Do clinical guidelines facilitate or impede drivers of treatment in Fabry disease?

Orphanet J Rare Dis. 2022 Feb 8;17(1):42. doi: 10.1186/s13023-022-02181-4.


Background: 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.

Results: 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.

Conclusions: 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.

Keywords: Cardiac; Chaperone therapy; Consensus; Enzyme replacement therapy; Fabry disease; Guideline; Neurological; Patient-reported outcome; Renal; Treatment initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Consensus
  • Disease Progression
  • Enzyme Replacement Therapy
  • Fabry Disease* / pathology
  • Heart
  • Humans
  • Male