The availability of enzyme replacement therapy for Fabry disease has had a major impact on the organization of patient care. Many countries have produced expert guidelines outlining the recommended requirements for investigation, treatment and follow-up of patients and their families. This chapter summarizes the standards of care that operate in some of the major centres that contribute patient data to the FOS – Fabry Outcome Survey – database.

Introduction

The successful use of enzyme replacement therapy (ERT) in Gaucher disease, where it is now the standard of care [1], has led to the recognition of its potential role in treating other lysosomal disorders, such as Fabry disease [2]. Drug development was also given further impetus by legislation in the USA and the European Union, which provided commercial incentives to companies producing 'orphan' drugs. ERT for Fabry disease was licensed in August 2001 (see Chapter 36), and is now widely available within Europe. However, the cost of treatment means that prescriptions are subject to rigorous scrutiny. This has made it necessary to develop explicit guidelines for the diagnosis, assessment, treatment and follow-up of patients and their families. There is no internationally centralized process for preparing such guidelines, and the USA, Australia, Canada and countries in Europe have produced their own [3–6].

There is considerable diversity within Europe with regard to how such treatments are funded. In some countries the main source of funding is private medical insurance. In most countries, however, there is a greater or lesser involvement of the state in funding these expensive treatments. Some countries are very specific in terms of the arrangements for the care of patients. For example, in the UK only nationally designated centres are able to prescribe therapy. The UK guidelines are multidisciplinary to reflect the need to involve the 'commissioners' – the agencies that fund therapy. In countries where there is substantial involvement of the state in funding treatment, the funds come from local government agencies representing the area of residence of the patient or from a central government source.

Assessment of patients

Once a diagnosis is confirmed, the aim of further investigations is to provide a precise assessment of the severity of the clinical manifestations of the disease. This will determine the requirement for specific and adjunctive therapies, and will provide the baseline against which the effectiveness of such therapies can be assessed. The results of clinical assessment and investigations may be used to calculate a disease-specific severity score, such as the Mainz Severity Score Index [7], to allow sequential monitoring of overall disease severity. Recommended investigations are listed in Table 1.

Table 1

Recommended investigations for patients presenting with Fabry disease.

There is often a requirement for patients to attend specialist centres (e.g. UK, Australia and Canada) to receive treatment according to approved protocols. It is expected that patient details will be entered into outcomes databases and reports made available to funding agencies.

Criteria for starting ERT

A previous attempt at producing expert guidelines [4] has been well received by clinicians, patients and carers worldwide. The main criteria for initiating ERT are listed in Table 2. There are four critical areas to consider when assessing whether ERT should be started in patients with Fabry disease: pain, renal disease, cardiac disease and cerebrovascular disease.

Table 2

Criteria for initiating enzyme replacement therapy.

We believe that ERT should be available for all symptomatic adult males, even if they do not have evidence of organ disease. Women and children require special consideration, and the criteria for initiating ERT therefore include evaluation of organ systems where disturbances will not cause life-threatening complications or where it is perceived that symptoms cause limited impairment of quality of life (e.g. dermatological changes, sensory organ disturbance and gastrointestinal disease). A challenge for the future is to question these assumptions and perceptions and to refine the criteria for initiating ERT accordingly.

Some countries give very specific guidelines on the degree of organ impairment, and some have developed major and minor criteria in an attempt to reflect the various effects of different disease manifestations on quality of life. Major criteria are typically significant renal, cardiac and cerebrovascular disease and pain; minor criteria are transient ischaemic attacks or abnormal brain magnetic resonance imaging with no other cause identified, gastrointestinal symptoms and sensory organ abnormalities.

Follow-up of patients

Follow-up should be at 6-monthly intervals in patients receiving ERT. For those patients not receiving ERT, follow-up should be every 12 months. The recommended evaluations are listed in Table 3.

Table 3

Recommended evaluations at follow-up.

An important aim of follow-up is to assess treatment efficacy, which involves evaluating the current status of signs and symptoms against the baseline assessment, with particular reference to the disease manifestations that led to the initiation of therapy.

A further major aim of follow-up is to assess the safety of treatment. ERT appears to be well tolerated by patients with Fabry disease. Antibody formation has been reported with both the available enzyme preparations, but there is no clear evidence that these antibodies impact on the clinical efficacy of treatment [8]. Antibody measurements should be made at regular intervals (e.g. every 12 months) and an extra sample should be taken if there are any clinical indicators of allergy (e.g. skin rash). Regular follow-up also allows the prescriber to confirm compliance with treatment. In addition, follow-up provides an opportunity to confirm that the patient is taking optimal adjunctive therapy in terms of renoprotective, cardioprotective and vasculoprotective medication.

Funding agencies in most countries require written information on the outcome of treatment as a prerequisite for continued funding of ERT.

Home therapy

The first ERT infusion should always be given in hospital. Subsequent infusions can be given in the home setting provided the patient tolerates treatment well and the carers consider it appropriate. Home therapy is frequently practised in the UK and Switzerland. A recent report from The Netherlands [9] gives practice guidelines for home therapy. Thirty of 36 patients eligible for home therapy in this study were able to receive it. Women tolerated treatment better than men (presumably because of a lower incidence of antibodies) and in men agalsidase alfa at its licensed dose of 0.2 mg/kg was easier to administer at home than agalsidase beta at its licensed dose of 1 mg/kg. Experience from the UK in delivering home treatment for patients with lysosomal storage diseases is generally very positive and has recently been reported [10].

Criteria for stopping treatment

Guidelines should also stipulate the criteria for stopping treatment. These would include intolerable adverse effects, development of complications as a result of ERT, or disease progression to such an extent that further ERT would be very unlikely to have a significant long-term impact on the disease (e.g. a severe cerebrovascular event). Treatment should be reviewed during pregnancy; although there are case reports of successful treatment during pregnancy, pregnancy and lactation are generally considered exclusion criteria.

Criteria for ERT in children under 18 years of age

The criteria for commencing ERT in adults and children differ, as it is very rare for children to develop cardiomyopathy, significant proteinuria or arrhythmias. Pain (including abdominal pain), impaired quality of life and abnormalities of growth and development are more important and relevant indications for initiating treatment in children. It is important to use age-appropriate pain scores in children; for example, those derived from the paediatric-specific Brief Pain Inventory and the Varney–Thompson Paediatric Pain Questionnaire. Age-appropriate quality-of-life scores, such as those derived from the KINDL, Short-Form-36 (SF-36) and European Quality of Life (EQ-5D) questionnaires, are also available.

Conclusions

The practice of evidence-based medicine requires written guidelines that are easily accessible, frequently updated and have ownership by all interested parties. As healthcare costs continue to rise, it is particularly important that available resources are optimally utilized. The two principal health economic arguments against funding orphan drugs are that the criteria for determining cost-effectiveness of therapies should be rigidly applied regardless of whether a condition is common or rare; and funding for expensive drugs for one indication inevitably incurs an 'opportunity cost' which will mean denying treatment provision for other indications [11, 12]. In this threatening environment, it becomes crucially important to have an evidence base for all interventions. The provision of guidelines and protocols, together with audit of practice against these documents, is likely to become an increasingly important aspect of medicine.

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