Management of Enzyme Replacement Therapy: Outcome and Expectations

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Dr Neal Weinreb of the University Research Foundation for Lysosomal Storage Diseases in Coral Springs, Florida gave an overview of enzyme replacement therapy and its outcomes based upon data collected and analysed by the Gaucher Registry, at the Gaucher Conference in the US on 11 October 2002.

'I first became interested in Gaucher disease over 30 years ago when I was a Research Associate for Dr Roscoe Brady at the National Institutes of Health in the USA,' explained Dr Neal Weinreb at the Gaucher Conference in Arlington, Virginia on 11 October 2002.

'I worked with Dr Brady to demonstrate that Gaucher disease is a lysosomal storage disease and I helped formulate some of the purification procedures for the enzyme. Now at my clinic in Coral Springs, Florida, I devote my entire professional attention to clinical research and management of patients with lysosomal storage diseases especially Gaucher disease and Fabry disease,

'Gaucher disease is a heterogeneous disorder (with varying symptoms) and individual responses to therapy vary dramatically in different patients.

Gene Mutations

'250 mutations have been discovered in the gene which causes the disease but even the same genotype (the two mutations which sufferers inherit from their parents) has displayed different symptoms or severity of symptoms in sufferers.

'The most common mutation N370S has been shown to protect patients from the neurological symptoms of Type 3 whilst patients who have two copies of the L444P mutation often display neurological symptoms but not inevitably.

'Most mutated genes produce some enzyme but the mutation 84GG has no enzyme production. It has been discovered that in some patients with two copies of the N370S mutation, there is a 55BP deletion. This may cause more severe disease but the whole area needs to be studied further.


'Patients who have a spleen may often have a low platelet count but after removal of their spleen, they rarely display this. However after splenectomy, they may get more severe skeletal abnormalities.

'There is a need for careful and thorough initial and serial assessment this is the key to good treatment.

'Doctors needs to give their patients time to assess their quality of life as well as symptoms. This needs to be reviewed regularly.

'Tests should include a DEXA scan (for bone density) in adults, a cardiac ECHO when first reviewing a patient for pulmonary hypertension, chitotriosidase levels (to help assess level of disease) and B12 levels.

'Monitoring can be decreased once a patient has stabilised and there is no concern over the formation of antibodies.

Enzyme Replacement Therapy

'3,500 sufferers of Gaucher disease are receiving enzyme replacement therapy world-wide. The details of 2,600 patients are anonymously listed on the Gaucher Registry, held by the International Gaucher Collaborative Committee, of whom about 500 are not receiving enzyme therapy.

'Initial dosage of enzyme replacement therapy should be individualised and adjusted based on clinical response and achievement of therapeutic goals.

'Francis Peabody said that the secret of the care of patients is in the caring of the patients. (Francis Peabody was a physician who lectured on the care of the patient in 1926).

'It is important to give symptom and pain relief as well as concentrate on technical aspects such as tests. And doctors should address all symptoms if possible.'

Current Proposed Treatment Goals

Dr Weinreb said that the goals of giving enzyme replacement therapy should be that:

· Anaemia should have normalised within 1-2 years of treatment, possibly earlier.

· Platelets should normalise within 1-5 years. By the first year, mild cases should normalise and in severe cases, their platelet count should double.

· The liver should respond to treatment within 1-5 years. In mild to moderate cases, livers should return to near normal size. Severe enlargement should decrease by 30% to 40%.

· Spleen size should also improve within 1-5 years with severe cases showing a 40%-60% reduction.

· Bone pain resolves in 50% of patients within 1-2 years of starting enzyme replacement therapy although some patients with pre-existing bone damage may not improve. Children show greater improvement whilst adults experiencing pain only show on average a 20%-30% improvement in bone pain. Some pain in patients improves due to receiving joint replacements. If children receive enzyme replacement therapy, this may substantially prevent bone disease.'

Goals for Skeletal Disease

Dr Weinreb said that new onset of bone pain in patients who had not already complained of pain has occurred in 4% of patients who had been on enzyme replacement therapy for up to two years; while 80%-90% of patients who had suffered prior bone crises had no recurrence during the first two years of therapy. Only one patient with no prior incidence of bone crises reported an incidence.

'Bone improvement in adults is rarely seen on X ray or MRI scans.

'The goals for skeletal disease should be:

· No further bone crises or fractures.

· Bone pain eliminated or reduced.

· To prevent irreversible damage relating to avascular necrosis (death in the bone)

· Bone marrow infiltration should decrease.

· Children should reach peak skeletal mass.

· Bone density should normalise

· To stabilise bones for prosthesis eg hip or other joint replacements.

· Attain predicted growth percentile according to age, sex and parental height.

Additional Goals

In addition further goals should be to:

· Identify and manage pulmonary (lung) manifestations including pulmonary hypertension.

· Document and sustain improved quality of life parameters.

· Achieve and maintain improvement in biochemical markets etc ACE, chitotriosidase.

· Achieve a normal life expectancy free of Gaucher disease associated causes of illness or death.

Dr Weinreb concluded that the future aim of improving enzyme replace-ment therapy is to modify it so that it can be given less frequently and at a lower cost.

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Source: Gauchers News April 2003.
© Copyright Gauchers Association 2003.