BSRBR 10th Anniversary brochure - The British Society for ...

The British Society for Rheumatology Biologics Registers
2001-2011
Celebrating 10 years

BSRBR: a cause for celebration
In 2001 BSR launched the Biologics Register to monitor the safety and efficacy of a new
generation of therapies for rheumatic diseases. Thanks to the collective endeavours of
rheumatologists and allied health professionals across the country, it has become a research
model respected worldwide. To mark its first decade, this report celebrates its achievements
and continuing importance for the future.
Professor David Isenberg, chair of the BSRBR Steering Committee from
2006 to 2011, discusses the virtues of the Register as a model for others.
2 | BSRBR 2001-2011
To me, the Biologics Register is the jewel in
the BSR’s crown, a wonderful creation that
led the way nationally and showed the
Society and its members were ahead of
the game.
One reason BSR started the Register was to
make sure everything was above board
when it came to studying the effects of
these exciting new biologic agents. When
corticosteroids were introduced in the late
1940s, for example, it wasn’t unknown for
those with a vested interest to phone up
the editors of journals who had published
articles detailing their side-effects and
harangue them for damaging the new
drugs’ reputation.
BSR and its Executive Committee wanted
to get it right on drug safety and Professor
Gabriel Panayi, the Society’s President at
the time, deserves great credit for driving
us on to create the Register.
With almost 20,000 patients enrolled, it is
now the world’s largest biologics registers, a
model for others to follow. That in itself is a
cause for celebration. Importantly, the way it
is set up has the full approval of the National
Institute for Health and Clinical Excellence
(NICE), because of the benefits it brings to
all parties involved.
Pharmaceutical companies pay for the
running of BSRBR and in return receive
relatively cheap, long-term follow-up data on
the drugs they produce. BSR enjoys the
kudos for the work it has done in
establishing and overseeing the Register.
The Arthritis Research UK Epidemiology Unit
at the University of Manchester has the
pleasure of publishing many articles in
learned journals based on researching
data collected by the Register.
A glass wall separates the parties involved.
Drug companies pay BSR to run the Register
rather than funding it directly. Researchers in
Manchester, for their part, submit their
papers for comment to the drug companies
and the BSRBR Steering Committee before
sending them to journals for publication.
Any issues raised are then fed back to the
committee. It passes on genuine concerns
for Manchester to answer. This process
allows everyone to have their say and
completes the audit loop.
The Register has evolved a great deal over
the past 10 years and a new register for
ankylosing spondylitis is about to start
recruiting patients. What has been most
gratifying for me is that BSR has been seen
to be going places and has set a standard
of excellence that is recognised worldwide.
When I am at conferences abroad, it is not
uncommon for delegates to come up and
tell me that we have got it right.
Clinical trials give an indication of whether
a new drug will be beneficial, but their
samples are usually small and to a degree
self-selecting. Often they don’t take into
account a patient’s full medical history.
BSRBR, though, tells you what is going on
in real life where patients have RA but may
also have other conditions too.
That makes BSRBR a more powerful
instrument for researchers than clinical
trials. It has allowed us both to identify
unexpected benefits of anti-TNA drugs
and to allay fears about these drugs.
The Register has also identified the
unexpected such as the small number of
patients who have developed psoriasis as
a result of their treatment.

