Case Study 7. Changing the treatment paradigm of rheumatoid arthritis: early diagnosis and aggressive treatment to attain remission leads to sustained improvements in health and quality of life
Submitting InstitutionUniversity of Leeds
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Research in Leeds led by Professor Paul Emery pioneered early
diagnosis and treatment for patients with rheumatoid arthritis (RA), with
the aim of disease remission rather than reduction of symptoms. This
approach has transformed management of RA and is now standard practice for
patients worldwide. It has led to greatly improved disease control,
increased quality of life and reduced disability as well as direct
productivity gains of an estimated £4 million per year to the UK economy.
Treatment for rheumatoid arthritis (RA) had traditionally been
conservative, using a step-wise approach to manage the symptoms of the
disease as they progressed. Paul Emery (Professor of Rheumatology,
Leeds, 1995- ) was the first to turn this model on its head, proposing an
ambitious protocol driven by early diagnosis and aggressive treatment with
the aim of achieving disease remission defined by complete suppression of
synovial and systemic inflammation. In 1995, Emery moved to Leeds to lead
a multi-disciplinary research group, who designed and delivered a series
of seminal studies to provide the evidence and establish the validity of
this proposed treatment model.
With Philip Conaghan (Senior Lecturer then Professor of
Musculoskeletal Medicine 1997- ), Joe Devlin and Andrew Gough
(both Research Fellows 1996-99), Emery showed that early RA
patients with a sustained acute phase response suffer irreversible joint
damage, resulting in pain and long term functional disability (1). Further
work demonstrated the substantial long-term consequences of incomplete
suppression of inflammation in early RA, where persistent synovial
inflammation led to increased functional disability, osteoporosis and
structural joint damage (2).
The group then carried out research looking at the effectiveness of early
diagnosis and aggressive treatment. Their work established that the
greatest predictor of persistence of disease was symptom duration of
greater than 12 weeks, a key step in establishing the importance of early
treatment. In collaboration with national (Maini, Imperial College London)
and international partners (Smolen, Vienna and Breedveld, Lieden), the
first international trials of anti-TNF therapy were conducted in patients
with RA . The Leeds group were the first to use biologic therapy for
remission induction in patients with very early disease and demonstrated
significant long benefits at eight years (3). In a subsequent study (4)
for the first time remission was used as an endpoint and the effectiveness
and lack of side effects demonstrated the feasibility of biologic therapy
first line. Consequently, remission has been accepted as the outcome of
choice in early therapy.
In addition, the Leeds group established the importance of using
validated outcome measures, which are both disease specific and reflect
what is important to patients. Alongside Richard Wakefield (Senior
Lecturer, Leeds 1996- ), they identified that clinical measures of
response to treatment are inadequate as subclinical synovitis exists in
patients who have satisfied clinical remission criteria, resulting in
"silent", irreversible joint damage (5). Importantly, the group identified
that this sub-clinical inflammation can be detected only through imaging
with MRI and ultrasound, questioning the importance of clinically driven
criteria as the sole foundation for treatment decisions.
With Alan Tennant (Professor of Rehabilitation Studies, 1999- ),
the Leeds team developed the RA-WIS, a work instability scale, which was
the first instrument designed and validated for the unique needs of
patients with RA. This tool is now widely used internationally to assess
the impact of RA on individuals' work. The RA-WIS was the primary outcome
for a novel randomised controlled trial led by Leeds of early treatment of
patients still in work with biologic agent adalimumab (6).
Work at Leeds established that the early diagnosis of RA results in
suppression of inflammation and leads to higher rates of remission.
Following on from this, the group designed a number of novel trials whose
primary endpoint was remission. The results of these studies established
that importantly, this remission could be sustained without the use of
expensive biologics (4). Long-term follow-up at eight years has confirmed
the success of this approach and the Leeds group have found that very
early treatment to remission results in the ability to cease therapy, and
have shown the immunological basis for this, proving the need to treat for
remission and not just symptom reduction.
References to the research
1) Devlin J, Gough A, Huissoon A, et al. The acute phase and
function in early rheumatoid arthritis. C-reactive protein levels
correlate with functional outcome. Journal of Rheumatology 1997; 24: 9-13.
