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Abstract：
To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.
摘要：
调查2013年至2022年德国抗IL-1自身炎症性孤儿病注册中心（GARROD）患者的临床症状和遗传变异。多中心,人口统计学的回顾性分析，接受抗IL-1靶向治疗的自身炎症性疾病（AID）患者的临床和遗传数据。该队列包括152名家族性地中海热患者（FMF；n=71），冷冻比林相关周期性综合征（CAPS；n=43），肿瘤坏死因子受体相关周期性综合征（TRAPS；n=19），甲羟戊酸激酶缺乏症(MKD;n=3)和未分类的AID(uAID;n=16)。61.2％的患者在18岁之前开始炎症发作。第一次AID发作和抗IL-1治疗之间的延迟为17.8年。单基因AIDs通过临床症状诊断。基因分析证实了87.3%的FMF患者的诊断，65.2%的CAPS和94.8%的TRAPS。在这个群体中,在22.5%的FMF患者中检测到杂合MEFV变体和未知意义的变体(VUS)，51.2%的CAPS和47.4%的TRAPS。VUS患者在疾病发作时年龄较大，这与较温和的表型一致。24例患者在开始抗IL-1治疗时出现继发性AA淀粉样变性（AA）。这些患者的平均年龄在首次发作时为16.4岁，在AA诊断时为44.9岁。与德国血统相比，土耳其-亚美尼亚血统与MEFV变体和更高的FMF疾病活动相关。分子遗传学分析应证实单基因AID的临床诊断。我们的数据支持VUS的可变外显率的概念，该概念可能与迟发性AID有关。
