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Below is an overview of the research we are currently undertaking
both at the Rayne Institute and Lupus Unit at St Thomas' hospital.
Introduction
Much of our work
here at St Thomas' hospital relates to the clotting disorder
the 'antiphospholipid syndrome' - 'APS' or Hughes Syndrome.
We work in two arenas - the clinic and the laboratory. These
two areas are, for us, very closely intertwined. At three meetings
every week, those working in the clinic compare notes with those
based in the laboratory. Clinical questions - such as why do
some patients develop artery disease, others miscarriage, others
DVT and why, others with positive blood tests for Hughes Syndrome
(APS), develop no clinical problems at all - are discussed regularly
with the laboratory colleagues. Perhaps there are genetic factors,
perhaps there are differences in the actions of different antibodies?
We believe that
our strength is in our clinical experience. There are many
basic research units, but few with the detailed clinical input
a unit such as ours can provide. Some of our current research
projects are listed here.
Central nervous system disease
The brain is the organ
most dramatically affected in Hughes Syndrome. Why? It is possible
that the blood supply and the anti-clotting mechanisms in the
brain are in some way different - more sophisticated perhaps.
We are looking at the clinical and laboratory aspects of brain
involvement in Hughes Syndrome. Detailed magnetic brain scans
(MRI) have been especially helpful in visualizing these changes
in the brain.
Kidney
Clotting in the kidney
veins and arteries is a potentially important (and certainly
under-recognised) aspect of Hughes Syndrome. We are looking
in particular at those Hughes Syndrome patients with raised
blood pressure (a possible sign of kidney problems) to assess
the relevance of kidney vessel thrombosis and narrowing.
Immunoglobulins
The
conventional treatment for Hughes Syndrome is anticoagulation
(aspirin or warfarin), or immunosuppressants. An innovative
(though expensive) treatment is with the use of intravenous
immunoglobulins. Such treatment, while still in its infancy,
offers potential ways forward in some of our more 'resistant'
cases and we are looking at different doses required.
Accelerated atheroma
In some patients with Hughes Syndrome (and with lupus), there
is clinical evidence of accelerated artery disease - eg. strokes
and heart attacks. In the old days, this was attributed to steroid
therapy, but it is now becoming clear that some of the antibodies
we measure in Hughes Syndrome (antiphospholipid antibodies and
anti B2 GP1 - for example) may have direct effects on the process
of atheroma. This is one of the most exciting and potentially
'headline' spinoffs of the description of Hughes Syndrome.
Epilepsy
One of the features
of Hughes Syndrome in some patients is seizures. In our early
descriptions of the syndrome, we described epilepsy. However,
it is not known whether, in an epilepsy clinic, Hughes Syndrome
is a major, hitherto undiscovered cause.
Statins
These are the new
'wonder drugs' for reducing cholesterol. Interestingly, they
have other effects - 'calming', for example, the lining of blood
vessels. In 2000, our groups working with Dr Pier-Luigi Meroni's
team in Milan, won the accolade of 'best abstract' at the annual
American College of Rheumatology meeting in Philadelphia for
our work on the effect of statins on blood vessels and clotting.
Genetics
In some families,
there are more than one person with Hughes Syndrome - a mother
and daughter, for example, with migraine and miscarriage. It
is clear that genetic aspects are important in Hughes Syndrome,
and we are actively collaborating with genetic research groups
(including a study with the team in University College of Los
Angeles) in the molecular genetics of the disease.
Hughes Syndrome and lupus
One of the more perplexing aspects of the syndrome is the link
with lupus. Certainly, some lupus patients (perhaps 1 in 5)
develop Hughes Syndrome. However, recent
research has shown that the opposite does not apply - in
other words, patients with Hughes Syndrome do not seem to go
on to develop lupus. In our Lupus Unit we are in an almost unique
position to study the links between these two diseases.
Sjogrens Syndrome
"Dry
eyes, dry mouth, mild lupus". This is the clinical shorthand
for Sjogren's syndrome - an important and common autoimmune
disease. Many patients with Hughes Syndrome have this clinical
link.
Audit
Fashionable. Cost effectiveness. Loved by managers, We are,
in fact, in a very good position, in an international referral
centre, to look at the cost effectiveness of different forms
of treatment.
Warfarin versus aspirin
This is one of our
most ambitious studies. For those people found to have positive
tests (antiphospholipid antibodies), the long term outlook is,
at present, uncertain. Logic dictates that low-dose aspirin
may be beneficial, but in some, this treatment has not prevented
more serious complications, such as stroke. Sponsored by the
Arthritis and Rheumatism Council, we are co-ordinating an international
trial comparing the outcome of aspirin versus low dose warfarin
over a five year period.
Migraine
When we opened this
Hughes Syndrome website we were besieged with patients with
migraine. Headache, in all its forms, is the dominant symptom
in Hughes Syndrome. It has been known for many years that some
migraine sufferers can develop stroke. We believe that Hughes
Syndrome, detectable by simple blood tests, is a possible (a
probable) link and are actively studying groups of patients,
and their reaction to migraine.
Negative blood tests
As always in medicine
there are patients who 'fit' into a clinical diagnosis, but
in whom the tests don't add up. The commonest explanation is
that the tests are imperfect. We are carefully studying patients
with the clinical features of Hughes Syndrome whose tests don't
fit. Perhaps there are as yet undiscovered tests - other antiphospholipid
antibodies for example.
Self-testing
In those patients
who require treatment with anticoagulants (warfarin), a simple
blood test - "INR" (an international ratio) is the
benchmark of how 'thin' or 'thick' the blood is. In the majority
INR testing is routine and easy. In others life is difficult:
the INR fluctuates like a yo-yo. In Hughes Syndrome careful
INR control is vital. Poor control could mean a thrombosis (eg.
a DVT) - or worse, a stroke. We, in our unit, have strongly
advocated 'self-testing' in some patients with Hughes Syndrome.
A simple 'self-testing' machine, such as that used for finger
print blood tests in diabetes (current cost £400) could
help the individual patient to self- monitor warfarin control
much more precisely.
We predict that self-testing INR will, one day, become a
cost effective procedure in the majority of patients with
Hughes Syndrome. There is also hope over the next few years
that newer blood thinning medications may become available
that do not need INR testing.
Causes of thrombosis
The association between
antiphospholipid antibodies and thrombosis is strong, but the
exact mechanism for the thrombosis remains uncertain. The antibodies
have been shown to alter platelets, clotting proteins and the
blood vessel lining itself. The Louise Gergel Fellowship
has now appointed a full-time Research Associate to look at
the mechanics of thrombosis at cellular and DNA levels in order
to discover how and why some blood is prone to clotting.
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