Professor Alex MacGregor, current chair of the BSRBR Steering
Committee, outlines future plans for the Register.
BSRBR was one of the first registers
monitoring the treatment of rheumatoid
arthritis with biologics. Now it sits in a
constellation of similar studies in Europe
and around the world and has inspired the
creation of registers for other rheumatic
diseases. Such long-term studies contribute
greatly to our understanding of these
conditions and their treatment.
Monitoring the long-term safety of patients
remains an essential part of BSRBR’s work.
Now, though, we are entering an age where
performance is assessed and resources
squeezed, especially in relation to the use of
expensive drugs. That makes capturing the
outcomes of treatments of increasing value
to our profession.
My role is strategic, leading the Register into
the future and helping to determine how it
can best serve BSR. One significant
development signposts the way ahead.
INBANK is an Arthritis Research UK project
that aims to link up all registers collecting
data on musculoskeletal diseases and join
them up with the electronic capture of
information from rheumatology clinics.
The vision is that in 10 years INBANK will
collect outcomes data on all patients with
rheumatic diseases. Setting up such a
comprehensive data collection system is a
big challenge. For a very defined use of
biologics in rheumatic diseases, we are well
on the way. To cover every patient will be a
much harder undertaking.
After 10 years of form-filling, some
contributors might blanche at the prospect.
But BSR members need to remember that
they own the data set from BSRBR; it
doesn’t belong to the Manchester team or
to the drug companies. We want more
rheumatologists and allied health
professionals to make greater use of the
Register. There’s no reason why they can’t
contact Manchester for information for use
in their own research and audit projects.
The Manchester team has begun to do local
presentations to explain what information is
available. Electronic data capture, with
information from BSRBR part of a much
wider data set, will make it much easier for
rheumatologists to access data.
This is important, because the government
wants the medical profession to record
outcomes in a consistent way. BSRBR is a
platform to build on for the supply of this
information. We already work closely with
NICE on outcomes, technology appraisals
and clinical guidelines. That relationship will
strengthen our position with regard to policy
decisions on biologics. The wealth of data
from BSRBR gives us the upper hand in
arguing the case for a consistent use of
these agents.
Our plan for the future development of
BSRBR is to broaden its remit by
encouraging work on health economics.
By recruiting a comprehensive cohort of
patients we can capture more data on
outcomes for health economics analysis.
Although BSRBR has thrived thanks to the
financial support of the drug companies,
the economic climate has introduced an
element of uncertainty to this arrangement.
We need to look for ways to diversify how
we fund the Register.
Potential backers include charities, such as
Arthritis Research UK, and the government,
which says it is committed to funding data
collection for research. But with a limited
pool of money available, we are going to
have to pull together rather than compete
for funding and try to make BSRBR a focal
point for research in rheumatology and a
conduit for channeling resources into
other projects.
www.rheumatology.org.uk/BSRBR | 3

Taking up the challenge
BSR was quick to grasp the importance of biologics and understood that a bold approach to
monitoring was needed in order to gain approval for the new treatments.
Professor Gabriel Panayi, BSR President from 2000 to 2002, recalls the
debates that surrounded BSR’s proposal to set up the Biologics Register.
4 | BSRBR 2001-2011
I was President of BSR just as biologics were
being introduced into rheumatology. Studies
showed that one drug, Infliximab, was having
a good impact in the treatment of
rheumatoid arthritis and we were keen to
have it approved for use in Britain.
The difficulty with disease-modifying drugs is
that the cost of monitoring them is often
more expensive than the drug itself. Clinical
trials use only a very small number of
patients, yet only when a new drug goes out
into the clinics do you see how effective and
safe they really are. To sell the fact we
needed this new drug to NICE, we came up
with the idea of a register of patients to spot
problems long term.
With a register we would be contributing to
patient safety, a key consideration for NICE,
and because treatments would be followed
for years we could study how long the drugs
maintained their efficacy, another important
point as far as NICE was concerned.
We had a model of what we wanted to do
and a good idea that our proposed register
would be based at what was then the arc
Epidemiology Unit in Manchester. Because
BSR could not afford to fund such a project,
we proposed the pharmaceutical companies
should fund it.
That decision came only after considerable
debate. We were well aware that we could
be saddling BSR with all sorts of problems.
Contracts to fund the register would have to
be negotiated with the drug companies.
There was also the very real possibility that
we could be laying ourselves open to legal
action, because of the role TNFs play in the
immune system. The introduction of these
new drugs might increase the risk of patients
developing cancerous tumours and
infectious diseases.
Andrew Bamji and his colleagues in the BSR
Clinical Affairs Committee played a crucial
role in the discussions surrounding these
issues. It was an act of bravery to establish
such a register, not least because everyone
was aware there were other complications,
too. Legal and insurance frameworks would
have to be in place if we received the
go-ahead. Not a lot of hard and fast
planning was done initially, because we
had no guarantees that either NICE or the
pharmaceutical companies would accept
our proposal.
NICE reviewed the clinical trial data on
anti-TNF drugs and made approval
conditional on the kind of long-term
monitoring that we proposed. It told the
drug companies they could set up registers
individually or they could go through the BSR.
Rheumatologists would own the data rather
than the drug companies, who were invited
to respond to any research about their
products in the usual manner of scientific
debate. It was a novel concept and
fortunately the pharmaceutical companies
came on board and supported it.
BSRBR was the first register of its kind in
rheumatology and it has changed the way
we approach the post-marketing surveillance
of drugs. In the past, surveillance depended
on drug companies and the NHS’s
yellow-card system. If a doctor saw a
reaction in a patient to a treatment, they
would fill in a card and post it to the
Department of Health.
That approach gives no indication of how
many patients are taking the drug at a given
time, making it hard to tell whether an
individual response is statistically important.
Also, doctors only report side-effects, not
the absence of side-effects.
By contrast, the Register is a never-ending
goldmine of information, a vast enterprise
that has made BSR known all over the world.

