EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
By Nigel Hawkes
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
BY NIGEL HAWKES
INSIDE
SECTION 1 WHAT IS RA? : P4
ABOUT THE AUTHOR
SECTION 2 MANAGING SYMPTOMS: THE PRE-BIOLOGIC ERA : P6
SECTION 3 ARRESTING DISEASE PROGRESSION: THE TREATMENT GOAL FOR THE MODERN ERA : P8
This report has been authored by Nigel Hawkes,
SECTION 4 THE AGE OF BIOLOGICS : P10
independent science and health journalist. Nigel
SECTION 5 RA CARE IN THE NEW ERA : P13
graduated from Oxford with a degree in metallurgy
in 1966, and has written about science, health and
WITNESSES + REFERENCES : P16
international affairs in a career that began on the staff
of Nature and included long spells at The Observer
(1972-90) and The Times (1990-2008). He retired from
The Times in 2008 after eight years as Health Editor,
and is now a columnist and regular contributor to the
British Medical Journal. Between 2009 and 2012 he was
Director of Straight Statistics, a pressure group set up
to campaign for the honest presentation and use of
statistical data by government, media, and others.
He has written a number of books, including “Structures”,
a book about building and civil engineering, and more
than 40 science and technology titles for children
and teenagers. He was awarded the British Nutrition
Foundation Prize in 1992, appointed CBE in 1998 for
services to the newspaper industry and science,
and was the Medical Journalists Association
health writer of the year in 2007 and freelance
writer of the year in 2011.
EXECUTIVE SUMMARY
The treatment of rheumatoid arthritis has been one of the
make the treatment revolution possible are expensive
great success stories of the past 20 years. A condition
and patients must often go through a trial by treatment in
that to many was a life sentence - with no chance of
order to gain access to them. Some are lucky enough not
parole - has become one which in most cases can be
to need them, in which case the guidelines in place work
well-managed, some can even enter remission, enabling
well: there is nothing the NHS is happier to prescribe than
patients to lead a normal life of work, family and private
a cheap drug that works.
enjoyment, mobile and out of pain.
But for those that do need biologics - and even more for
Yet this success is not fully appreciated by the public,
those who go on to need more than one in succession -
nor celebrated by the National Health Service (NHS) as
a series of hurdles have been erected that, when taken
it deserves. The revolution has come about as a result
in the round, are out of step with current clinical practice.
of improving drug treatments and a radical change in
It is right that NHS resources should be prudently
strategy, which links early detection of the condition
accounted for, but to judge the impact of the biologics
to prompt treatment. When all goes well, the results
only in terms of the individual patient’s cost and benefit
are good, with as many as half of patients going into
is to see the issue through a distorting lens. The majority
remission: to all outward appearances, cured.
of RA patients are of working age, and to keep them at
work, generating wealth, paying taxes, off benefits and
But all does not invariably go well. Patients with painful
able to look after their families, creates an economic
joints are too reluctant to go and see their doctor, while
return that dwarfs the narrow focus on costs of medicines
those GPs poorly-trained in the diagnosis of RA may only
versus quality life years saved.
send them away with a prescription for painkillers. It can
The Eye Witness report has been commissioned and funded by Pfizer. Health journalist
Nigel Hawkes developed the report based on insights from patients, public figures and
leading rheumatology professionals who have been affected by the evolution of rheumatoid
arthritis (RA) treatment and Pfizer’s input has solely been to approve the final report in line
with the ABPI Code of Practice.
take several visits to get a referral to a specialist who
The battle is not won. There are still some patients who
then has to make the best of an imperfect situation. The
do not benefit from the existing biologics and depend on
window of opportunity for achieving remission is too often
future research to generate new products tailored to the
slammed shut by delays that could be avoided.
small print of a disease that varies so much from patient
to patient. Patients, public, and the profession need to
Nor are specialists allowed as much freedom of action
unite to ensure that today’s success is not allowed to slip
as they would like. The biological drugs that have helped
away, but provides a springboard for tomorrow’s.
[COMM111] 8th December 2014
2
3
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
SECTION ONE WHAT IS RA?
690,000
For many years, rheumatoid arthritis was a disease in
but it could be an infection, an injury, stress, a genetic
the shadows. Doctors did not understand its causes and
predisposition, or other factors yet to be discovered.
lacked the means to treat it effectively, many wrongly
There are
affected people in the
UK and 26,000 new diagnoses every year, which makes
it commoner than multiple sclerosis...
believing that with bed rest and pain-killers the majority
The immune system is complex and exquisitely specific.
of patients got better. The public saw it as a disability of
Normally it is marshalled into action by the presence of
the old with vague and sometimes disbelieved symptoms,
an invader, such as a virus, a bacterium, or a tumour.