This paper provided the rationale for the suppression of inflammation
in the treatment of patients with RA showing the first good data that
CRP as a surrogate marker correlated with function which was seen as the
gold standard measure.
2) Conaghan PG, O'Connor P, McGonagle D, et al.
Elucidation of the relationship between synovitis and bone damage: a
randomized magnetic resonance imaging study of individual joints in
patients with early rheumatoid arthritis. Arthritis & Rheumatism 2003;
This landmark study simultaneously imaging of synovitis and bone damage
in the same patients over 12 months provided the conclusive data that
inflammation and joint damage are strongly related and that in the
absence of inflammation there was little joint damage.
3) Quinn MA, Conaghan PG, O'Connor PJ, et al. Very early
treatment with infliximab in addition to methotrexate in early,
poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging
evidence of synovitis and damage, with sustained benefit after infliximab
withdrawal: results from a twelve-month randomized, double-blind,
placebo-controlled trial. Arthritis & Rheumatism 2005; 52: 27-35.
This was the first remission induction study with a TNF inhibitor which
showed that patients rapidly reached remission and maintained that state
when the biologic was withdrawn.
4) Emery P, Breedveld FC, Hall S, et al. Comparison of
methotrexate monotherapy with a combination of methotrexate and etanercept
in active, early, moderate to severe rheumatoid arthritis (COMET): a
randomised, double-blind, parallel treatment trial. Lancet 2008; 372:
This international collaboration showed that therapy with combination
of a TNF inhibitor and methotrexate was effective but also that serious
adverse events were not increased by therapy. It also was the first
study to use the now standard outcome of remission as an end point.
5) Brown AK, Conaghan PG, et al. An explanation for the apparent
dissociation between clinical remission and continued structural
deterioration in rheumatoid arthritis. Arthritis Rheum 2008; 58: 2958-67.
A year-long study of patients in remission at baseline showing for the
first time that sensitive imaging with ultrasound and MRI could detect
sub-clinical synovitis in patients treated with DMARDs in remission and
that sub-clinical disease correlated with significant radiological
progression in that individual joints. This formed the basis of current
use of high resolution ultrasound.
6) Bejarano V, Quinn M, Conaghan PG, et al. Effect of the early
use of the anti-tumor necrosis factor adalimumab on the prevention of job
loss in patients with early rheumatoid arthritis. Arthritis &
Rheumatism 2008; 59: 1467-74.
A long-term follow up of (4) showing that one year's treatment with
biologics produced significant benefits eight years later in a small
number of patients. It was the first study to find that early, biologic
therapy combined with methotrexate reduced job loss and improved
Details of the impact
RA is a chronic, systemic, inflammatory joint disease, affecting 600,000
people in the UK and is the largest cause of treatable disability in the
Western world. Given its high prevalence in the working population, RA
represents a major economic burden through both direct costs of care and
through loss of employment, with one in five employed RA patients having
to stop work within the first 12 months of illness. Treating RA costs the
NHS an estimated £560 million each year, with wider annual costs
associated with sick leave and work related disability of £1.8 billion.
With inclusion of nursing home costs and private expenditure, the
estimated costs are as high as £3.8 billion a year. The research
undertaken by the Emery group at Leeds has had a major impact on how the
disease is viewed, diagnosed and treated, leading to substantial
improvements in the health and quality of life of patients with RA and
reduced financial costs, both within the UK and internationally.
Impact on health and welfare
Research at Leeds has shown the need and impact of early, aggressive care,
a model that has been universally adopted in the UK.
The National Audit Office's guidelines on the management of RA — a
pivotal document commissioned by the House of Lords to review the NHS
standards of treatment for patients — cites Leeds work prominently [A].
Our work (4) provided the basis for a recommendation that: "It is
important that treatment is started early to minimise damage to joints,
and there is increasing evidence that aggressive treatment very soon after
the onset of symptoms can lead to remission." In the same report, the
Rheumatology Service at Leeds is used as an example of excellence in early
treatment and multidisciplinary care.
