Immunological, serologic, and imaging biomarker predictors of flare in pediatric spondyloarthritis

项目摘要 在世界各地，脊柱关节炎（SpA）是青少年关节炎最常见的形式， 三分之一的病例。自从引入生物疾病修饰剂如肿瘤坏死 因子抑制剂（TNFi），非活动性疾病是脊椎关节炎（SpA）儿童的现实目标。然而，在这方面， TNFi的副作用包括感染、银屑病、脱髓鞘疾病和恶性肿瘤的风险增加。 此外，TNFi是昂贵的，并且可能不利地影响患者和护理者的生活质量和焦虑。 最近，COVID-19大流行引发了许多关于TNFi是否增加的询问 被感染的风险，以及如果被感染，是否在TNFi上增加了发病的风险。在 在没有明确答案的情况下，许多家庭的下一个问题是，“我们能停止药物治疗吗？”我们必须 解决两个关键的知识差距，为SpA儿童TNFi降级策略提供信息。一是 不清楚亚临床成像是否代表耀斑风险或是否代表良性残留活动。 目前，临床平衡存在于盆腔MRI上的亚临床炎症是否会影响治疗 因为我们不知道SpA和轴性疾病的患病率或临床表现， 这些MRI结果的相关性。第二，细胞生物标志物预测治疗后复发的作用， 青少年SpA的升级尚不清楚。先前对多关节幼年型关节炎的研究已经确定了细胞 可以区分与复发高度相关的疾病状态的人群和生物标志物。类似 尚未在青少年SpA中进行研究。我们的目的是检测免疫学，血清学 和成像生物标志物与疾病发作的风险在儿童与SpA通过利用基础设施和 母公司试验的资源，生物消除和捕获儿童的结果和耀斑频率， Juvenile SpA（JSPA）进行机械研究，以解决这些关键的知识差距。这 本申请具有2个具体目的：1）在药物治疗时测试成像生物标志物的能力， 升级以预测患有轴性关节炎的儿童的后续发作，以及2）测试细胞免疫的能力， 在所有SpA儿童中，在药物减量时使用生物标志物来预测随后的发作。的 本申请中提出的工作将直接影响临床护理，并显著增强证据基础 临床医生、家庭和患者用来决定是否降低生物制剂的剂量， 疗法

PROJECT SUMMARY Across the world, spondyloarthritis (SpA) is the most common form of juvenile arthritis, accounting for as many as one-third of all cases. Since the introduction of biologic disease modifying agents such as tumor necrosis factor inhibitors (TNFi), inactive disease is a realistic goal for children with spondyloarthritis (SpA). However, side effects of TNFi include increased risk of infection, psoriasis, demyelinating disorders, and malignancy. Additionally, TNFi are expensive and may adversely impact patient’s and caregiver’s quality of life and anxiety. Recently, the COVID-19 pandemic prompted numerous inquiries regarding whether being on a TNFi increased the risk of becoming infected, and, if infected, whether being on a TNFi increased the risk of morbidity. In the absence of definitive answers many families’ next question was, “Can we stop the medication?” We must address two critical knowledge gaps to inform strategies for TNFi de-escalation in children with SpA. First, it is unknown if subclinical imaging represents a risk for flare or whether it represents benign residual activity. Presently, clinical equipoise exists in whether subclinical inflammation on pelvic MRI should impact treatment decisions about children with SpA and axial disease because we do not know the prevalence or the clinical relevance of these MRI findings. Second, the role of cellular biomarkers to predict flare after therapy de- escalation in juvenile SpA is unknown. Prior studies in polyarticular juvenile arthritis have identified cellular populations and biomarkers that can distinguish disease states that are highly associated with relapse. Similar studies have not been done in juvenile SpA. Our objective is to test the association of immunologic, serologic and imaging biomarkers with the risk of disease flare in children with SpA by leveraging the infrastructure and resources of the parent trial, Biologic Abatement and Capturing Kids’ Outcomes and Flare Frequency in Juvenile SpA (BACK-OFF JSpA) to perform mechanistic studies to address these critical knowledge gaps. This application has 2 specific aims: 1) to test the ability of imaging biomarkers at the time of medication de- escalation to predict subsequent flare in children with axial arthritis, and 2) to test the ability of cellular biomarkers at the time of medication de-escalation to predict subsequent flare in all children with SpA. The work proposed in this application will directly impact clinical care and significantly enhance the evidence base that clinicians, families, and patients use to make decisions about whether or not to de-escalate biologic therapy.