while a lot of patients persuaded themselves it was a
It recognises the invader as foreign, and attacks it
RA is not a rare condition. There are 690,000 affected
The effects can be crippling, both physically and
consequence of age which they must bear with as much
using weapons designed to defeat the invasion without
people in the UK and 26,000 new diagnoses every year,
psychologically. When Mary Cowern was diagnosed with
stoicism as other aches and pains. Many spent their lives
damaging anything else, desisting as soon as the battle
which makes it commoner than multiple sclerosis or
RA at the age of 20, her first reaction was disbelief.
out of sight, unable to work and trapped in their homes,
is won. To pull this off, it has to distinguish between “self”
leukaemia . Nor is it restricted to older people; 12,000
“I think my first words were ’You must have got that
with occasional respite visits to hospital. “There was no
and “non-self”, between its own tissues and those of the
children under 16 suffer the juvenile form of the disease (2).
wrong – I can’t have rheumatoid arthritis, I’m too young.”
talk about remission, or even getting your disease under
invader. In RA and other auto-immune diseases something
Although the joints are the principal focus, RA can affect
But disbelief quickly turned into despair as her symptoms
control” says Ailsa Bosworth, founder of the National
goes wrong. The tissue of the joints is mistakenly seen
many other organs as well. There is considerable variation
worsened and her work as a shop manager became more
Rheumatoid Arthritis Society, who was diagnosed with RA
as “non-self” and a concentrated attack is launched.
in the symptoms. Professor Ali Jawad, Consultant
and more difficult for her. “I was worried about how my life
in her early 30s. “It was very much about ‘yes, how can we
And because the joint tissue never goes away, the attack
Rheumatologist at the Royal London Hospital says:
would pan out” she says. “I could see myself becoming
relieve your pain?’”
continues: acute inflammation becomes chronic, damage
“Two thirds of patients present with arthritis affecting
more disabled and then wondering where this would end.
multiplies (including pain and swelling), and the joints
mainly the small joints of the fingers on both hands.
I was only in my 20’s and my life seemed to be quite over.”
are eroded.
Quite often the wrists are affected and the knees, the feet
Since RA was first given a name in the mid-19th century,
(1)
many theories about its origins have been advanced,
to a lesser extent. Then in decreasing order it would be the
The data show her fears were not exaggerated.
some favouring an infectious cause, others believing there
elbows and the shoulders and the hips.”
The National Audit Office (NAO) found in a report
published in 2009 (3) that people with RA take 40 days sick
to be a genetic link. Today it is known that the symptoms
of RA are caused by friendly fire, when the body’s immune
system turns its energies into attacking itself it belongs to the class known as auto-immune diseases.
What triggers this misdirected attack remains unknown,
“ I was worried about how
my life would pan out ”
leave a year, compared with the national average of 6.5
days. A third have been forced to give up work within two
years, and half within ten years. Since three quarters of
those diagnosed with RA are of working age, the impact
on the benefits system and the economy as a whole is
Women are around
three times
more likely to develop
RA than men
4
Women are around three times more likely to develop
substantial. While the NAO found that healthcare costs
RA than men and it runs in families, but not especially
for treating RA are large, at £560 million a year, they are
strongly. “It is not a genetic disease as such, but there
dwarfed by the costs in sick leave and disability payments
are genetic factors” says Dr David Walker, consultant
of £1.8 billion. The NAO does not attempt to estimate the
rheumatologist at Newcastle upon Tyne NHS Foundation
cost to the economy of the lost productivity of RA patients
Trust. Once the immune system begins to misdirect its
but the NRAS puts it at £8 billion a year (1).
fire, the damage it does can be extensive. While disease
progression varies greatly from patient to patient, if
left untreated RA will cause irreversible damage to the
joints, which may need to be pinned or replaced. Unlike
osteoarthritis, which affects only the joints, RA can also
cause inflammation elsewhere and damage the lining of
the heart and lungs, as well as the blood vessels and eyes.
5
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
biopsies every two years in case it was damaging the
and you are struggling to move so it is taking your energy
liver. We were very anxious about using it because of that,
and your energy goes. That’s how it affected me.
because a liver biopsy has a mortality attached to it.”
I wanted to do things but I was just physically and
mentally exhausted. I just couldn’t do it.”
SECTION TWO
MANAGING SYMPTOMS: THE PRE-BIOLOGIC ERA
12,000
children under 16
suffer the juvenile form of the disease
In the middle of the Ashdown Forest in Sussex, a leading
inflammation and suppress the immune response had
centre for hip and knee replacement surgery operates
been hailed as a huge advance, but experience showed
with great success far from the great centres of medicine
that the side-effects were severe and in some cases fatal.
