MARION SELFE vividly remembers the day her body launched its attack upon
itself. 鈥淚t happened literally overnight,鈥� she recalls. 鈥淚 woke up paralysed and
in terrible pain. All my joints felt like they had hot needles in them.鈥� At
first she thought she had fallen victim to a bizarre disease caught during her
recent trip to Australia. The truth was less exotic but no less appalling. Selfe
had developed rheumatoid arthritis, a crippling and incurable condition that
affects 650,000 people in Britain alone. She was just 25.
Doctors were unable to give Selfe anything beyond painkillers, and a warning.
鈥淭hey told me that if I didn鈥檛 keep my joints moving, I鈥檇 end up in a
wheelchair鈥攚hich really scared me,鈥� she says. Today, 35 years later, she
has managed to avoid that fate, though she has lost the use of her wrists and an
elbow. Yet over all those years Selfe, like many other people with rheumatoid
arthritis, has clung to the hope that one day someone might find a cure. Perhaps
that day has come.
Two rheumatologists think they have finally unlocked the mystery of this
baffling disease. But the medical establishment first stonewalled, then
pilloried their radical new theory. Despite this, Jonathan Edwards and Geraldine
Cambridge from University College, London, claim to have the first evidence that
a safe and effective cure for rheumatoid arthritis may finally be in sight. They
have already had some success with a small number of patients, and are convinced
they can repeat this.
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Why would the body鈥檚 immune system turn traitor, attacking the lining of the
joints? This is the central puzzle of rheumatoid arthritis. For years
researchers trying to understand the 鈥渁uto-immune鈥� nature of the disease pinned
the blame on T lymphocytes, white blood cells that play a important role in the
immune system. T cells have two main functions: they take part in a direct
attack on invading organisms, and they control the production of
disease-fighting antibodies by another denizen of the immune system, the B
cell.
The usual suspect
Suspicion fell on T cells because patients who鈥檝e had rheumatoid arthritis
for some time have relatively high levels of T cells in their joints, and
because T cells interact with a molecule sitting on the surface of cells that
geneticists associate with the disease. But, quite why, or how, T cells should
suddenly turn traitor was far from clear. What鈥檚 more, studies of arthritis in
lab animals showed that when T cells become confused, the resulting autoimmune
disease isn鈥檛 at all like rheumatoid arthritis. 鈥淚t usually dies down after a
few weeks,鈥� says Edwards. 鈥淭his is quite different from autoimmunity in people,
where once it develops it often goes on forever.鈥� Then there鈥檚 the awkward fact
that T cells are not present in arthritic joints when they first become
inflamed.
Such findings persuaded Edwards to look for an alternative to the T cell
theory. He decided to focus on the hard facts about rheumatoid arthritis and
homed in on one particular question: why does the disease attack the lining of
joints, the synovium? Edwards was intrigued by the odd similarity between the
synovium and an apparently totally unrelated tissue in the lymph
system鈥攚hich just happens to be home to the immune system鈥檚 B cells. Cells
in both the synovium and certain lymphatic tissues, particularly the spleen,
express two molecules on their surface鈥攁nd these are linked to the
survival of B cells.
The significance of this became clear when Edwards pondered the ingenious
method by which B cells ensure that they can recognise invaders鈥攅ven ones
they鈥檝e never encountered before. Like T cells, they do it by randomly
rearranging their genes to create receptor molecules on their surfaces that are
capable of detecting new invading organisms. But B cells also release these same
molecules straight into the bloodstream, where they roam around as free-floating
antibodies ready to stick to infectious organisms and earmark them for
destruction.
B cells, again unlike T cells, never give up their genetic rummage for novel
molecules to combat invaders. Successful B cells thrive, while those that fail
to hit the jackpot are destroyed. And that, Edwards realised, could be the key
to the whole problem. What if some of those 鈥渇ailures鈥� aren鈥檛 killed off? And
what if they include B cells remiss enough to have produced antibodies against
friendly tissue? Worse still, what if these autoimmune B cells find themselves
in a place where they can actually thrive?
Edwards suddenly realised the significance of that odd similarity between
synovial and lymph cells. Perhaps synovial cells were nurturing B cells in
joints, mimicking the role played by lymph cells. But that still left him
wondering exactly how and why B cells turn traitor.
The answer lay in studies of the antibodies produced in rheumatoid arthritis.
Research dating back 60 years reveals something strange. Surprisingly, the
antibodies found in diseased synovial membranes don鈥檛 bind to cells in the
joint鈥攖hey actually bind to themselves. Normally, a mechanism in the body
would destroy B cells that produce antibodies to friendly tissue. But by binding
together, antibodies stop this mechanism being activated, allowing the B cells
and antibodies to proliferate. Worst of all, these antibodies can interact with
a receptor on the synovial cells to trigger damaging inflammation.
With so many strange coincidences about rheumatoid arthritis now making
sense, Edwards and his colleague Cambridge became convinced they had made a
major breakthrough. They could explain the autoimmune nature of the disease
through the link with confused B cells. Their theory also explained why anyone
might develop rheumatoid arthritis tomorrow and be afflicted for the rest of
their life. Remember that, unlike T cells, we continue to produce new types of B
cells throughout our adult lives. So there is ample opportunity for a freak
mutation to emerge and produce the antibody that sparks rheumatoid arthritis.
The theory even explained why those B cells that goof are not killed off and why
the disease focuses on joints.
Yet when Edwards and Cambridge tried to get their ideas published the
response was decidedly lukewarm. 鈥淥ne referee for a leading medical journal even
said that as there was a perfectly good T cell theory for rheumatoid arthritis,
there was no need for an alternative,鈥� recalls Edwards. Eventually, two years
later, the immunology journals agreed to run the paper. Then Edwards and
Cambridge waited for the questions and debate to begin. Instead, all they got
was silence. 鈥淭here was no reaction at all,鈥� says Edwards.
