Paediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Spitalstrasse 33, CH 4031, Basel, Switzerland.
Paediatric Rheumatology, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.
Pediatr Rheumatol Online J. 2021 Mar 25;19(1):46. doi: 10.1186/s12969-021-00514-4.
Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients.
A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted.
Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.
Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.
生物制剂和 Janus 激酶（JAK）抑制剂被用于治疗成人和儿科风湿病学中的疾病。由于年龄相关的变化、疾病进程和药代动力学过程，儿科炎症性风湿病（PiRD）患者与成人风湿病患者不同。
对 2020 年 7 月之前在 Medline、clinicaltrials.gov、clinicaltrialsregister.eu 和会议摘要中进行的针对接受生物制剂和 JAK 抑制剂治疗的 PiRD 的随机临床试验（RCT）进行了系统的文献检索。如果（i）患者年龄≤20 岁，（ii）患者有预先确定的风湿病诊断，（iii）RCT 报告了预先确定的结果，则纳入 RCT。如果（i）为观察性或单臂研究，或（ii）样本量≤5 例，则排除所选研究。提取研究特征。
在筛选出的 608 篇参考文献中，有 65 篇参考文献被选中，报道了 35 项独特的 RCT。所有 35 项 RCT 均报告了疗效，其中 34 项提供了安全性结果，16 项/35 项提供了药代动力学数据。最常见的治疗方法是 TNF 抑制剂（60%）、IL-1 抑制剂（17%）和 IL-6 抑制剂（9%）。未发现巴利昔单抗、布罗达umab、certolizumab pegol、古塞库单抗、risankizumab、利妥昔单抗、sarilumab、secukinumab、tildrakizumab 或 upadacitinib 有已发表结果的 RCT。在幼年特发性关节炎（JIA）患者中进行了 25/35 项 RCT。其余 10 项 RCT 是在非 JIA 患者中进行的，包括斑块状银屑病、川崎病、系统性红斑狼疮和非感染性葡萄膜炎。在 JIA-RCT 中，对照组主要为安慰剂，同时治疗为甲氨蝶呤、非甾体抗炎药（NSAID）或皮质类固醇。非 JIA 患者主要接受 NSAID。目前正在进行临床试验，以评估 abatacept、阿达木单抗、巴利昔单抗、布罗达umab、certolizumab pegol、依那西普、古塞库单抗、英夫利昔单抗、risankizumab、secukinumab、托法替尼和 tildrakizumab 的疗效。
尽管 FDA 现代化法案和主要儿科风湿病学网络（如儿科风湿病学合作研究组（PRCSG）和儿科风湿病学国际试验组织（PRINTO））的支持导致了 PiRD 适应证的药物批准，但 PiRD 患者的 RCT 仍然有限。由于治疗反应受到年龄相关变化、药代动力学过程和疾病进程的影响，因此在 PiRD 患者中使用生物制剂和 JAK 抑制剂时，考虑到发育变化非常重要。因此，协作并进行国际 RCT 以适当评估和描述生物制剂和 JAK 抑制剂在儿科风湿病学中的疗效、安全性和药代动力学非常重要。