– quite a long way, indeed, from any other hospital. The
Steroids provided no permanent answer, but continue
Horder Centre is remote because it started its life as a
to have a role in damping down flares. Gold-based
place where patients with RA, with no cure in sight and
medicines and penicillamine were more encouraging,
not much to alleviate their pain, could find peaceful respite
the first to have an effect on the progress of the disease
among the trees. Inspired by its founder Cecilia Bochenek,
rather than merely its symptoms. “Some of the happiest
who had contracted juvenile RA at the age of six, the
patients are the ones that respond really well to gold”
centre was opened in 1966 by Princess Margaret. Without
says Dr Walker. Sulfasalazine, one of the anti-bacterial
stretching a point, it offered hospice care to the living at a
sulfa drugs, had been tried in the 1950s because of
time when medicine could offer little more.
suspicions that RA might be caused by an infection, and
it proved moderately effective. Hydroxychloroquine, an
Many patients then spent part or all of their time in
anti-malarial drug, was found to have immune-suppressing
hospital. The 1993 edition of the Primer on Rheumatic
qualities and joined the armoury. Most importantly, a
Diseases, the leading professional title on the subject, said
cancer drug, methotrexate, was found to work surprisingly
that the foundation of treatment was rest combined with
well. This group of disease modifying anti-rheumatic
anti-inflammatories such as ibuprofen and naproxen (4).
drugs (DMARDs) formed the basis of treatment in the
Caution was the watchword. The pyramid approach meant
starting slowly, one drug at a time, then trying another if
Orthopaedic surgeons were kept busy carrying out a range
that failed, and slowly building up to the more potent but
of operations on hands, knees and other joints. Mary
potentially more toxic drugs such as methotrexate.
Cowern had her first knee replacement when she was 29.
Dr Louise Warburton, a GP with a special interest in
“I was very young to have a joint replacement but that’s
rheumatology, recalls her first job at the Robert Jones
how bad and how quickly my disease had progressed”
and Agnes Hunt Hospital in Oswestry, in 1992. “We just
she says. “We were at the point where my surgeon had to
had the basic DMARDs – I don’t even think we used
do it, there was no option.” Ailsa Bosworth, then a director
methotrexate then, because it wasn’t around, so we used
of an engineering company and with a young child, had
sulfasalazine as one of them, and hydroxychloroquine,
four operations on her hand and wrists. “For a period of a
and there was something called penicillamine. They were
year I couldn’t use one or other of my arms or hands, so
fairly basic drugs. They are not very effective in aggressive
my husband had to learn to cook pretty quickly. I have had
disease and they have lots of horrible side effects, really.
four foot and ankle operations where you are non weight-
When I first started that job, it was a shock to the system
bearing for 12 weeks and when you can’t hop around on
to say the least because there were people with extremely
crutches because both your elbows have been replaced
advanced joint disease that wasn’t being properly
these throw up real challenges.” Her operation count now
controlled. They were awfully disabled – they came in
stands at 19.
wheelchairs, or with walking sticks or Zimmer frames.
It was a huge, massive problem for them all.”
Alison Kent, a rheumatology nurse specialist at Salisbury
NHS Foundation Trust, began work at about the same time
as Dr Warburton. “The treatment goals were about trying
“ And it didn’t just affect your joints, it affected everything ”
to keep patients’ disease as quiet as you possibly could,
and keep them pain-free. The treatment pyramid was to
Professor Jawad carried out an audit of the time RA
start slowly and build up, so as your disease progressed
inpatients spent at the Royal London in 1999, and
you received higher treatment. I would spend a lot of time
discovered it totalled 2,400 bed days – equivalent to 240
doing counselling and education and supporting, because
patients each spending an average of ten days in the
it was helping people to live with the condition. We hardly
hospital during the course of the year (5). At that time, the
ever used the word ‘remission’ at all.”
London employed four surgeons who operated on the
hands of the RA patients – two orthopaedic surgeons and
Pamela Adams, an RA patient from Worcester, was
two plastic surgeons. Professor Peter Kay, consultant
diagnosed with the disease more than 30 years ago,
orthopaedic surgeon at Wrightington Hospital near Wigan,
when she was 29. She had never heard of RA: “My
who is National Clinical Director for Musculoskeletal
says Professor Jawad, patients were provided with special
understanding was old people got it. It was a bit of a
Services, says that it used to be commonplace to
shoes or splints and if the disease flared up they were
shock at the time because my first thought was that I was
see people with RA who were really quite crippled,
going to end up in a wheelchair. The main thing that was
with deformities – twisted hands and fingers, and in
affected were my knees – walking the older children to
wheelchairs. “We still do joint replacements in RA patients,
school and pushing the pushchair, I was struggling.
but it is less common than it used to be,” he says.
I shuffled a lot because my feet and my fingers started
“The really bad deformities that you used to get,
to swell.
particularly affecting the hands and upper limbs, that was
The bottom line of its treatment pyramid lists “education,
pre-biologic era. (It was the success of these drugs that
rest, exercise, social services, salicylates or other non-
caused the Horder Centre to switch from RA to hip and
steroidal anti-inflammatory drugs (NSAIDs)”. In addition,
given injections in their joints or short courses of cortisone
tablets. “This was in 1993, so that is not so long ago.”