Professor Alan Silman, director of the arc Epidemiology Unit from 1989
to 2007, explains why the Manchester unit was the ideal choice to run
BSRBR even though setting it up wasn’t without its challenges.
For many years Manchester had been home
to the national epidemiological research unit
charged with undertaking long-term studies
of patients with rheumatic diseases, which
meant it already had the skills and expertise
needed for a project such as the BSRBR.
The data handling and statistical analysis
requirements were bread and butter for the
Manchester team.
Importantly, because Manchester was a
national resource, it sat outside conventional
academic competition for research projects.
Everyone already went there for information
on all kinds of rheumatic diseases. It had
the expertise, the capacity and the historical
pedigree for large data collection studies
such as BSRBR. That position meant it
could act as an honest broker when it came
to setting up the Register.
We faced contractual challenges initially,
however. The process required a strange set
of contracts designed to keep BSRBR at
arm’s length from the drug companies.
We also engaged in numerous discussions
with the rheumatology community about the
kind of background data to be collected.
While I handled the contractual negotiations,
my colleague Deborah Symmons took charge
of designing the questions and forms for the
study and worked on resolving logistical
issues with the unit’s statisticians and
database experts. Kath Watson was a key
appointment for BSRBR. She had done her
PhD at the unit and has an incredible
number of skills associated with developing
and managing data collection systems.
With hindsight, it is clear that some tricks
were missed because no one envisaged the
study continuing for so long. When patients
failed to respond to biologics, for example,
we didn’t capture any data once they
switched to other treatments, an
opportunity missed.
BSRBR was also built in a way that
depended on a paper-based model.
Clinics had to fill in forms that were then
faxed or posted to Manchester where the
team entered the data into computers,
a time-consuming process that added to
the complexity of data collection. It was
a 20th-century solution rather than a
21st-century one.
Now we would look automatically to
electronic data capture, but at the time
many clinics weren’t geared up for that and
firewalls existed between the NHS and the
outside world that wouldn’t allow it. Instead
we had to take a blunderbuss approach to
something that could have been done much
more easily. Registers in other countries
have been able to avoid such problems.
Obtaining ethical approval was another
issue we had to face. That wasn’t a given
because, unlike now, no centralised system
for approval was in place. Everything was
done at local level, so we had to make
representations about the proposed study to
individual trusts, which added to the time it
took to secure approval nationwide.
A real sense of excitement surrounded the
launch of the Register, with the
rheumatology community solidly behind the
project, because everyone knew we were
breaking new ground.
BSRBR was the first time in British medical
history that a surveillance study was
undertaken by an independent academic
group rather than by drug companies. It has
been incredibly successful and the
rheumatology community can feel genuinely
proud of being part of such a study. It has
led the world, inspiring others abroad and
influencing government and other medical
specialties at home. It shows British
rheumatology at its best, working together
for the benefit of public health.
www.rheumatology.org.uk/BSRBR | 5

Changing our specialty
The advent of biologics heralded a revolution in the treatment of rheumatic diseases.
Monitoring by BSRBR has played a key role in shaping policy and refining the way the new
drugs have been used.
Dr Andrew Bamji, Chair of BSR’s Clinical Affairs Committee from 1998 to
2001 and President from 2006 to 2008, explains how BSRBR helped to
inspire a more systematic approach to treatments.
Biologics and BSRBR changed the way
we treat rheumatic diseases. Previously,
treatment plans had often been very
informal. The Register has made RA a
protocol-driven disease where treatment
no longer flies by the seat of its pants but
follows a set regime.
The use of drugs in combination is now
standard practice. We treat RA earlier and
more aggressively to prevent the condition
worsening and hopefully to kick it into
remission without recourse to the most
expensive therapies. What were once
considered early signs of disease are now
considered late signs.
BSR was quick to grasp that biologics would
have a dramatic effect on the treatment of
rheumatic diseases, but members were also
aware that these new drugs were expensive.
A lot of discussion took place on the need to
develop strict criteria for prescribing them in
order to convince the government and NICE
that we were going to use them in a
sensible, cost-effective way.
The big question mark surrounding biologics
was whether they carried any significant risk
of side-effects. Precedent made us cautious.
Data collection had been haphazard under
the yellow-card system operated by the
Committee on Safety of Medicines and in
the case of Opren, an anti-inflammatory
drug, it had taken considerable time before
anyone realised the drug was causing kidney
and liver failure in elderly patients.
We also had to address the problem that no
one was doing any systematic research on
joint activity in terms of swelling,
inflammation, pain and blood markers.
So we wanted an approach that would
monitor both the expected and unexpected
effects of biologics. A register appeared the
best way forward as it would centralise the
collection of data and provide much earlier
warning of side-effects.
While BSRBR was set up to watch for
side-effects, it has become a useful tool for
a much wider range of applications. The
volume of data it has produced has allowed
us to compare drugs and study disease
progression in much greater detail.
One reason for this is the questions that
were asked at the outset. We took a long
hard look at how to assess RA in a more
systematic way. It was agreed that patients
would have to fulfill certain criteria before
they could receive the new treatments, be
diagnosed earlier and be assessed on a more
regular basis, with their treatment subject to
long-term monitoring.
The impact of biologics isn’t confined to RA.
Treatments have moved sideways into other
inflammatory joint diseases such as juvenile
arthritis, psoriatic arthritis and ankylosing
spondylitis. These are also being monitored
and we are finding they respond to these
treatments in very different ways.
What began as a medium-term study into
possible side-effects has become an ongoing
observational study producing robust data.
The publications BSRBR has produced are
numerous and authoritative and the quality
of information it provides has played a key
role in our submissions to NICE.
BSRBR is a superb model for disease
management, admired and copied
worldwide. It must still serve its original
purpose, however. Unforeseen side-effects of
biologic agents may emerge after 20 years.
Should that happen, the Register means we
will be alerted early and able to react quickly.
6 | BSRBR 2001-2011

