; Doeleman et al, 2019 ; Verstegen et al, 2020 ). Similarly, despite the increased prevalence of ADA in patients treated with anakinra (82% at 12 months), the majority of patients develop non-neutralizing antibodies and do not lose treatment response ( Lovell et al, 2000 ; Ilowite et al, 2009 ).…”

“…Although the prevalence of tocilizumab ADA is low in JIA, 43% of patients with neutralizing ADA experienced treatment failure compared with 6% of JIA patients with no detectable ADA ( Brunner et al, 2015 ). Concomitant use of methotrexate has a protective role against the development of adalimumab ADA [risk ratio 0.33; 95% Confidence interval (95% CI) 0.21, 0.52] ( Doeleman et al, 2019 ). The above findings regarding adalimumab were also reported in relation to patients receiving this drug for JIA-associated uveitis ( Skrabl-Baumgartner et al, 2019 ).…”