Ailsa Bosworth remembers the period without any hint
of nostalgia. “I was diagnosed in the days when all you
knee implant surgery for osteoarthritis.)
“ They waited until you were disabled before they gave
you anything faintly useful ”
a major problem but you see an awful lot less of that.”
had were NSAIDs and painkillers and they waited until
But the prospects for many patients remained poor.
you were disabled before they gave you anything faintly
“We used to wait until patients had bone erosions on their
“And it didn’t just affect your joints, it affected everything.
useful” she says. “I had endless swollen joints, a lot
X-rays before we would intervene with the odd DMARD
It affects your organs as well because you are breathing
of pain, endless aspirations of joints and injection with
that we had, so it was late and inadequate treatment with
steroids, and putting legs in plaster, wearing leg splints
potentially toxic and not very effective drugs” Dr Walker
and wrist splints, all sorts of things. I had drawers-full of
says. “Methotrexate came along in the early 1990s. It was
the wretched things.”
an old-fashioned cancer drug but the dermatologists had
been using it for psoriasis, and they used to do liver
The use of steroids such as cortisone to reduce
6
7
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
SECTION THREE
ARRESTING DISEASE PROGRESSION:
THE TREATMENT GOAL FOR THE MODERN ERA
Proper testing emerged at the same time as an
it, compared to a third given antimalarials or injected gold,
improvement in treatment using non-biological DMARDs.
30% given penicillamine, 25% sulfasalazine and 18%
The key was the more intensive use of methotrexate. In the
oral gold. The authors of the study called these results
1980s it was given to very few RA patients, but numbers
disappointing but concluded that methotrexate was the
rose in the 1990s and continued rising in the 2000s as
best of the bunch.
methotrexate became the “anchor drug” in most RA clinics.
While a large dose of methotrexate kills cells, lower doses
Despite the high drop-out rate, however, it was clear for
given weekly have an immune-modulating effect, with a
the first time that it might be possible to stop the disease
much lower risk of serious side-effects.
developing and prevent the erosion of the joints; some
patients might even go into remission. Emboldened by this,
Many patients do well on methotrexate. “Roughly a third
the old concept of a slow build-up in treatment intensity
Before the 1990s, those treating RA had no agreed
go into remission so yes, they do very well” says Dr Walker.
was abandoned in favour of a strategy of hitting the disease
measure of what success meant: nor could the
Pamela Adams is one of them. “It’s worked OK for me”
hard and early.
severity of the disease be accurately assessed.
she says. “I can still work part-time as an administration
That changed with the introduction of the Disease
clerk, four to six hours a day. You do get your days with
“Fifteen years ago we used to say you start with one drug,
Activity Score (DAS) from 1993 onwards. DAS
this complaint – there are days when it flares up and
maybe start with hydroxychloroquine, if the patient is not
recognised that measuring disease activity in RA
you just feel sore and it is difficult to move. But without
better within six weeks then add in another one and then
is not straightforward, and cannot rely on a single
methotrexate I would be worse.”
add in another one” says Professor Jawad. “The problem
was we noticed the effect on the bones. The reason why
symptom. The patient’s own experience of joint
tenderness, for example, may reflect factors such as
But her daughter Donna Saunders, who also has RA,
we have to treat the patients early is because at the time of
pain threshold, depression, degenerative changes
takes a different view. She is on biologics and believes her
diagnosis, let’s say around half the patients will have holes
and other conditions such as fibromyalgia as much
mother should be, too. She says her mum is too stoical and
in the bones, erosions. If you don’t treat effectively then
as they do the objective severity of the disease.
underrates the pain she feels. “Although she is saying she
within two years 80% will have these erosions and once
manages, I do think she could be better and on biologics
they happen they are very difficult to treat.
Today disease activity in RA is assessed on a
that would make a difference. But she doesn’t meet
scale called DAS-28, so-called because it includes
the criteria.”
assessments of swelling and tenderness in 28 joints,
The National Audit Office found
together with the results of one of two possible
Mrs Adams takes methotrexate once a week by self-
biological tests, for erythrocyte sedimentation rate
administered injection. “The next day I feel sick and poorly,
(ESR) and c-reactive protein (CRP), both of which
really drained, but that will wear off. For the rest of the week
are measures of the degree of inflammation. ESR
it works. Without it you would really be struggling to do
measures the rate at which red blood cells sediment
anything but with the medication you can get about a bit
in a period of an hour: when inflammation is present
more than you would without.”
