背景:戈谢病(GD)治疗的有益效果是降低无血管性骨坏死(AVN)的发生率。然而,在接受酶替代疗法(ERT)的患者中有AVN的报道,目前还不知道它是否与个体治疗有关,GBA基因型,表型,残留疾病活性或抗药物抗体的生物标志物。
目的:受几例接受ERT的患者发生AVN的促进,我们旨在描述在三级转诊中心20年期间接受ERT或eliglustat底物减少治疗(SRT)的患者AVN的决定因素.
方法:对2001年至2021年的155例GD患者进行纵向随访,分析治疗时AVN的发作情况,治疗类型,GBA1基因型,脾脏状态,生物标志物,和其他疾病指标。我们应用混合效应逻辑模型来描绘接受治疗时AVN的独立相关性。
结果:患者累计接受1382年的治疗。14例患者有16例AVN发作,有两集,每个发生在两个病人。在治疗期间,杂等位基因p.Asn409SerGD1患者发生骨坏死的可能性是p.Asn409Ser纯合子患者的10倍(95%CI,1.5-67.2)。治疗开始前的AVN病史与治疗后AVN风险增加4.8倍相关(95%CI,1.5-15.2)。与接受imigluceraseERT的患者相比,接受velagluceraseERT的患者发生AVN的风险高4.68倍(95%CI,1.67-13)。没有接受eliglustatSRT的患者出现AVN。GlcSph水平与AVN之间存在显著的相关性。一起,这些生物标志物可靠地预测了治疗期间AVN的风险(ROCAUC0.894,p<0.001).
结论:有一个低点,但在ERT/SRT时代GD发生AVN的风险显著。我们发现AVN的风险增加与GBA基因型有关,治疗开始前的AVN病史,残余血清GlcSph水平,以及ERT的类型。没有接受SRT的患者出现AVN。这些发现举例说明了一种在罕见的先天性代谢错误中应用生物标志物的新方法,以评估全面随访患者的临床结果,并将有助于识别具有较高AVN风险的GD患者,他们将从更密切的监测和治疗优化中受益。
资助:从赛诺菲到MB的LSD培训奖学金。
A salutary effect of treatments for Gaucher disease (GD) has been a reduction in the incidence of avascular osteonecrosis (AVN). However, there are reports of AVN in patients receiving enzyme replacement therapy (ERT) , and it is not known whether it is related to individual treatments, GBA genotypes, phenotypes, biomarkers of residual disease activity, or anti-drug antibodies. Prompted by development of AVN in several patients receiving ERT, we aimed to delineate the determinants of AVN in patients receiving ERT or eliglustat substrate reduction therapy (SRT) during 20 years in a tertiary referral center.
Longitudinal follow-ups of 155 GD patients between 2001 and 2021 were analyzed for episodes of AVN on therapy, type of therapy, GBA1 genotype, spleen status, biomarkers, and other disease indicators. We applied mixed-effects logistic model to delineate the independent correlates of AVN while receiving treatment.
The patients received cumulative 1382 years of treatment. There were 16 episodes of AVN in 14 patients, with two episodes, each occurring in two patients. Heteroallelic p.Asn409Ser GD1 patients were 10 times (95% CI, 1.5-67.2) more likely than p.Asn409Ser homozygous patients to develop osteonecrosis during treatment. History of AVN prior to treatment initiation was associated with 4.8-fold increased risk of AVN on treatment (95% CI, 1.5-15.2). The risk of AVN among patients receiving velaglucerase ERT was 4.68 times higher compared to patients receiving imiglucerase ERT (95% CI, 1.67-13). No patient receiving eliglustat SRT suffered AVN. There was a significant correlation between GlcSph levels and AVN. Together, these biomarkers reliably predicted risk of AVN during therapy (ROC AUC 0.894, p<0.001).
There is a low, but significant risk of AVN in GD in the era of ERT/SRT. We found that increased risk of AVN was related to GBA genotype, history of AVN prior to treatment initiation, residual serum GlcSph level, and the type of ERT. No patient receiving SRT developed AVN. These findings exemplify a new approach to biomarker applications in a rare inborn error of metabolism to evaluate clinical outcomes in comprehensively followed patients and will aid identification of GD patients at higher risk of AVN who will benefit from closer monitoring and treatment optimization.
LSD Training Fellowship from Sanofi to MB.