National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
Arthritis Rheumatol. 2021 Oct;73(10):1886-1895. doi: 10.1002/art.41743. Epub 2021 Aug 31.
Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP.
Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations.
Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count <200 ×10 /μl differentiated VEXAS-RP from RP with 100% sensitivity and 96% specificity.
Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis, and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.
UBA1 中的体细胞突变导致了一种新定义的综合征，称为 VEXAS（空泡、E1 酶、X 连锁、自身炎症、体细胞综合征）。目前，超过 50%的被诊断为 VEXAS 的患者符合复发性多软骨炎（RP）的诊断标准，但尚未确定 RP 患者队列中 VEXAS 的临床特征。我们进行这项研究是为了确定 RP 患者中 UBA1 体细胞突变的患病率，并创建一种算法来识别 RP 患者中经基因证实的 VEXAS 患者。
对一组前瞻性观察性 RP 患者进行 UBA1 外显子组和靶向测序。根据 UBA1 突变的存在与否，比较 RP 患者的临床和免疫特征。使用随机森林方法得出一种临床算法来识别 UBA1 突变患者。
92 例 RP 患者中有 7 例（7.6%）存在 UBA1 突变（这里称为 VEXAS-RP）。VEXAS-RP 患者均为男性，发病时平均年龄≥45 岁，常见症状有发热、耳软骨炎、皮肤受累、深静脉血栓形成和肺部浸润。没有 VEXAS-RP 患者有气道或肋软骨炎。VEXAS-RP 的死亡率高于 RP（23%对 4%；P=0.029）。VEXAS-RP 中常见的是急性期反应物和血液学异常（如巨红细胞贫血、血小板减少、淋巴细胞减少、多发性骨髓瘤、骨髓增生异常综合征）。基于男性、平均红细胞体积>100fl 和血小板计数<200×10/μl 的决策树算法可以 100%的灵敏度和 96%的特异性将 VEXAS-RP 与 RP 区分开来。
在一部分 RP 患者中，UBA1 突变是疾病的原因。该亚组患者的发病年龄在 50 岁以后，为男性，耳部/鼻部软骨炎和血液学异常。鉴于 VEXAS 相关的高死亡率，早期识别非常重要。
