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Interpretation on the 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency, and Deficiency of the Interleukin-1 Receptor Antagonist
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摘要: 白细胞介素1(interleukin-1，IL-1)介导的自身炎症性疾病是以IL-1生成增多或通路激活为特征的一大类自身炎症性疾病，主要包括家族性地中海热、冷炎素相关周期性综合征、肿瘤坏死因子受体相关周期性综合征、甲羟戊酸激酶缺乏症以及IL-1受体抑制剂缺陷。此类疾病起病早，受累器官广泛，若未经有效治疗，可导致进行性器官损伤、多种并发症甚至死亡。2016年，欧洲抗风湿病联盟已发布针对家族性地中海热的诊疗推荐意见。为提高该类疾病的诊断能力、治疗及长期管理效果，欧洲抗风湿病联盟及美国风湿病学会于2022年共同发布了针对其他4类疾病的诊疗指南。本文将详细介绍该指南要点，以期指导临床实践。Abstract: Interleukin-1 mediated autoinflammatory diseases, a large class of autoinflammatory diseases characterized by increased release of interleukin-1 or activation of the interleukin-1 pathway, mainly include familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor associated periodic syndrome, mevalonate kinase deficiency syndrome and deficiency of the interleukin-1 receptor antagonist. These diseases present in early childhood and affect multiple systems, which, if untreated, may result in progressive organ damage, morbidity and mortality. In 2016, European Alliance of Associations for Rheumatology (EULAR) published recommendations for familial Mediterranean fever. For the latter four types of diseases, EULAR and the American College of Rheumatology developed several points in terms of diagnosis, management and monitoring in 2022. This article aims to introduce the application of these points.
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Key words:
- autoinflammatory diseases /
- diagnosis /
- treatment /
- guideline /
- children
作者贡献：周煜负责查阅文献、撰写论文；宋红梅负责指导论文修订。利益冲突：所有作者均声明不存在利益冲突 -
表 1 FDA或EMA批准用于儿童IL-1相关自身炎症性疾病的IL-1拮抗剂及其用法
疾病 药物 推荐剂量 FDA EMA CAPS 轻型 卡那单抗 2~8 mg/kg，每8周1次(最大600 mg) √ √ 利纳西普 起始剂量4.4 mg/kg，每周1次(最大320 mg) 维持剂量2.2 mg/kg，每周1次(最大160 mg) √ × 中型 阿那白滞素 1~2 mg/kg，每日1次 × √ 卡那单抗 2~8 mg/kg，每8周1次(最大600 mg) √ √ 利纳西普 起始剂量4.4 mg/kg，每周1次(最大320 mg) 维持剂量2.2 mg/kg，每周1次(最大160 mg) √ × 重型 阿那白滞素 1~8 mg/kg，每日1次 × √ 阿那白滞素 1~8 mg/kg，每日1次 √ √ 卡那单抗 2~8 mg/kg，每4周1次(最大600 mg) × √ TRAPS 卡那单抗 2~4 mg/kg，每4周1次(最大300 mg) √ √ MKD 卡那单抗 2~4 mg/kg，每4周1次(最大300 mg) √ √ DIRA 阿那白滞素 1~8 mg/kg，每日1次 √ × 利纳西普 4.4 mg/kg，每周1次(最大320 mg) √ × 注：√表示已批准，×表示未批准；FDA：美国食品药品监督管理局；EMA：欧洲药品管理局；IL-1：白细胞介素-1；CAPS：冷炎素相关周期性综合征；TRAPS：肿瘤坏死因子受体相关周期性综合征；MKD：甲羟戊酸激酶缺乏症；DIRA：白细胞介素-1受体抑制剂缺陷 
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表 2 IL-1介导的自身炎症性疾病随诊推荐评估项目及其间隔时间
项目 具体内容 间隔时间 (1)系统炎症指标 针对4种疾病 红细胞沉降率、C反应蛋白、血常规+分类、S100、血清淀粉样蛋白、肝脾肿大、淋巴结肿大、乏力症状 每次复诊时 蛋白尿 每6~12个月 生长情况(身高、体质量)/青春期发育情况 每次复诊时 (2)疾病特异性症状及其结局 CAPS 发热、皮疹(荨麻疹样)、耳聋、头痛、晨起头痛及呕吐、肌肉骨骼症状、结膜炎、认知水平发育情况 每次复诊时 TRAPS 发热、皮疹(游走性)、眶周水肿、疼痛(腹痛、胸痛、睾丸疼痛)、肌痛 每次复诊时 MKD 周期性发热情况、皮疹(荨麻疹或斑丘疹)、胃肠道症状(腹痛、腹泻、呕吐)、颈部淋巴结肿大、阿弗他溃疡、认知损害 每次复诊时 DIRA 脓疱性银屑病样皮疹、肌肉骨骼疼痛、指甲改变 每次复诊时 针对4种疾病 生活质量评估、医师总体评估、患者或家长总体评估、误工/停学时间 每次复诊时 (3)器官/系统损伤 CAPS 肾脏(关注淀粉样变)：尿液分析 每次复诊时 耳(关注听力)：听力检测 每3~6个月稳定后每6~12个月 眼部疾病：眼科检查(视力、视野、视网膜等) 每6~12个月 中枢神经系统：腰椎穿刺、头部MRI(评估耳蜗，是否存在脑萎缩、脑室扩大等) 每12~36个月/按需 骨骼：四肢MRI、长度 每12~36个月/按需 TRAPS 肾脏(关注淀粉样变)：尿液分析 每次复诊时 骨骼：四肢MRI、X线片 每12~36个月/按需 MKD 肾脏(关注淀粉样变)：尿液分析 每次复诊时 眼部疾病：眼科检查 按需 神经系统：神经心理测试 按需 DIRA 骨骼：脊柱MRI，四肢X线片或MRI 按需 (4)治疗相关并发症 感染 临床表现，尤其注意有无皮肤感染 每次复诊时 IL-1抑制剂相关 血常规+分类、尿常规、肝肾功能、血脂 每次复诊时 激素相关(若应用激素) 血常规+分类、肝肾功能、血压、血脂、库欣综合征容貌
眼压、视力、眼前节病变
骨密度、25羟维生素D每次复诊时
每3~6个月
每6~12个月IL-1、CAPS、TRAPS、MKD、DIRA、FDA、EMA：同表 1
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