the red blood cells form clumps which tend to sink
in a report published in 2009
faster. CRP is a ring-shaped protein made by the
Dr Walker is taking part in a national survey of
liver in response to inflammation and detectable in
methotrexate. “We just did 100 patients who are on a
that people with RA take
blood plasma.
stable dose of methotrexate and planning to continue and
“ If we attack with vigour at
the beginning you are more
likely to stop the erosions from
happening. Early diagnosis is
important, early intervention
is important ”
asked them what they were putting up with, and 56 had
“What we did as a result is that we found if we attack with
No single measure on its own clinches a diagnosis
something: fatigue for a day, and nausea which can be very
vigour at the beginning you are more likely to stop the
of RA, but in combination they can be assembled
unpleasant as it’s almost anticipatory. They look at a bottle
erosions from happening. Early diagnosis is important, early
a year, compared with the
into a score that correlates well with joint damage,
and start retching. Patients sometimes describe it as a
intervention is important. Hit it on the head.”
with a clear relation between the DAS-28 score over
‘methotrexate day’. It’s really very unpleasant. Women also
national average of 6.5 days.
a period of time and the joint damage found on
complain about hair loss.”
40 days sick leave
A third have been forced to give
up work within two years, and
half within ten years...
This marked a big change in treatment, turning the old
treatment pyramid upside down. Guidance from the
X-rays. So DAS-28 has become the standard, with
scores above 5.1 representing high disease activity,
A retrospective study (6) of almost 2,300 patients treated
National Institute for Health and Care Excellence (NICE)
those lower than 3.2 low disease activity, and those
between 1985 and 1994 showed that methotrexate was
now says that newly-diagnosed patients should be treated
below 2.6 remission.
better tolerated than other DMARDs. Fewer patients
with a combination of three drugs right from the start, of
discontinued taking it, and a lower proportion of those who
which methotrexate should be one, together with at least
did blamed inefficacy. While many did give up, complaining
one other DMARD, plus short-term steroids (7).
of side effects and poor results, even larger numbers
abandoned the other DMARDs. After roughly three years
half the patients prescribed methotrexate were still getting
8
9
EYE WITNESS REPORT
The potential for monoclonal antibody medicines in RA
emerged with the discovery that a naturally-occurring
BIOLOGICS IN RHEUMATOID ARTHRITIS
protein, tumour necrosis factor (TNF) is a major regulator
of the inflammation process. TNF (which acquired its
SECTION FOUR THE AGE OF BIOLOGICS
misleading name from experiments showing it could
destroy tumour cells in test tubes) is a cytokine, a class of
“ I have not looked back
since. It has completely
transformed my life ”
small proteins that act as messengers. Of these, a form of
Since
three quarters
of those diagnosed with RA are of working age...
TNF called TNF alpha is the most important in RA, acting
Not everybody reacted so swiftly or so well, but the clinical
as a ringleader encouraging other cytokines such as
results show that biologics plus methotrexate work much
interleukin-1 (IL-1) and interleukin-6 (IL-6) to produce the
better than methotrexate alone. “You get this much benefit
enzymes that actually destroy cartilage and bone. In 1993
from methotrexate” says Dr Walker with his fingers close
a study at the Kennedy Institute at Hammersmith Hospital
together, “you get this much benefit from biologicals” -
in London demonstrated that a monoclonal antibody drug
widening the spacing - “and if you take the two together
targeted at TNF alpha produced a marked reduction in
you get this much benefit” opening his hands wide.
inflammation (9). The drug was infliximab, developed in
the US.
His experience is that roughly 80% of patients respond
in a worthwhile way. This is measured by a system
Biologics reached the clinic in the late 1990s, producing
devised by the American College of Rheumatology, which
compelling results in many patients. Mary Cowern had her
comprises three categories, ACR20, ACR50 and ACR70,
The key ingredients of most drugs are chemicals in the
half its parentage to a cancer, a teratoma. Later, because
first injection on a Tuesday. She had read about the new
the numbers referring to the percentage improvement in
form of small molecules able to penetrate almost any
the product of such cells is a single line of identical
drugs and admits it was quite a scary moment for her. Not
symptoms. “It’s roughly how much better they are, so an
part of the body through the bloodstream. They work by
antibodies, they became known as monoclonal antibodies.
only was she terrified of needles, but she worried that this
ACR70 means that the patient is 70% better. Nearly all the
was her last chance and that it might not work.
figures with all the biologics are that 60% get an ACR20,
40% an ACR50, and 20% an ACR70.”
