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Dr Pram Mistry Director of the Gaucher Disease Treatment Center at Mount Sinai School of Medicine, New York, gave a talk on the medical management of Gaucher disease at the Gaucher Conference in Memphis on 10 October 1998. Dr Mistry is known to UK members for his work at the Royal Free Hospital, London and Addenbrooke's Hospital, Cambridge.
'Enzyme replacement therapy under-pins much of the modern management of Gaucher disease,' explained Dr Mistry. 'There has been significant progress since its introduction in 1990 by Dr Barton and Dr Brady on how enzyme replacement therapy should be used optimally so that we can now harness its full potential though individualized treatment, ie treatment tailored to individual needs.
In the early days, enzyme replace-ment therapy was recommended to patients who had symptoms of ill health attributable to Gaucher disease.
Signs and Symptoms
Increasingly, we recognize that many patients have significant signs of Gaucher disease, ie enlargement of the liver or spleen and/or bone involve-ment but surprisingly no symptoms of pain or disability. It is remarkable that in some patients, advanced tissue damage and scarring can occur without any symptoms whatsoever. Clearly, enzyme replacement therapy should be considered in these patients, especially when there is evidence of progressive disease on serial (consecutive) evaluations. A critical issue with this group of patients is the optimal timing to start treatment so that irreversible organ damage is prevented.
It has long been recognized that there are affected patients who have no symptoms of the disease nor any signs like liver/spleen enlargement, changes in blood counts or bone involvement. This applies particularly to patients with two copies of the N370S mutation among whom it has been estimated that up to 50-60% may go though life without ever coming to harm from Gaucher disease. These patients are not candidates for enzyme replacement therapy but it is important to monitor their Gaucher disease at regular intervals of every 2-3 years.
The most important goals of enzyme replacement therapy are to relieve symptoms and ameliorate disability due to Gaucher disease.
It is also of practical importance to consider what we are trying to achieve at the cellular level with enzyme infusions: first to switch off; the activity of Gaucher cells that cause tissue damage and second to reduce the number of Gaucher cells.
Interestingly, stored glycolipid (fatty tissue) in each organ represents only a small percentage of total weight of the organ; for example in a typical patient total glucocerebroside content of the liver, spleen and lung is less than 1% of the organ weight; in the bone it represents about 5% of the marrow weight.
Organ damage and symptoms of the disease is likely to result more from the 'activation' of Gaucher cells rather than simply passive accumulation of the cells. Thus, the disease evolves to cause extensive scarring and infarction (damage) in all the major sites like the spleen, bones, liver and rarely in the lungs. This type of damage can not be reversed by enzyme therapy underscoring the importance of starting treatment before such complications arise.'
Dr Mistry cautioned against inappropriate emphasis on age and supposedly mild genotypes (gene mutations inherited from each parent) in making treatment decisions. He described the case histories of a number of patients to illustrate his concern. One such patient was a writer in his 80s with so-called 'mild' genotype, N370S/N370S, who had suffered from life-threatening complications of Gaucher disease for over a decade until he was confined to a wheel-chair. Each time his Gaucher disease was considered too mild and in any case he was deemed 'too old' for starting enzyme replacement therapy.
Enzyme Replacement Therapy
Dr Mistry described the effects of enzyme replacement therapy as:
Two patients with severe lung involvement have been reported by Dr Beutler. Both had been incapacitated by shortness of breath and had dramatic relief of their symptoms after being on enzyme therapy. However patients with the specific complication of pulmonary hypertension respond poorly to enzyme treatment.
Dr Mistry showed data from the Gaucher Registry of the ICGG (International Collaborative Gaucher Group) that has permitted analysis of results of enzyme therapy of over 1,000 patients world-wide. On average, haemoglobin rose from 9.5 g% to 12.5 g% (normal male 13.9-16.3 and female 12-15) and platelets from 60,000 to 140,000/mm3 over 24 months. In addition, spleen size was reduced by 50% and liver size by about 25%. There was significant reduction of Gaucher cell infiltration in the bone marrow although mineral density is taking longer to improve.
It is important to appreciate that there is considerable variability on how patients have responded. The majority of patients have a good response with some showing dramatic improvement but there is a small number of patients in whom the response to enzyme therapy have been modest. This type of variability in responsiveness is noted at different doses as well as in different groups of patients. In a recent paper by Dr Gregory Grabowski, when these patients were treated with weekly infusions instead of every other week, the response was significantly better.
The standard criteria of organ size and blood work give a good indication of effectiveness of enzyme replacement therapy in the early years after treatment is started.
An increasingly important issue is that of maintenance treatment and how to monitor that Gaucher disease is under control.
A recently discovered blood test for the enzyme chitotriosidase by Dr Hans Aerts in the Netherlands, is especially sensitive for monitoring Gaucher disease activity during the maintenance phase of enzyme treatment. There is considerable genetic variability in chitotriosidase levels, and therefore serial (regular) measurements in individual patients is an extremely useful way of tracking the progress of disease.
Measuring chitotriosidase is also an aid to decide when treatment should be started. Dr Mistry gave an example of a patient who had no symptoms but signs of Gaucher disease and had successive increases in chitotriosidase levels. After 12 months of enzyme treatment her chitotriosidase was reduced from 16,000 to 2,000 nmol/hr/ml ( normal is less than 70).
Splenectomy is now rarely indicated with the availability of enzyme replacement therapy but in a small number of patients, the spleen is severely damaged through fibrosis (scarring) and infarction. This type of spleen cannot be treated with enzyme infusions and in fact can act as a sink for the enzyme, diverting enzyme away from other sites affected by the disease. In such cases, removal of the spleen has to be considered but it is important to make provisions for the patients to remain on long-term enzyme therapy beforehand.
Vaccinations for pneumococcal, haemophilus type B and mennin-gococcal infections has to be administered. Patients should also be aware of the high risk of acquiring infections that invade red blood cells ie malaria in the tropics and babesiosis in Eastern United States.'
Dr Mistry concluded by commenting on how the management of Gaucher disease necessitated a multi-disciplinary approach to evaluate the patient as a whole. This allows monitoring for any complications of Gaucher disease as well as assessing the impact of any other concurrent conditions on Gaucher disease itself.
My Aching Bones and Fosamax
Gene Therapy: The Next Frontier
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Source: Gauchers News January 1999
© Copyright Gauchers Association 1999