Professor Deborah Symmons, director of the Arthritis Research UK
Epidemiology Unit, describes how data from BSRBR has encouraged
vigilance in some areas and offered reassurance in others.
The most significant difference BSRBR has
made to the way clinicians treat patients is
that it has helped to clarify which patients
are most at risk of infectious diseases when
taking anti-TNF drugs and when they are
most likely to develop them.
Because of TNFs’ role in the immune system,
we knew that in theory biologics carried an
increased risk of infectious diseases. Data
from BSRBR has confirmed a small but
significant risk of serious infections and,
more importantly, that it is at its greatest
within the first six months of starting anti-TNF
treatments then declines. This knowledge is
helpful for clinicians, as it encourages
vigilance in looking for symptoms of
infectious diseases and emphasises the
importance of educating patients about
how best to avoid complications.
Tuberculosis is one disease of concern,
although it is unusual in that the background
risk is low; chest and skin infections make
up the majority of illnesses associated with
anti-TNFs. Since the risk of contracting TB
was confirmed, all patients are now screened
before starting treatment with biologics, a
step that has brought down the rate of
infection. There is also an increased risk of
patients developing TB after they stop taking
anti-TNFs, however, and clinicians should be
alert to that possibility.
Research based on BSRBR data has allowed
us to draw comparisons between drugs.
The risk of developing TB on Etanercept, for
example, is much lower than on the
monoclonal antibodies Infliximab or
Adalimumab. This is useful ammunition for
a clinician trying to secure funding for
treatment with Etanercept from an NHS trust.
While the Register has been an important
tool in identifying risks and helping clinicians
to minimise them, it has also produced some
reassuring publications. No signals for an
increase in malignancy have been detected,
for example, although that was a concern
when anti-TNF therapies were first
introduced.
Data from BSRBR also indicates that
patients who respond to anti-TNFs have
fewer heart attacks in the first six months of
treatment than expected. The drugs appear
to stabilise the lesions that cause heart
attacks. No long-term certainty regarding
the reduced risk of heart attacks can be
confirmed, but in the short term this is a
positive development.
Information from BSRBR has also influenced
decisions made by NICE, in particular its
guidelines on sequential therapy for patients
failing a first anti-TNF. Usually, if a patient
fails to respond to a first anti-TNF, they are
prescribed rituximab and methotrexate.
NICE’s guideline means clinicians can now
prescribe an alternative anti-TNF. Since
cost-effectiveness is an important part of
NICE’s decision-making process, this is an
important development for clinicians.
It is worth noting, too, that without the
Register, NICE would have to rely on data
from other countries when preparing
guidelines. Most UK clinicians would view
that as less than satisfactory because it
would not represent the patients they
treat on a daily basis.
The team in Manchester does not operate
in isolation. We receive many queries from
clinicians seeking advice on particular
problems that prompt us to look into areas
we have not previously considered. In some
instances, we are able to offer reassurance
that the problem is unlikely to be caused by
the drugs. In others, their concerns have led
us to undertake a proper analysis and
opened up new avenues of research.
Ultimately, the Register gives a collective
experience for rheumatologists. Clinicians
contribute data to it and get information out
of it that can only benefit their patients.
www.rheumatology.org.uk/BSRBR | 7