The researchers realised that if they wanted other scientists to take their
ideas seriously, they would have to put it to the ultimate test: a trial with
human patients. If their view of rheumatoid arthritis was right, then the key to
tackling it lay in breaking the vicious cycle of faulty B cell production.
Edwards draws an analogy with a computer program that鈥檚 locked in an endless
loop. 鈥淭he solution would be to turn everything off and start up
afresh鈥攔ebooting the whole system.鈥�
Switching off a vital component of the human immune system might seem like
asking for trouble, but Edwards points out that most people can live without any
B cells for a while. 鈥淭he key thing is that when the B cells come back, the ones
causing the disease should have gone鈥攁nd if they did eventually return, we
could repeat the treatment,鈥� he says.
To reboot the immune system, the UCL team needed a monoclonal
antibody鈥攁 molecular 鈥済uided missile鈥� that would seek out and destroy B
cells. They decided to use rituximab, a drug originally developed to treat
lymphoma鈥攁 malignant proliferation of B cells鈥攁longside more
traditional drugs that also deplete B cells. Finally, in November 1998, Edwards
and his colleagues were ready to put their theory to the test. They selected
five patients with severe and long-standing rheumatoid arthritis which had
failed to respond to all conventional treatments. Each patient was given four
intravenous doses of rituximab, together with oral doses of the other drugs,
over a three-week period.
With the patients鈥� B cells gone, Edwards and his colleagues waited to see
what would happen to their rheumatoid arthritis. Five months into the trial, the
results were spectacular. 鈥淲hen the patients鈥� B cells disappeared, so did most
of their arthritis,鈥� says Edwards. Three patients remained well, but symptoms of
the disease came back in two patients once their B cells returned. The side
effects were also minor: one patient had a temporary drop in blood platelet
count, and another had a chest infection. 鈥淚t was better than we could have
hoped for鈥攁nd better than virtually everything else so far reported in the
literature,鈥� says Edwards.
Going public
Even so, getting the new results published proved another uphill struggle.
The initial report was rejected as inconclusive. A year later, with the patients
still doing well, referees were still refusing to accept the findings. Finally,
last October the leading British journal Rheumatology ran the paper. By
then, the UCL team were treating 20 patients and all but two were doing well.
Edwards and Cambridge decided it was time to announce their work to a major
international conference, so they gave a presentation at the annual meeting of
the American College of Rheumatology in Philadelphia.
This time the response of the medical community to the findings was anything
but indifferent. By the time Edwards and Cambridge appeared before their peers
in Philadelphia, the story had been covered by newspapers, TV and radio around
the world. Despite the small scale of their clinical studies, people were saying
the researchers had found 鈥渢he cure鈥� for rheumatoid arthritis. The result was
predictable: a torrent of enquiries from sufferers, and accusations of
outrageous hype from the rheumatologists, many of whom where hearing about the
work for the first time.
In the weeks that followed, patients jammed arthritis charities help-lines
asking for more information and wanting to be included in the drug trials. The
UCL offices of Edwards and Cambridge also received over 600 letters and e-mails
from patients. 鈥淭he great majority fully recognised that the research is
preliminary, and simply wanted to know more,鈥� says Edwards. The verdict of the
medical profession was not so positive. An editorial in the British Medical
Journal expressed 鈥渙utrage鈥� at the way the UCL work was reported, and
condemned the 鈥渋rresponsibility鈥� of researchers talking to the press about
results from small studies.
But now the original furore has died down, along with much of the hostility.
Researchers have been able to take a cool look at the science behind the
sensational headlines and a growing number of them think that Edwards and
Cambridge may indeed have made a breakthrough. 鈥淐ertainly their B cell approach
has achieved a long-lasting remission in a few individuals鈥攖hough whether
this represents a cure is not clear and depends on the definition of cure,鈥� says
Dhaval Patel, a rheumatologist from Duke University Medical Centre in Durham,
North Carolina. 鈥淚t鈥檚 my opinion that the approach has outstanding potential in
a subset of patients.鈥�
Gabriel Panayi, professor of rheumatology at King鈥檚 College, London, is also
excited by the results so far. 鈥淚t鈥檚 a very small trial, and what we need to
know is what short and long-term side effects there might be. But it鈥檚
definitely a line of research that鈥檚 worth pursuing,鈥� he says. Panayi accepts
that B cells may indeed play a major role in rheumatoid arthritis鈥攂ut says
that it is too early to say whether Edwards and Cambridge have overturned the
orthodox thinking.
Patel points out that the patients received a cocktail of drugs and without
more detailed analysis the researchers can鈥檛 be sure that the effect is a result
of eradicating B cells. John Isaacs of the Molecular Medicine Unit at St James鈥檚
University Hospital in Leeds is even more cautious. 鈥淚 feel the evidence for B
cells in rheumatoid arthritis is not compelling鈥攂ut the same could be said
for many other cells implicated in the disease,鈥� he says.
What everyone wants is more evidence. Edwards and Cambridge are now hard at
work providing that. A major trial comparing the effectiveness of the elements
of the treatment to standard therapy is under way in Europe, Canada and
Australia, involving 160 patients. Results are expected early next year.
After years in a scientific no-man鈥檚 land, these are exciting times for
Edwards and Cambridge. Despite all the opprobrium heaped on them, they still
believe they are justified in using the 鈥淐-word鈥� when describing their approach:
鈥淥ur treatment was specifically designed to be a safe and effective cure鈥擨
see no reason to be reticent about using that word,鈥� says Edwards. 鈥淲e have yet
to achieve it, but I鈥檓 convinced we鈥檝e taken some important steps.鈥