Treatment of Duchenne muscular dystrophy - defining the gold standards of management - 124th ENMC International Workshop
32 participants representing parents, funding
agencies and clinicians involved in the care of children with DMD from Belgium,
Canada, Denmark, Finland, France, Germany, Italy, the Netherlands, Spain,
Sweden, the UK and the USA met in Naarden from 2nd - 4th
April 2004.
The meeting was held under the auspices of the ENMC Clinical
Trials Network, and with the additional support of the United Parent Project.
The aims of the workshop were to define the need for clinical trials in Duchenne
Muscular Dystrophy (DMD) and develop a protocol for such trials, relating
primarily to the use of steroids (prednisolone, prednisone and deflazacort) in
DMD. The meeting heard that a major worry for parents is the lack of
availability of steroids at all in some countries, the multiplicity of steroid
regimes used and the problems of getting firm information about which type of
steroid or which regime for using steroids was best.
This was
reflected in the variation in practise amongst the participants at the Workshop,
who between them used at least seven different regimes for giving
steroids.
The meeting was divided into three parts. First, the evidence
for the use of steroids in DMD was considered. Second, the meeting split into
small groups for the development of various aspects of a protocol that could be
used for a trial of corticosteroids or for the monitoring of their use in
clinical practice, and third a strategy to develop and fund a trial or trials in
DMD were considered.
There can no longer be any doubt that use of
steroids in ambulant children with DMD alters the natural history of the
condition. Children treated with daily steroids walk for longer, have improved
respiratory function, may avoid the need for spinal surgery and might have
better heart function than untreated children. Benefits of starting steroids in
children who have already lost ambulation are not yet established. The two main
types of steroid used (prednisone or prednisolone and deflazacort) appear to be
equally effective.
Side effects seen with the long term use of steroids
in DMD use include weight gain, (which may be less prominent using deflazacort)
loss of height, asymptomatic cataracts (with deflazacort predominantly) and
thinning and possibly fractures of the bones. Nonetheless, many centres have
used daily steroids for many years, and ways to help to avoid or treat many of
these side effects are available.
There
are alternative ways to use steroids to try and minimise the side effects. These
include giving a lower dose, or using steroids in an intermittent way (on
alternate days, for periods such as 10 days on and 10 days off, or at the
weekends only). The rationale behind using these other regimes is to give the
body a rest from steroids at times, and/or with some but not all of the regimes
to give a lower overall dose.
People using all of these different regimes
report that they have a positive effect in improving strength and function in
DMD. However none of them have been tested formally against daily steroids to
see if there is a difference in how effective they are and what the actual level
of reduction in side effects is.
It was agreed steroids are the gold
standard of treatment in DMD against which other treatments should be judged. To
provide answers on the relative merits of the different regimes a trial is
needed to look at the efficacy and side effects of a range of regimes compared
to daily steroid over a long period of time. Protocols were discussed that would
allow differences in strength and function to be picked up and that would
monitor for side effects while also trying to prevent them as much as possible.
It was felt to be very important to monitor effects on quality of life as well
as muscle strength and function. Alongside testing different steroid regimes,
the ideal trial would also look at the best way to prevent the development of
heart problems and protection of bone strength. As this trial will need to
recruit large numbers of patients, a multinational effort will be required and
different national funding agencies are likely to be involved.
In advance
of this trial, it was felt that it would be useful to develop some basic advice
to be disseminated about the monitoring and management of possible side effects
of steroids in DMD. Problems with bone density and weight are two of the major
concerns as children with DMD can have problems in these areas even without
steroids. For example, even young children with DMD may have bones which are
less strong than normal. This is believed to be because they are less active
than other children. Exercise helps bones to grow strong, so boys with DMD
should be encouraged to be active. It is also important for growing bones to
have proper levels of vitamin D and calcium. The best way to achieve this is by
diet and sunshine- supplements are not as well absorbed. Because of their weaker
bones, boys with DMD may have a higher risk of breaking their bones, but they
heal normally. It is though important that broken bones are treated with as
short periods of immobilisation as possible.
Using steroids in DMD has
multiple effects on bones. Increased strength leads to more exercise and can
strengthen the bones. However, steroids are known to have a bone weakening
effect and this may become more prominent with long term use. Again, diet and
sunshine are currently the best way to try and prevent problems. Broken limbs in
steroid treated boys can be treated the same way as boys not on steroids. In
long term use of steroids some people have seen weakening of the back bones and
this can rarely cause pain, though it can be treated. The issue of prophylaxis
for these problems will be the topic of further trials.
Weight is another
worry for people using steroids. Boys with Duchenne muscular dystrophy sometimes
have a tendency to too much weight gain. This may partly relate to their lower
levels of activity. So the tendency to gain weight can be most when activity is
declining. In itself, of course, increased weight can also make walking more
difficult. Sweets and fast foods are best avoided where possible. Alternatives
to these kinds of treats are available, and low fat or low calorie alternatives
to many foods can be easily obtained. The need to control weight is even more
important in children with DMD treated with steroids. Appetite increases
immediately in many people who take steroids, and the family needs to be ready
for that. The highest risk of weight gain on starting steroids is in the first
few months so if particular attention can be paid to healthy eating at this
stage and continued with the steroid treatment, problems may be less. Additional
diet issues for children on steroids include adequate calcium and vitamin
D.
Further patient information material will be prepared and
disseminated.
This workshop was organised by Prof. Kate Bushby (UK), Prof.
Francesco Muntoni (United Kingdom), Prof. Andoni Urtizberea (France), Prof.
Richard Hughes (United Kingdom) and Prof. Robert Griggs (U.S.A.).
Other
participants were:
Dr. Anna Ambrosini (Italy), Prof. Corrado Angelini
(Italy), Dr. Carole Bérard (France), Dr. Doug Biggar (Canada), Dr. John Bourke
(United Kingdom), Dr. Jaume Colomer (Spain), Prof. Denis Duboc (France), Dr.
Michelle Eagle (United Kingdom), Prof. Brigitte Estournet (France), Dr. Kevin
Flanigan (U.S.A.), Dr. Patricia Furlong (U.S.A.), Dr. Nathalie Goemans
(Belgium), Dr. Imelda de Groot (The Netherlands), Dr. Sharon Hesterlee (U.S.A),
Dr. Anneke van der Kooi (The Netherlands), Prof. Rudolf Korinthenberg (Germany),
Dr. Adnan Manzur (United Kingdom), Dr. Richard Moxley (U.S.A.), Prof. Giovanni
Nigro (Italy), Dr. Helena Pihko (Finland), Dr. Michael Rose (United Kingdom),
Dr. Thomas Sejersen (Sweden), Ms. Birgit Steffensen (Denmark), Dr. Tony Swan
(United Kingdom), Dr. Marcello Villanova (Italy),Ms. Elizabeth Vroom (The
Netherlands) and Dr. Maggie Walter (Germany)