Advancing knowledge
Data collected through BSRBR’s long-term monitoring of patients has produced a wealth of
information for researchers studying the impact of biologic therapies on rheumatoid arthritis.
Dr Kimme Hyrich, principal investigator at the Arthritis Research UK Epidemiology Unit in
Manchester, lists some of the landmark papers based on BSRBR data that highlight its value
as a research tool.
Serious infection following anti–tumor
necrosis factor α therapy in patients with
rheumatoid arthritis: Lessons from
interpreting data from observational studies.
Arthritis and Rheumatism 2007
Drug-specific risk of tuberculosis in patients
with rheumatoid arthritis treated with
anti-TNF therapy: results from the
British Society for Rheumatology Biologics
Register (BSRBR).
Annals of the Rheumatic Diseases 2010
8 | BSRBR 2001-2011
TREATMENT RESPONSE
Predictors of response to anti-TNF-α therapy
among patients with rheumatoid arthritis:
results from the British Society for
Rheumatology Biologics Register.
Rheumatology 2006
Comparison of the response to infliximab or
etanercept monotherapy with the response
to cotherapy with methotrexate or another
disease-modifying antirheumatic drug in
patients with rheumatoid arthritis: Results
from the British Society for Rheumatology
Biologics Register.
Arthritis and Rheumatism 2006
Changes in disease characteristics and
response rates among patients in the United
Kingdom starting anti-tumour necrosis factor
therapy for rheumatoid arthritis between
2001 and 2008.
Rheumatology 2010
INFECTION
Rates of serious infection, including
site-specific and bacterial intracellular
infection, in rheumatoid arthritis patients
receiving anti–tumor necrosis factor therapy:
Results from the British Society for
Rheumatology Biologics Register.
Arthritis and Rheumatism 2006
Anti-TNF therapy is associated with an
increased risk of serious infections in
patients with rheumatoid arthritis especially
in the first 6 months of treatment: updated
results from the British Society for
Rheumatology Biologics Register with
special emphasis on risks in the elderly.
Rheumatology 2011
MALIGNANCY
No evidence of association between
anti–tumor necrosis factor treatment
and mortality in patients with rheumatoid
arthritis: Results from the British Society
for Rheumatology Biologics Register.
Arthritis and Rheumatism 2010
Influence of anti-tumor necrosis factor
therapy on cancer incidence in patients
with rheumatoid arthritis who have had a
prior malignancy: Results from the British
Society for Rheumatology Biologics Register.
Arthritis Care and Research 2010
OTHER OUTCOMES
Pregnancy outcome in women who were
exposed to anti–tumor necrosis factor agents:
Results from a national population register.
Arthritis and Rheumatism 2006
Anti-TNF therapies and pregnancy: outcome
of 130 pregnancies in the British Society for
Rheumatology Biologics Register.
Annals of the Rheumatic Diseases 2011

Exceeding our Goals
The BSRBR has exceeded expectations and now tracks the progress of almost 21,000 patients.
The register continues to expand by monitoring new treatments to assess their efficacy and
safety in clinical practice.
CURRENT RECRUITMENT AND
FOLLOWING UP
With your help recruitment to the BSRBR
register has been very successful and we
now track the progress of almost 21,000
patients. All of these patients provide
important data which increases our
understanding of the safety and
effectiveness of biologic treatments in
routine use. The University will continue to
follow up these patients to 2018, which
means that some of them will be providing
data to the register for over 15 years.
The RA register continues to grow and
encompass the monitoring of new
treatments to assess their efficacy and
safety in clinical practice. We have recently
added certolizumab pegol and tocilizumab
to the register, as well as developing a
contemporary comparison cohort of patients
newly receiving treatment with anti-TNF
therapy (adalimumab, etanercept or
infliximab). All of the three new recruiting
cohorts are eligible to count as accrual data
on the NIHR CRN Portfolio. Please continue
to make the register a success by helping
to recruit and follow the progress of these
patients.
CERTOLIZUMAB PEGOL
Certolizumab pegol was launched in the UK
in 2009 and has a different molecular
structure from that of the earlier anti-TNF
agents, and therefore may carry a different
safety profile. Many NHS Trusts are being
asked to prescribe certolizumab pegol as a
first choice due to the patient access
scheme, whereas others may prefer to use
alternative agents with a longer track record
due to their familiarity with the product.
In order to understand whether this new
pegylated form of anti-TNF has the same
safety profile long-term as the other anti-TNF
options it is imperative that patients starting
this agent receive the same careful follow-up
that those on previous anti-TNF agents have
received.
TOCILIZUMAB
The monoclonal antibody, tocilizumab, has
been approved for use in rheumatoid
arthritis for patients who have failed an initial
biologic therapy in the UK since 2010, and
more recently approved as a first line
biologic in patients resistant to DMARD
therapy. Tocilizumab blocks the action of the
cytokine IL-6 and it is thought this may
reduce inflammation in the joints, prevent
long term damage and relieve certain
systemic effects of rheumatoid arthritis.
We are aiming to recruit and follow a cohort
of at least 500 patients over the next few
years, and have currently recruited 141
patients receiving this drug to the BSRBR.
Recruitment Levels and Cohort Status for RA Register
Drug Total Recruited* Cohort status
ANTI-TNF COMPARISON COHORT
Recruitment began in January 2012 for a
comparison cohort which will recruit patients
who are anti-TNF naive and are starting one
of the established anti-TNF therapies:
etanercept, adalimumab or infliximab. These
patients are being recruited across the UK to
provide a contemporary comparison group to
assess the safety profile of newly available
biologic agents. The recruits must have a
diagnosis of RA, be biologic naïve before
registration, and have received the first dose
of the drug in the six months prior to
registration with the BSRBR. Recruitment
to this cohort is open to all rheumatology
centres in the UK so please contribute to
this important new BSRBR cohort.
Tocilizumab 292 Recruiting and active follow-up
Certolizumab 290 Recruiting and active follow-up
Etanercept 5317 Recruiting and active follow-up
Infliximab 4858 Recruiting and active follow-up
Adalimumab 4714 Recruiting and active follow-up
Rituximab 1643 Closed to recruitment, active follow-up only
DMARD control cohort 3775 Closed to recruitment, active follow-up only
*Data to 05/04/2012
To register patients to any of these registers
please contact us on 0161 275 7390/1652
or email to biologics.register@manchester.ac.uk
For further information visit our website:
www.rheumatology.org.uk/BSRBR/RA
www.rheumatology.org.uk/BSRBR | 9

