Department of Paediatric Rheumatology and Immunology, University of Münster, Münster, Germany.
Department of Paediatrics, Clemenshospital GmbH Münster, Münster, Germany.
Ann Rheum Dis. 2019 Aug;78(8):1107-1113. doi: 10.1136/annrheumdis-2019-215051. Epub 2019 Apr 20.
The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases.
Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA ) or polyarticular disease (SJIA ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA , n=45; SJIA , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays.
Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA from SJIA well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA vs SJIA ) and 77% (SJIA vs infection) of all cases.
Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.
国际风湿病协会联盟分类标准将全身型幼年特发性关节炎（SJIA）定义为发热、皮疹和慢性关节炎。最近修订当前标准的举措认识到，关节炎的缺乏会使早期诊断变得复杂，而后来，一部分患者会发展为侵袭性关节疾病。SJIA 的双相模型也暗示了消除慢性关节炎发展的“机会之窗”。我们旨在确定不同疾病阶段的新型 SJIA 生物标志物。
将有活动的 SJIA 患儿根据临床特征亚组为发热的全身自身炎症性疾病（SJIA ）或多关节疾病（SJIA ）。每个 SJIA 亚组（SJIA ，n=10；SJIA ，n=10）和感染组（n=10）的患儿进行无偏液体色谱质谱联用（LC-MS/MS）和免疫测定筛选的发现队列。在一个独立的验证队列中（SJIA ，n=45；SJIA ，n=29；感染，n=32），使用多重反应监测 MS（MRM-MS）和靶向免疫测定测量候选生物标志物。
能够区分 SJIA 两种表型的特征。LC-MS/MS 在发现队列中能够很好地区分 SJIA 与 SJIA ，但与感染的区分效果较差。靶向 MRM 验证了发现数据，并且与靶向免疫测定相结合，正确地识别了所有病例的 91%（SJIA 与 SJIA ）和 77%（SJIA 与感染）。
确定了区分 SJIA 两种表型的分子特征，表明这种双相疾病中潜在免疫过程发生了转变。在初始自身炎症阶段将 SJIA 与主要鉴别诊断（即感染）区分开来的生物标志物特征可以辅助早期诊断决策，而表型转换的标志物可以为靶向治疗策略提供信息。
