Klervi Golhen (1)(*), Carolyn Winskill (2)(*), Cynthia Yeh (2), Nancy Zhang (2), Tatjana Welzel (1)(3)(*) & Marc Pfister (1)(2)(*)
(1) Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel (UKBB), University of Basel, Basel, Switzerland (2) Integrated Drug Development, Certara LP, Princeton, New Jersey, USA (3) Pediatric Rheumatology, University Children’s Hospital Basel (UKBB), University of Basel, Basel, Switzerland (*) Klervi Golhen and Carolyn Winskill have contributed equally to this work and share first authorship. (*) Tatjana Welzel and Marc Pfister have contributed equally to this work and share last authorship.
Introduction/Objectives: Pediatric inflammatory rheumatic diseases (PiRD) is an umbrella term for chronic inflammatory conditions affecting infants, children and adolescents. Juvenile idiopathic arthritis (JIA) is one of the most common pediatric inflammatory rheumatic diseases (PiRD). Uncontrolled disease activity is associated with decreased quality of life and chronic morbidity. Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus kinase (JAK) inhibitors have considerably improved clinical outcomes. For optimized patient care, understanding the efficacy-safety profile of bDMARDs and JAK inhibitors in subgroups of JIA is crucial. This exploratory meta-analysis based on published randomized controlled trials (RCTs) aims to assess efficacy and safety data of bDMARDs and JAK inhibitors in children with various JIA subgroups after three months of treatment, with the goal to facilitate risk-benefit assessment and dose optimization of bDMARDs in pediatric drug development and clinical practice.
Methods: This exploratory meta-analysis was based on RCTs previously identified in a systematic literature search, updated in February 2022 in line with the previous review protocol [1]. Aggregate (summary) level data was extracted for each included RCT. Baseline demographic and clinical characteristics such as study design (i.e., parallel or withdrawal), location, patient population, sample size, age criteria, treatment, efficacy, and safety data were captured. Data for American College of Rheumatology (ACR) pediatric (Pedi) 30, 50, and/or 70 responses after three months of treatment were selected from RCTs investigating bDMARDs or JAK inhibitors in JIA according to pre-defined inclusion/exclusion criteria. Treatment and control arms were compared by calculating risk ratios (RR) with 95% confidence intervals (CI). Incidence of overall and serious adverse events (AEs) and infections were analyzed for each bDMARD or JAK inhibitor vs control arm. Forest plots were generated to summarize treatment responses across studies, JIA subgroups and type of bDMARDs or JAK inhibitors.
Results: A total of 28 out of 41 PiRD RCTs investigated bDMARDs or JAK inhibitor treatments in JIA. Of these 28 RCTs, 23 reported Pedi ACR 30/50/70 at any time point, while 12 reported Pedi ACR 30/50/70 three months after treatment initiation. All bDMARD or JAK inhibitor arms showed improved ACR Pedi responses over controls. RR ranged from 1.05-3.73 in ACR Pedi 30, 1.20-7.90 in ACR Pedi 50, and 1.19-8.73 in ACR Pedi 70. Significant ACR Pedi 30 treatment responses were observed for tocilizumab in systemic JIA and tofacitinib in polyarticular JIA (PJIA) vs placebo. An enhanced effect for ACR Pedi 70 was observed with infliximab combined with methotrexate in PJIA vs methotrexate monotherapy. A slightly higher risk of gastrointestinal AEs and infections was observed with bDMARD or JAK inhibitor arm compared to placebo or methotrexate monotherapy. Overall, no unexpected safety outcomes were found in this analysis.
Conclusions: Investigated bDMARDs and JAK inhibitors showed superior treatment responses compared to controls after three months of treatment, more pronounced at ACR Pedi 50 and 70 versus ACR Pedi 30. Remission and minimal disease activity is associated with prevention of disease-related damage and is nowadays the target in daily clinical practice [2]. Therefore, it would be desirable that future RCTs in JIA report ACR Pedi 50, 70, 90 after 3 and 6 months. Higher susceptibility to infections associated with bDMARDs or JAK inhibitors compared to control arms should be weighed against efficacious treatment of the underlying disease and prevention of disease-related damage. Additional RCTs and pharmacometric analyses to characterize dose-exposure-response relationships are warranted to further inform development and utilization of biologics in this particularly vulnerable population of patients with JIA.
References:
[1] Welzel T, Winskill C, Zhang N, Woerner A, Pfister M. Biologic disease modifying antirheumatic drugs and Janus kinase inhibitors in paediatric rheumatology – what we know and what we do not know from randomized controlled trials. Pediatr Rheumatol Online J. 2021/03/27. 2021;19(1):46.
[2] Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, et al. Treating juvenile idiopathic arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2018/04/13. 2018;77(6):819–28.
Reference: PAGE 30 (2022) Abstr 10109 [www.page-meeting.org/?abstract=10109]
Poster: Drug/Disease Modelling - Paediatrics