New fields of research
The BSR Biologics Registers team are pleased to announce the launch of the Ankylosing
Spondylitis register. The BSRBR now runs two biologics registers: the rheumatoid arthritis register
(BSRBR-RA) and the newly launched ankylosing spondylitis register (BSRBR-AS).
The British Society for
Rheumatology
Biologics Registers
Ankylosing Spondylitis
The British Society for
Rheumatology
Biologics Registers
The British Society for
Rheumatology
Biologics Registers
Rheumatoid Arthritis
AS REGISTER LAUNCHED
After a long gestation, the contacts between
the BSR and Abbott and Pfizer – marketing
authorisation holders for adalimumab and
etanercept, the two biologics currently
authorised by NICE for Ankylosing Spondylitis
– were signed in late 2011.
The contract with the University of Aberdeen,
who will be hosting the register, has also
been agreed and the study officially started
on April 1st, 2012. Meanwhile, ethics
approval for the register has been granted,
and the Aberdeen team are working on R&D
approvals and, for centres in England, the
required CLRN approval which will fund the
nurse support for the study.
Recruitment to the register is scheduled to
begin in Scotland in October 2012, with
recruitment in England starting in January
2013. The aim is to recruit 1300
biologics-naïve patients with ankylosing
spondylitis, half of whom are newly starting
on either adalimumab or etanercept, and
half of whom are not. They will then be
followed for up to five years, and the study
is powered, primarily, to detect a doubling in
the risk of serious infection between the
cohorts. However, other adverse outcomes,
and information regarding quality of life will
also be collected.
Please contact us to express an interest in
recruiting patients to this important new
register via bsrbr@rheumatology.org.uk.
RENAMING THE BSRBR
To incorporate our new register we are adding
an ‘s’ to our name, so BSRBR now stands for
the BSR Biologics Registers. The name
BSRBR will be used as an umbrella term to
refer to both these registers (and any more
registers we might run in the future). From
now on the rheumatoid arthritis register will
be referred to as the BSRBR-RA and the new
ankylosing spondylitis register will be the
BSRBR-AS. We have developed these logos
to reflect these changes and enable clear
labelling of each register.
10 | BSRBR 2001-2011

