Review
European expert consensus statement on therapeutic goals in Fabry disease

https://doi.org/10.1016/j.ymgme.2018.06.004Get rights and content

Highlights

  • Therapeutic goals for Fabry patients should be individualized based on patient characteristics, disease variant and stage.

  • Reversal of symptoms or prevention of disease progression is the goal for most parameters associated with Fabry disease.

  • Disease management requires multidisciplinary input based on a comprehensive organ assessment and regular monitoring.

  • Early initiation of disease-specific therapy can delay progression in patients with Fabry disease.

  • Optimal disease management should consider anticipated clinical benefits and potential therapy-related challenges.

Abstract

Background

Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation.

Methods

A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion.

Results

A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis.

Conclusions

These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.

Section snippets

List of abbreviations

ACEiangiotensin-converting-enzyme inhibitor
ARBangiotensin II receptor blocker
BPIBrief Pain Inventory
CKDchronic kidney disease
CNScentral nervous system
ECGelectrocardiogram
eGFRestimated glomerular filtration rate
EOWevery other week
ERTenzyme replacement therapy
ESKDend-stage kidney disease
EQ-5DEuroQoL 5 Dimensions questionnaire
FOSFabry Outcome Survey
GFRglomerular filtration rate
GL-3globotriaosylceramide
GSRSGastrointestinal Symptom Rating Scale
lyso-GL-3globotriaosylsphingosine
LVleft

Methods

A European panel of experts was established with the objective of developing a set of detailed, organ-specific therapeutic goals for Fabry disease based on expert consensus and a systematic literature review that included articles published up to and including January 2017 [[3], [4], [5], [6]]. The development of the therapeutic goals was guided by a number of key questions:

  • 1.

    What are the relevant clinical parameters that should be considered?

  • 2.

    What is a reasonable response to therapy, and how

Plasma GL-3

Plasma GL-3 is the most widely available indicator of glycosphingolipid load in patients with Fabry disease, although it must be noted that because of their heterozygosity for Fabry mutations and their X-chromosome inactivation patterns, the majority of female patients have normal plasma GL-3 levels [7]. Evidence from placebo-controlled clinical trials indicates that ERT can reduce or normalize plasma GL-3 levels [[8], [9], [10], [11]] but no prospective studies have been carried out to date to

Heart involvement

Cardiac manifestations are common in Fabry disease, occurring in 40–60% of patients [[37], [38], [39], [40], [41]]. The spectrum of cardiac complications is similar in both the classic and the later-onset cardiac phenotype and includes left ventricular hypertrophy (LVH), conduction abnormalities, bradycardia and chronotropic incompetence, supraventricular and ventricular tachyarrhythmias, myocardial fibrosis, valve disease, and microvascular dysfunction [42,43].

Cardiac complications are the

Kidney involvement

The cellular kidney pathology is associated with progressive CKD with increasing albuminuria leading to overt proteinuria and reduced GFR, ultimately progressing to end-stage kidney disease (ESKD), if untreated [77]. Microscopic haematuria and nephrotic proteinuria are relatively uncommon manifestations of Fabry nephropathy. The renal complications of Fabry disease are key contributors to the morbidity and mortality associated with the disorder [78]. Effective management of underlying kidney

Brain and peripheral nervous system involvement

The first neurological symptoms of Fabry disease occur in the peripheral nervous system (PNS) as a result of damage to neurons. Small, unmyelinated or thinly myelinated nerve fibres are particularly affected and small fibre peripheral neuropathy contributes to peripheral neuropathic pain (chronic and acute excruciating pain), and accounts for dysaesthesias, deficits of thermal sensation and of physiologic pain perception, neuropathic pain, impaired sweating, GI dysmotility, and other sensory

Dermatological abnormalities/angiokeratoma

Dermatological abnormalities have been reported to be present in 78% of males and 50% of females with the classic phenotype of Fabry disease [157]. Angiokeratoma is the most common dermatological abnormality occurring in 66% of males and in 36% of females, and is the most visible early clinical feature of classic Fabry disease. They typically appear as either single or groups of superficial small reddish purple skin lesions that increase in number and size with age [157,161]. Lesions appear on

QoL in Fabry disease

Systematic review of clinical evidence has confirmed that patients with Fabry disease have a lower QoL compared with the general population [178]. Factors that reduce QoL in Fabry disease include Fabry-related chronic pain and pain crises, GI symptoms, hearing loss, physical inactivity, and fatigue. Importantly, the burden of organ damage also severely affects QoL. Experts note, however, that a diagnosis of Fabry disease followed by a treatment plan may improve QoL in some patients because of

Discussion and concluding remarks

The therapeutic goals in this review represent the consensus from a European panel of experts and knowledge from recent clinical studies. It is hoped that these goals will help establish an individualized approach to the management of patients with Fabry disease. The goals presented in this paper are intended to be used in conjunction with the consensus recommendations on best practice management of patients with Fabry disease with ERT [183,184]. Moreover, it is important that as our

Disclosures

The development of this publication and the meetings of the European expert panel were sponsored by Sanofi Genzyme. The authors received editorial/writing support in the preparation of this manuscript from Rosalie Gadiot, PhD, and Tom Rouwette, PhD, of Excerpta Medica, which was funded by Sanofi Genzyme. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.

Conflicts of interest

  • Christoph Wanner has received research support from Sanofi Genzyme; is a consultant for Actelion Pharmaceuticals, Protalix, Boehringer Ingelheim, and Sanofi Genzyme; is a member of the European Advisory Board of the Fabry Registry.

  • Michael Arad has received travel support from Sanofi Genzyme and Shire.

  • Ralf Baron has received speaker honoraria from Astellas, Bayer-Schering, Boehringer Ingelheim Pharma, Desitin, Eisai, Grünenthal, Lilly, Medtronic Inc. Neuromodulation, MSD, Mundipharma, Pfizer,

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