interfering with the activity of the protein molecules, a
thousand times larger, that make up the organs. But this
Their advantage was that they could be produced in
The effect was swift, and took her by surprise. “A couple
is not how the body’s own defences work; the immune
vast quantities, to target almost any antigen. Their
of days later I had got up, gone downstairs and was
system does not generate tiny active substances akin
disadvantage was that they were based on mouse, not
making a cup of tea, and I suddenly thought ‘Oh my God,
to drugs, but instead mobilises large proteins called
human cells, and would be recognised as foreign by
that was so easy’. It literally was that instantaneous for
antibodies to attack invaders. These are tailored to the
any patient into whom they were injected and attacked
me. Whereas normally I would struggle out of bed, I would
precise job they have to do, and switched off when that
by the patient’s own immune system. Producing human
shuffle downstairs, I would struggle to fill the kettle.
job is done. Matching this precise and specific mode of
monoclonal antibodies proved difficult, but there were
It was so much easier and I was thinking this must be in
action has long been a dream of drug developers.
ways to “humanise” mouse monoclonal antibodies, also
my head. I rang my Rheumatology Team and spoke to the
pursued at Cambridge, using recombinant DNA methods.
nurse there and she said: ‘You aren’t the first patient to
The first sign that it might be possible came in 1975,
While Milstein (who shared the 1984 Nobel Prize for
say this’.
when César Milstein and Georges Köhler at the Medical
Medicine with Köhler and a third scientist, Niels Jerne,
Research Council’s Molecular Biology Laboratory in
for the discovery) did not at first realise the economic
Cambridge devised a way of creating an endless supply
potential, it has proved enormous: the market for
of antibodies in a test tube. Building on the work of many
monoclonal antibody drugs now exceeds $50 billion
previous researchers, they did this by taking immune
a year (8).
system cells from the spleen of a mouse that had been
challenged by a foreign protein (sheep red blood cells)
to stimulate the production of antibodies. The problem
that had stumped earlier researchers was that such cells,
grown outside the mouse in a culture medium, do not
continue producing antibodies for very long.
“ 80% of patients respond
in a worthwhile way ”
...the impact on the benefits system
and the economy as a whole
is substantial.
Milstein and Köhler had the bright idea of immortalising
the immune system cells by fusing them to mouse tumour
cells. Tumours do not die off as normal cells do, but
continue proliferating indefinitely. The two scientists hoped
this fused hybrid cell would produce an immortal line
of cells generating a single antibody against the foreign
protein. To their joy, they were right. They called the
product a hybridoma, because it was a hybrid that owed
10
11
Trial results of five biologics (infliximab, etanercept,
lot more about disease assessment, education about
adalimumab, golimumab and certolizumab) confirm his
the medication, side effects and self-management. It is
view that all fall within a similar range of effectiveness.
more of a positive message to be able to give to people
Benefits have included far fewer inpatient stays. At the
because you can say: ‘Well, if this one doesn’t work then
Royal London they fell from 2,400 bed days in 1999 to just
there is another one’ whereas it used to be ‘If this doesn’t
180 in 2006, after biologics became established . “That is
work we are at the end of our possibilities.”
(5)
a dramatic impact” says Professor Jawad. The number of
surgeons who operate on damaged joints at the hospital
GP Louise Warburton says a major change has been that it
has fallen from four to one. “Really you could say we have
is now often impossible to tell that a patient has RA.
shifted the expectations” he says. “Now we are achieving
“A patient would come in with no sign of disease and you
remission in RA, we are preventing an accumulation of
would think ‘Why are they in this clinic?’ It wasn’t until you
damage and we are preserving quality of life.”
looked back at the notes that you saw they had had very
EYE WITNESS REPORT
BIOLOGICS IN RHEUMATOID ARTHRITIS
SECTION FIVE RA CARE IN THE NEW ERA
The biologics are expensive drugs, and need to
justify their cost by the outcomes they achieve. In
the NHS this calculation is the responsibility of NICE,
which has issued guidance both on the individual
medicines and, in NICE clinical guideline 79, on the
active disease and that it was much better.”
A diagnosis of RA has in the past generally led sooner
or later to leaving the job market. But many patients on
biologics can continue in work, or return to it like Mary
Cowern. She now works as the Welsh Director of the
charity Arthritis Care. “I am back working full time which I
never thought I would be able to do ten years ago. I am in
a relationship and I have a step-daughter so I have family
life. All the things I thought had been taken away from me,
I got back. It might sound a bit corny but I have got the
old me back, because I am a lot more positive. It is really
phenomenal for me the difference it has made.”
“ My job has changed dramatically because we are
now talking to patients about
remission, and keeping them
in work ”
Success in so many cases means that RA, once invisible
because it drove people from sight, is now invisible
Life expectancy in RA patients is lower than in matched
because it is so much better treated. That’s a slight
control populations, so better control of the disease ought
worry for Professor Peter Kay, who as National Clinical
to reduce that difference. A study published in 2007
Director for Musculoskeletal Services is anxious to ensure
(10)
management of RA as a whole, in adults (7). This
guidance calls for the urgent referral of patients if
the small joints of the hands or feet are affected,
more than one joint is affected, or there has been a
delay of three months or longer between onset of
symptoms and seeking medical advice.
