University Hospital Tuebingen, Tuebingen, Germany.
Rady Children's Hospital and University of California at San Diego, San Diego, California.
Arthritis Rheumatol. 2017 Nov;69(11):2233-2240. doi: 10.1002/art.40208. Epub 2017 Oct 17.
Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β (IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants.
A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed.
The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients.
Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non-IL-1β-mediated inflammatory pathway activation.
细胞溶质分裂蛋白酶激活的 NLR 家族蛋白 3（NLRP3）相关周期性发热综合征（CAPS）是由 NLRP3 基因的功能获得性突变引起的，其导致白介素-1β（IL-1β）的过度释放和全身炎症。虽然致病性 NLRP3 变体表型已得到很好的描述，但低外显率 NLRP3 变体仍然是一个重大的临床挑战。本研究旨在确定低外显率 NLRP3 变体患者的临床表型、体外生物学表型以及抗 IL-1 治疗的效果。
对 2012 年 5 月至 2013 年 5 月期间从 7 个中心连续招募的低外显率 NLRP3 变体的症状性患者进行了一项多中心研究。观察到的发现被转移到一个研究数据库中，从中提取出来进行分析。对照为已知致病性 NLRP3 变体的患者。采集炎症性 CAPS 标志物的临床表现。进行包括半胱天冬酶 1 活性、NF-κB 释放、细胞死亡和 IL-1β释放在内的炎性小体激活的功能测定。确定了 IL-1 的治疗效果。比较了低外显率和致病性 NLRP3 变体。
研究纳入了 45 例患者，其中 21 例为女性（47%）；26 例患者（58%）为儿童。患者的 NLRP3 低外显率变体包括 Q703K（19 例）、R488K（6 例）和 V198M（20 例）。在对照中，28 例有致病性 NLRP3 变体。低外显率 NLRP3 变体患者的发热（76%）和胃肠道症状（73%）更为常见；眼部疾病、听力损失和肾脏受累较少见。与野生型和致病性 NLRP3 变体相比，低外显率 NLRP3 变体的功能性炎性小体检测显示出中间表型。所有接受治疗的患者均对 IL-1 抑制有反应，50%的患者记录到完全缓解。
低外显率 NLRP3 变体患者表现出独特的临床表型和中间生物学表型，包括 IL-1β 和非 IL-1β 介导的炎症途径激活。