Guidelines from the National Institute for Clinical and Health Excellence
(NICE) recommended urgent treatment for RA [B]. The full guideline
document quotes two Leeds papers which established the superiority of
imaging to detect synovitis and the need to identify this early and a
further five papers establishing the importance of aggressive treatments
particularly in early disease and where the prognosis is poor. Underlining
the importance of early diagnosis, the British Society of Rheumatology has
recommended banded tariffs to see patients within three weeks of referral
Early, aggressive treatment improves patients' quality of life by
reducing pain and increasing functional ability and participation in
valued activities, including work. Access to early referral is now
expected by patients and is part of the Arthritis and Musculoskeletal
Alliance "Standards of Care for Rheumatoid Arthritis" [D]. This defines
appropriate support to enable those with RA to lead independent lives and
reach their full health potential. Standard 4 says: "All people with
suspected inflammatory arthritis should be seen by a specialist in
rheumatology within 12 weeks of referral from their GP, to confirm
diagnosis and enable prompt and effective treatment" citing Leeds
Based on the Leeds model, the care of patients with RA has been
transformed across the globe [E,F]. Early, aggressive treatment is part of
the joint European and American Guidelines [G], which directly influences
the care of more than 11.4 million people with RA. Treating to remission
is now a target recommended by several international bodies, which cite
Leeds research in the evidence, including that of an international
taskforce which refers to 17 Leeds papers [G,H]. Through Leeds' highly
successful International Fellowship programme, we have hosted over 25
clinical fellows from 15 countries, which has directly led to the setting
up of arthritis networks in Argentina and Brazil and the Gulf states, in
addition to Sweden, Netherlands and Germany.
Impact on the economy
The National Audit Office estimates that the financial impact to the NHS
of adopting the early treatment model is substantial [A]. Figures suggest
26,000 newly diagnosed patients in the UK each year, half of whom seek
early referral. While earlier, more rapid treatment increases the initial
costs, modelling has suggested that these costs would be more than offset
by decreases in lost productivity and improved quality of life. It is
estimated that by treating those who are seen early is associated with an
additional annual cost of £2.2 million but productivity gains of £6.2
Impact on public policy and services
Emery was instrumental in launching the Fit for Work Europe
an organisation showing that improvements in early intervention, treatment
and return to work practices could help people of working age stay in work
[I]. This report, launched at the Houses of Parliament in 2009, gained the
attention of policymakers and the media, informed Government thinking on
early intervention, prompted a debate in the UK parliament and contributed
to the initiation of a Government review of the costs and benefits of
treatment and care for rheumatoid arthritis patients in the UK. As a
result, in September 2010, the Fit for Work Europe Coalition was launched
in Brussels to highlight to policymakers and relevant stakeholders the
importance of early detection, prevention and management of
musculoskeletal disease [I]. The European League Against Rheumatism
estimates that this has led to many millions of additional funding
allocated to musculoskeletal disease [F].
Sources to corroborate the impact
[A] National Audit Office. Services for people with rheumatoid arthritis
(see pg 11, 28).
[B] National Collaborating Centre for Chronic Conditions. Rheumatoid
arthritis: national clinical guideline for management and treatment in
(see pg 25, ref 20 (1); pg 32 ref 64 (4) and pg 44 ref 69 (2).
[C] British Society of Rheumatology. Best Practice Tariff: Early
[D] The Arthritis and Musculoskeletal Alliance Standards of Care for
people with Inflammatory Arthritis (2004). (see pg 21 which cites two
[E] Corroborative Letter from British Society of Rheumatology President,
Professor Chris Deighton. Available on request.
[F] Corroborative Letter from EULAR President, Professor Maurizio Cutolo.
Available on request.
[G] Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis
classification criteria: an American College of Rheumatology/European
League Against Rheumatism collaborative initiative. Annals of the
Rheumatic Diseases 69: 1580-88. (see page 1583).
[H] Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid
arthritis to target: recommendations of an international task force.
Annals of the Rheumatic Diseases 69: 631-37.
[I] Corroborative Letter from President of WorkFit, Steve Bevan.
Available on request.