While the NAO found that
healthcare costs for treating
RA are large, at
£560 million
“ Patients delay, up to three
months or even longer;
and then GPs delay in
referring them ”
found that after adjusting for disease severity treatment
the specialty has a visible profile. “The trouble with
with TNF-blockers was found to be associated with
musculoskeletal stuff is that it is not quite as emotive as
reduced death rates in women, though not in men at that
kids, cardiac and cancer” he says. “It doesn’t hit the
time. Longer-term studies may show both sexes gain
same priority.”
a year, they are dwarfed by
should be conventional DMARDs, which must include
That is important because despite the great success of
the costs in sick leave and
short-term steroids. This should be done as soon
disability payments of £1.8 billion.
of symptoms. That is a hard target to meet, and it is
The NAO does not attempt
“I quote this report all the time when I am lecturing
to estimate the cost to the
three months or even longer; and then GPs delay
economy of the lost
average of nine months for patients to be put on the
some years of life.
For arthritis nurse specialist Alison Kent, biologics have
RA treatment in the biologic era, not every single patient
changed the whole dialogue of the clinic.
benefits. There are some for whom biologics work less
well, not at all, or diminish in effectiveness over time.
“My job has changed dramatically because we are now
There are also fears over the ability of the NHS to exploit
talking to patients about remission, and keeping them in
the “window of opportunity” to stop RA in its tracks by
work. In the past a lot of our work was about counselling
prompt diagnosis, referral and treatment.
and supporting and pain control, whereas now it is a
The first treatment option, says the NICE guidance,
methotrexate and at least one other DMARD, plus
as possible, ideally within three months of the onset
not being met, the NAO found in its 2009 report (3).
GPs” says Dr Warburton. “Patients delay, up to
in referring them. The net effect is that it takes an
right treatment.”
productivity of RA patients
but the NRAS puts it at
£8 billion a year.
12
13
If having these drugs enables somebody to go back to work and
start paying tax instead of claiming benefits, that has a
direct impact
on the wider society and on government.
The rigid interpretation by her Clinical Commissioning Group
(CCG) of the NICE guideline forced her to take rituximab with
methotrexate when she failed on her first biologic, against
her wishes and those of her consultant because it was
contraindicated. “The CCG insisted that the pathway be followed,
even though NICE says that you must also look at the patient’s
response”, she says. “I am not alone. I am on the RA bulletin
boards, on Facebook, on NRAS; it is a repeated problem.”
Like others, she is critical of delays in referral. “Some GPs (but
not mine!) are woefully ignorant - the problem is that they receive
very little musculoskeletal and auto immune disease training.
This needs to be remedied.” It is a criticism echoed by
Dr Warburton: “GP training schemes don’t spend much time on
RA, and the problem is that GPs will probably only see one case
every two years of new rheumatoid in their surgery. The obvious
If patients do not respond to conventional DMARDs
therapies is heavily restricted until a patient’s burden of
cases are obvious, but even some of those are not referred
within six months, and their DAS28 score is greater than
disease has become severe. Compared to other European
promptly”. Ailsa Bosworth believes that occasions where patients
5.1 on at least two occasions one month apart, they may
countries this seems to be too little, too late.”
are being referred as rapidly as the guidelines suggest are
“very rare”, despite evidence that if you can treat somebody
then be prescribed biologics, normally in combination
with methotrexate. Biologic treatment should only be
These findings were supported by a 2010 report (13) by
within that 12-week window of opportunity you have a much
maintained if there is an improvement of at least 1.2 in
Professor Sir Mike Richards, the former National Director
better chance of getting them into remission. The NAO report
the DAS28 score at six months, and if it is sustained
for Cancer, and now Chief Inspector of Hospitals. Charged
found that people with RA visit a GP four times on average
at subsequent six-monthly appointments. If the first
by the Health Secretary with investigating the international
before being referred – and 18% of them visit eight times before
biologic fails, patients may move on to rituximab plus
variation in the use of drugs in 14 countries, he concluded
a referral(3).
methotrexate, which should also be subject to the same
that the UK came tenth out of 14 in its use of RA drugs –
six-monthly checks.
two places worse than in its overall ranking, which
Peter Kay, with overall responsibility for musculoskeletal
was eighth.
conditions for NHS England, says: “These are expensive drugs
but the response is quite impressive. Obviously if you consider
Ailsa Bosworth of NRAS does not believe that this
guidance ensures that all patients who should be on
The UK approach to biologics has found a doughty
the societal costs, they are not as expensive as they seem. I
biologics actually are. She argues that the threshold is too
opponent in Sal Brinton, Liberal Democrat health
regard it as being really important that people present early,
high and the sequencing has more to do with the order
spokesperson in the House of Lords, who suffers from RA.
are diagnosed early, and receive treatment early.”
