Abstract：
Variable disease progression confounds accurate prognosis in Fabry disease. Evidence supports the long-term benefit of early intervention with disease-specific therapy, but current guidelines recommend treatment initiation based on signs that may present too late to avoid irreversible organ damage. Findings from the \'PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease\' (PREDICT-FD) initiative included expert consensus on 27 early indicators of disease progression in Fabry disease and on drivers of and barriers to treatment initiation in Fabry disease. Here, we compared the PREDICT-FD indicators with guidance from the European Fabry Working Group and various national guidelines to identify differences in signs supporting treatment initiation and how guidelines themselves might affect initiation. Finally, anonymized patient histories were reviewed by PREDICT-FD experts to determine whether PREDICT-FD indicators supported earlier treatment than existing guidance.
Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations.
Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.
Current guidelines generally aligned with PREDICT-FD on indicators of renal involvement, but most lacked specificity regarding cardiac indicators. The prognostic significance of neurological indicators such as white matter lesions (excluded by PREDICT-FD) was questioned in some guidelines and excluded from most. Some PREDICT-FD patient-reported signs (e.g., febrile crises) did not feature elsewhere. Key drivers of treatment initiation in PREDICT-FD were: (A) male sex, young age, and clinical findings (e.g., severe pain, organ involvement), (B) improving clinical outcomes and preventing disease progression, and (C) a family history of Fabry disease (especially if outcomes were severe). All guidelines aligned with (A) and several advocated therapy for asymptomatic male patients. There was scant evidence of (B) in current guidance: for example, no countries mandated ancillary symptomatic therapy, and no guidance advocated familial screening with (C) when diagnosis was confirmed. Barriers were misdiagnosis and a lack of biomarkers to inform timing of treatment. Review of patient histories generally found equal or greater support for treatment initiation with PREDICT-FD indicators than with other guidelines and revealed that the same case and guideline criteria often yielded different treatment recommendations.
Wider adoption of PREDICT-FD indicators at a national level could promote earlier treatment in Fabry disease. Clearer, more concise guidance is needed to harmonize treatment initiation in Fabry disease internationally.
摘要：
可变的疾病进展混淆了法布里病的准确预后。证据支持疾病特异性治疗早期干预的长期益处，但目前的指南建议根据可能出现得太晚的症状开始治疗，以避免不可逆的器官损伤。“法布里病临床追踪早期疾病指标”（PREDICT-FD）倡议的结果包括关于法布里病疾病进展的27项早期指标以及法布里病开始治疗的驱动因素和障碍的专家共识。这里,我们将PREDICT-FD指标与欧洲Fabry工作组的指导和各种国家指南进行了比较,以确定支持开始治疗的体征的差异,以及指南本身可能如何影响开始治疗.最后,PREDICT-FD专家审查了匿名患者病史,以确定PREDICT-FD指标是否支持比现有指南更早的治疗.
目前的指南在肾脏受累指标上与PREDICT-FD基本一致，但大多数缺乏关于心脏指标的特异性。某些指南对诸如白质病变（PREDICT-FD排除）等神经系统指标的预后意义提出了质疑，并且大多数指南都将其排除在外。一些预测FD患者报告的体征(例如，发热危机)在其他地方没有出现。PREDICT-FD开始治疗的主要驱动因素是：（A）男性，年轻的年龄,和临床发现(例如，剧烈疼痛,器官受累)，(B)改善临床结果和防止疾病进展，和(C)Fabry病家族史(特别是如果结果严重)。所有指南均符合（A）和一些提倡的无症状男性患者治疗。目前的指南中缺乏(B)的证据:例如，没有国家要求辅助对症治疗，并且没有指南提倡在确诊时使用（C）进行家族性筛查。障碍是误诊和缺乏生物标志物来告知治疗时机。对患者病史的回顾通常发现，与其他指南相比，PREDICT-FD指标对治疗开始的支持相等或更大，并且发现相同的病例和指南标准通常会产生不同的治疗建议。
在国家一级更广泛地采用PREDICT-FD指标可以促进法布里病的早期治疗。更清晰,需要更简洁的指导来协调法布里病的国际治疗开始。
目前的指南在肾脏受累指标上与PREDICT-FD基本一致，但大多数缺乏关于心脏指标的特异性。某些指南对诸如白质病变（PREDICT-FD排除）等神经系统指标的预后意义提出了质疑，并且大多数指南都将其排除在外。一些预测FD患者报告的体征(例如，发热危机)在其他地方没有出现。PREDICT-FD开始治疗的主要驱动因素是：（A）男性，年轻的年龄,和临床发现(例如，剧烈疼痛,器官受累)，(B)改善临床结果和防止疾病进展，和(C)Fabry病家族史(特别是如果结果严重)。所有指南均符合（A）和一些提倡的无症状男性患者治疗。目前的指南中缺乏(B)的证据:例如，没有国家要求辅助对症治疗，并且没有指南提倡在确诊时使用（C）进行家族性筛查。障碍是误诊和缺乏生物标志物来告知治疗时机。对患者病史的回顾通常发现，与其他指南相比，PREDICT-FD指标对治疗开始的支持相等或更大，并且发现相同的病例和指南标准通常会产生不同的治疗建议。
在国家一级更广泛地采用PREDICT-FD指标可以促进法布里病的早期治疗。更清晰,需要更简洁的指导来协调法布里病的国际治疗开始。
