法布里病(OMIM#301500)是由α-半乳糖苷酶A缺乏引起的X连锁病症,具有两种主要的临床表型:不同预后的经典和非经典。从2001年开始,酶替代疗法(ERT)已经可用。我们旨在确定抗药物抗体的流行病学和功能特征。来自法国多中心队列FFABRY的患者(n=103例患者,用自制的酶联免疫吸附测定(ELISA)前瞻性地筛选了53名男性)的总抗胶糖苷酶IgG和IgG亚类,用中和测定法和lysoGb3血浆水平评估的酶抑制,并比较临床结果。
在接触半乳糖苷酶的患者中,40%的男性(n=18/45)和8%的女性(n=2/25)具有对两种ERT具有完全交叉反应性的抗体。在具有非错义GLA突变(相对风险2.88,p=0.006)和经典表型(58.6%(17/29)vs6.7%(1/16)的男性中优先开发抗体,p=0.0005)。特异性抗糖苷酶IgG1是最常见的观察(16/18男性),但IgG4的浓度最高(中位数为1.89μg/ml,四分位数间距(IQR)[0.41-12.24])。在暴露于半乳糖苷酶的男人中,抑制与总IgG滴度相关(r=0.67,p<0.0001),尤其是IgG4(r=0.75,p=0.0005)和IgG2(r=0.72,p=0.001)。在用IgG阳性与阴性血清培养的Fabry患者白细胞的细胞内证实了抑制作用(中位数:42.0vs75.6%,p=0.04),与IgG2水平(r=0.67,p=0.017,n=12)和IgG4水平(r=0.59,p=0.041,n=12)相关。血浆LysoGb3水平与总IgG相关(r=0.66,p=0.001),IgG2(r=0.72,p=0.004),IgG4(r=0.58,p=0.03)和IgG1(r=0.55,p=0.04)滴度。在经典群体中,没有观察到临床差异,但抗体阳性患者的lysoGb3水平较高(中位数33.2ng/ml[IQR20.6-55.6]vs12.5[10.1-24.0],p=0.005)。
抗半乳糖苷酶抗体优先在严重的经典法布里表型中发展。它们通常与酶抑制和更高的lysoGb3水平相关。因此,它们可以被认为是与经典表型相关的严重程度标志.现在,在有关法布里病及其当前和未来疗法的研究中,临床表型的区分应该是强制性的。
Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-
agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes.
Among the patients exposed to
agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-
agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 μg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to
agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005).
Anti-
agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.