in which the drugs were introduced than it does to their
Baroness Brinton has found accessing biologics difficult
clinical benefits. “The threshold was cautiously set, quite
and their effect limited. Diagnosed eight years ago, she is
The danger, as Ailsa Bosworth sees it, is that NICE’s remit is
rightly at the time, because we didn’t know what the long-
one of the unlucky ones who do not respond well, and she
drawn so narrowly that it leaves too much out of consideration.
term outcomes would be, and we were concerned about
is now in a wheelchair. Her blood tests were negative –
“NICE has done a lot of good, but is only looking at half the
greater cancer risk, so it was right to be cautious. But
“therefore I don’t get an automatic route to biologics until
picture. If having these drugs enables somebody to go back to
there are quite a large number of people who fall into the
a whole string of other things have been tested” she says.
work and start paying tax instead of claiming benefits, that has a
3.6 to 5.1 DAS score who will do as badly as people with a
“It took quite a while even to get on to methotrexate. I also
direct impact on the wider society and on government.
DAS score of greater than 5.1. So I think we are not doing
had ten DMARDs before moving on to biologics.”
Not to take that into account when you are evaluating the
enough.” The British Society for Rheumatology agrees,
health economic benefit of these drugs is completely illogical
arguing that the threshold should be reduced to a DAS
and misleading.”
score of 3.2 together with at least three or more tender
and three or more swollen joints (11).
A comparison of the variations in guidelines in use across
Europe, funded by Merck Sharp and Dohme, found little
consistency in the 12 countries studied (12).
“The potential to tackle RA and limit the burden of disease
is now well-established, but the will to do so in some
The potential to
tackle RA
and limit the burden
of disease is now
well-established
“ I regard it as being really
important that people present
early, are diagnosed early,
and receive treatment early ”
countries appears to be weak”, the report concluded.
“Of the 12 countries studied this lack of will is most
evident in England, where access to modern biologic
14
15
EYE WITNESS REPORT
References
BIOLOGICS IN RHEUMATOID ARTHRITIS
1 Biologics: the story so far, National Rheumatoid Arthritis
Society, 2013
BY NIGEL HAWKES
2. British Society for Rheumatology, http://www.rheumatology.org.
uk/patient_information/simple_tasks/did_you_know.aspx
THE WITNESSES
3. Services for people with rheumatoid arthritis, National Audit Office
July 2009
4 Primer on the Rheumatic Diseases, edited by H Ralph
Schumacher, Arthritis Foundation; 10th edition (December 1993)
5. Personal communication, unpublished data
6. Galido-Rodriguez G et al, Retrospective audit of records of
patients with RA onset between January 1985 and June 1994,
J Rheumatol 1999; 26:2337-2343
7. The management of rheumatoid arthritis in adults, Nice clinical
guideline 79, issued February 2009, last modified August 2013,
https://www.nice.org.uk/guidance/cg79
Professor Ali Jawad, Consultant Rheumatologist, The Royal
London Hospital
8. The market for therapeutic antibodies, Biotech Spain, 11 July
2013, http://biotechspain.com/en/article.cfm?iid=market_
therapeutic_antibodies
Professor Peter Kay, National Clinical Director for Musculoskeletal
Services for NHS England and Consultant Orthopaedic Surgeon,
Wrightington Hospital
9.
Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis
P, Brennan FM, Walker J, Bijl H, Ghrayeb J, et al. Treatment of
rheumatoid arthritis with chimeric monoclonal antibodies to tumor
necrosis factor alpha, Arthritis Rheum. 1993 Dec; 36(12):1681-90.
Pamela Adams and Donna Saunders, RA patients (mother and
daughter), Worcester
10.Jacobsson LTH et al, Annals Rheum Dis 2007; 66:670-675
11.Deighton C et al, BSR and BHPOR rheumatoid arthritis guidelines
on eligibility criteria for the first biological therapy, 2010,
Rheumatology doi:10.1093/rheumatology/keq006b
12.Hockley T and Costa-Font J, A common disease with uncommon
treatment: European guideline variation and access to innovative
therapies for Rheumatoid Arthritis, Policy Analysis Centre
Dr David Walker, Consultant Rheumatologist, Freeman Hospital
Dr Louise Warburton, GP, Malling Health
Mary Cowern, Director, Arthritis Care Wales
Alison Kent, Rheumatology Nurse Specialist, Salisbury
NHS Foundation Trust
Baroness Brinton, Liberal Democrat Health Spokesperson,
House of Lords
Ailsa Bosworth, Founder and Chief Executive, National
Rheumatoid Arthritis Society
[COMM111] 8th December 2014
13.Richards M, Extent and causes of international variations in drug
usage, Department of Health July 2010, https://www.gov.uk/
government/uploads/system/uploads/attachment_data/
file/216249/dh_117977.pdf