Monitoring the use of biologics has spread from rheumatoid arthritis to other musculoskeletal
diseases, and in 2012 recruitment will begin for BSR’s new ankylosing spondylitis register.
Professor Gary Macfarlane, leader of the team that runs the new
BSRBR-AS register, outlines the aims and ambitions for it.
Rheumatologists in Scotland have a history
of working together, so when I moved from
Manchester to Aberdeen in 2005 it wasn’t
long before I was approached about doing a
research project. Ankylosing spondylitis soon
emerged at the top of the agenda, so we set
up the Scotland and Ireland Registry for AS
(SIRAS), which quickly attracted funding
from the pharmaceutical companies.
When BSR proposed to set up an AS register
to run parallel to BSRBR-RA, we were keen
to get involved, because it seemed a natural
progression to expand our work into England
since we already had links with some English
centres.
SIRAS has approximately 1,400 patients
registered. It covers everyone with a clinical
diagnosis of AS, regardless of the therapies
they are on. The BSRBR-AS will be slightly
different as it will aim to recruit an initial
cohort of 650 AS patients being treated with
biologics and a similarly sized comparison
cohort who are not on biologics.
Twenty centres in England and Wales have
expressed an interest in taking part, so we
should have 33 centres including the 13
already in SIRAS.
Although BSRBR-AS is a separate
undertaking, it will have strong links with
Manchester as the unit there will collect
safety data on any adverse events that occur
to AS patients on biologics. Their expertise
in this field meant it seemed silly for us to
try and collect this information separately,
although we will analyse the data they
collect.
Efficacy is another area we will look at;
do patients on biologics fare better than
patients not on these treatments? Because
clinicians put patients on biologics for
specific reasons, for example, if their
condition is deteriorating, and because
patients have the right to choose not to go
on biologics, it is a challenge to compare
efficacy between one treatment and another.
We have models that allow us to take the
register’s observations of what happens and
use them as the basis for making
comparisons between similar groups
of people.
Other important questions occur, too.
For example, when people go on biologic
therapies, why do some fare better than
others? If we can understand that, it can
help us to make informed decisions on
treatments in the future.
What takes time, though, is setting
everything up, obtaining the funding and
support of drug companies and the
participation of regional centres. Then there
is the technical part of designing the
database and finalising the data sheets.
For this, it is important to look at similar data
collections, so we have set up a committee
that includes representatives from Europe,
North America and Australia to look at what
other countries are doing and how we can
collaborate with them.
There are bureaucratic hurdles, too. Before
a study can take place, an NHS ethics
committee has to give its approval. It will
assess whether the overall balance of risk
to benefit is acceptable, check through all
issues of indemnity and ensure that patients
are provided with enough information and
given enough time to make an informed
decision when they are approached to
participate.
Setting up BSRBR-AS has involved a lot of
planning and preparation. The hope is that
it will make a valuable contribution both to
our knowledge and to the wellbeing of our
patients.
www.rheumatology.org.uk/BSRBR | 11

Wider perspectives
BSRBR-RA doesn’t just benefit researchers and clinicians. Its findings inform the work of allied
health professionals who play a key role in collecting data and the pharmaceutical companies
who find the study.
Kate Gadsby, an advanced clinical educator, explains how BSRBR-RA has
an ongoing role to play in helping rheumatology nurse specialists to discuss
treatments with patients.
Although I’ve been a rheumatology nurse
specialist for 22 years, for the past 10 years
I have had a unique role as an advanced
clinical educator. I still have a clinical
caseload working with patients going onto
biologics, but the bulk of my time is devoted
to teaching rheumatology to medical
students, junior doctors and nurses.
With rising numbers of trainees heading into
general practice, it is important they gain a
thorough understanding of rheumatology
and orthopaedics, because about a quarter
of their workload will involve treating
musculoskeletal diseases. Our eight-week
course aims to equip them with that
knowledge.
Biologic agents are one of my main areas of
interest, partly because when they started I
saw patients, who were failing on traditional
DMARDs, go onto the new anti-TNFs and
witnessed the difference these made to
patients’ lives.
The benefits they feel make patients think
you are wonderful when it is they themselves
who have made the difference by choosing
to go onto these drugs. Particularly at the
outset, when little was known about the
long-term effects of anti-TNF treatments,
that was a big decision to make.
In Derby, every patient who went onto
biologics was asked to go on the Register
and we also recruited for the control cohort
of patients on traditional DMARDs. With the
quotas for the first anti-TNFs filled, we have
continued to recruit patients for BSRBR-RA
as new treatments have been added.
Collecting data for the Register is a lot of
work, much of it done by nurse specialists,
but the information it provides is invaluable.
A key part of my work is to clinically manage
and maintain standards of treatment to
ensure nurse specialists all follow the same
procedures when dealing with patients.
Findings based on BSRBR-RA research allow
nurses to talk confidently to new patients
about their treatment, for example allaying
fears about possible adverse side-effects
such as an increased risk of cancer.
Because the Register has added so much to
our knowledge, it is important we carry on
recruiting and following up patients on
existing biologics, as well as recruiting
cohorts of patients to follow on new
treatments as these become part of the
portfolio.
With the current squeeze on jobs and
specialist units, we need to remind
stakeholders of the continued importance
of maintaining and growing the Register.
Rheumatology’s research networks are a
potential boon in this respect as they can
help to find the money that will fund nurses
to do the form-filling required to keep
populating the Register.
The BSRBR-RA paperwork has become
easier over time but the study’s importance
hasn’t diminished. Real life is what goes on
in clinical practice. By capturing that, the
Register has given us evidence that these
drugs work and allowed us to impart valuable
information about them to patients.
12 | BSRBR 2001-2011

Dr Jon Ryland, UK medical director of Abbott Laboratories, manufacturer of
adalimumab, explains the value of BSRBR-RA’s real-life data for both
pharmacovigilance and furthering research.
Once a treatment such as adalimumab is on
the market, we want to monitor its ongoing
safety profile and ensure there are no
unusual side-effects. A well-constructed
register such as BSRBR-RA that produces
real-life data is a very effective way for us
to do that.
Clinical trials are strict about who goes into
the studies with restrictions based on age,
other medical conditions and other
treatments. All those qualifying criteria
disappear on registers, so they produce
very different sets of data and that is very
important to us.
Our pharmacovigilance group is in regular
contact with the Manchester unit, because
our main concern is the maintenance and
surveillance of adalimumab’s safety profile.
Data on safety from BSRBR-RA has been
very reassuring in that it has produced a
similar profile to other safety sources
around the globe.
Abbott’s UK team also likes to see the
company investing in research in this country.
Participating in the Register has been an
opportune way for us to do that. The quality
of information coming out of it has reassured
our colleagues abroad and allowed us to
invest further in this country.
What has surprised me most about the
research produced by BSRBR-RA is the
baseline data on patients treated between
2001 and 2008. It shows the gap between
diagnosis and treatment fell from 15 years
to 11.4 years in that time and the Disease
Activity Scores (DAS) fell from 6.77 to 6.38,
so there have been improvements over that
period. The figures, though, are a long way
off the targets contained in BSR guidelines
that initially set DAS targets of 5.1, a figure
that has now been reduced to 3.1. While we
are going in the right direction, there are still
patients out there who aren’t being
diagnosed or being treated early enough to
enjoy the full benefits of anti-TNF therapies.
The fact BSRBR-RA produces data specific
to the UK is important in itself. Because of
NICE’s role in assessing health technologies,
it is invaluable to have UK-specific data
when we are working with other stakeholders
to support access for appropriate patients
to an expensive treatment such as
adalimumab.
NICE evaluations rely heavily on models of
values to determine cost-effectiveness.
We use real-life data from BSRBR-RA to
create models of our own and have lobbied
NICE to take into account other costs and
benefits outside the NHS when it is
considering treatments for long-term
conditions such as RA. Progress is slowly
being made on this score.
www.rheumatology.org.uk/BSRBR | 13

Dr Joshua Vecht, medical advisor at UCB Pharma, manufacturer of
certolizumab pegol, considers the breadth of information provided by
BSRBR-RA to be one of its greatest strengths.
When UCB launched certolizumab pegol for
the treatment of RA in the UK in October
2009, we didn’t hesitate over making the
decision to join BSRBR-RA. It represented a
genuine opportunity for enhanced
pharmacovigilance based on data
generated through real-life experience.
We relished the prospect of the inclusion of
Certolizumab pegol in the study of a wide
range of outcomes over large sections of
the population. Such registry data generates
important additions to the knowledge we
can gain from strictly controlled clinical
trials.
The transparency and credibility of data
produced by BSRBR-RA make participation
an attractive proposition. The number of
data-driven questions it contains and the
breadth of data it collects has surprised
many of my global colleagues at UCB.
Such data is essential in this age of
evidence-based medicine. The Register’s
breadth and size make it a pillar of stability,
because no one can argue with it as a
statistical platform. All of its classifications
on safety and the way safety outcomes are
constantly updated, for example, command
respect.
BSRBR-RA has been the source of an
impressive volume of posters and
manuscripts. Important data seems to come
out of the Register at every conference and
scientific meeting. It provides a constant
supply of snapshots of real clinical scenarios
and risk-benefit profiles that drive innovation
in biotechnology. Companies such as UCB
will use that information to supply future
needs.
It is early days in terms of the planned cohort
recruitment for certolizumab pegol, which
began in January 2011. So far, the register
is collecting data on about 290 patients on
the drug and we are waiting for the first
report on it to come through in early 2012.
A final point that deserves to be emphasised
is that we are really enjoying our involvement
with the team that run the Register. For UCB,
it is a very valuable and important
relationship. BSRBR-RA staff are very
accessible and we communicate often
and meet regularly. It is a healthy, interactive
environment that we value enormously.
Since giving this interview Dr Vecht has
changed positions and no longer works
for UCB Pharma.
14 | BSRBR 2001-2011

www.rheumatology.org.uk/BSRBR | 15

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