The development of anti-TNF therapy
Uncovering the importance of anti-TNF
The introduction of a new class of treatments for inflammatory arthritis, known as biological therapies, in the early 2000s revolutionised the treatment of this condition. The first of these were treatments targeting a molecule called TNF, which occurs naturally in the body and plays a key role in inflammation. This groundbreaking research is one of our key achievements to date.
Professors Sir Marc Feldmann and Sir Ravinder (Tiny) Maini, together with their teams at the Kennedy Institute of Rheumatology, have dedicated their lives to studying the causes of rheumatoid arthritis.
In this quest they uncovered a key molecule that causes inflammation and joint damage – known as tumour necrosis factor or TNF.
Initial studies led by Professor Fionula Brennan identified TNF as a key therapeutic target. At the time, it wasn’t widely accepted that blocking a single molecule could stop rheumatoid arthritis.
But in February 1994, Tiny and Marc held a press call to announce the success of the first clinical trial of anti-TNF therapy, which involved just 20 patients.
They showed a now legendary video of a patient, formerly severely disabled due to rheumatoid arthritis, walking unaided up a flight of stairs.
The announcement caught the attention of the national media, and the Kennedy Institute received more than 4,000 calls from people desperate to get hold of this new therapy.
We were key funders of this work through grants to Professors Feldman, Maini and Brennan.
Using anti-TNF in combination with other treatments
Subsequent studies in mice, led by Dr Richard Williams, showed that use of anti-TNF in combination with a treatment targeting T-cells improved treatment response. Large clinical trials demonstrated that combining an anti-TNF blocker called infliximab with methotrexate significantly improved disease symptoms. It also reduced joint damage, which had previously been thought to be progressive and irreversible.
This pioneering work has had a massive impact. Drugs such as infliximab have transformed the treatment of rheumatoid arthritis and improved the quality of life for many patients.
Changing the guidelines
Anti-TNF treatment is recommended by the National Institute for Health and Care Excellence (NICE) for people with moderate to severe rheumatoid arthritis who:
- haven’t responded to disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate.
- have severe, active and progressive disease but haven’t previously been treated with DMARDs.
Globally, infliximab (brand name Remicade) has been used to treat more than 1.9 million patients with inflammatory disease since its approval in 1998, which also includes conditions such as Crohn’s disease and ulcerative colitis.
In 2014, three of the four top-selling drugs globally were anti-TNF treatments, with combined worldwide sales of $32.3 billion.
The success of anti-TNF therapy has led to the development of a broader therapeutic field of drugs called biological therapies, which target or mimic the action of biological molecules, including anakinra and tocilizumab.
Exercise to reduce the pain of osteoarthritis
The ESCAPE-pain programme
Research has highlighted the important role that exercise can play in reducing pain and increasing function in people with osteoarthritis.
We supported Professor Mike Hurley at St George’s, University of London, to develop an exercise intervention programme called ‘Enabling Self-management and Coping with Arthritis Pain through Exercise’ – or ESCAPE-pain.
ESCAPE-pain is a six-week programme of integrated exercise and self-management delivered in a group setting by a physiotherapist.
As well as a tailored exercise routine, patients learn about the causes of pain and self-management techniques.
The programme aims to:
- improve people’s understanding of their problem
- advise them what to do and what not to do
- help them realise that exercise is a safe self-management strategy that can reduce the impact of joint pain and improve their quality of life.
The benefits of ESCAPE-pain
ESCAPE-pain has been shown to:
- reduce pain
- improve physical function
- increase quality of life and general well-being
- reduce use of healthcare services and medication.
In addition, it’s also cheaper and more cost-effective than usual care.
Clinical improvements were found to continue for more than two years after patients completed the programme.
The impact of ESCAPE-pain has been vast. The programme is now being delivered successfully in community centres across the UK. Patients can either be referred from a healthcare professional or refer themselves.
Clinics are reporting:
- improved patient outcomes
- reduced costs
- increased professional development opportunities for staff (in terms of gaining additional skills required to deliver the programme).
In Kent, the intervention is estimated to have led to a 50% reduction in the costs of physiotherapy for chronic joint pain.
Healthcare professionals can visit www.escape-pain.org to access the resources they need to run the programme.
The programme will also soon be running in other physiotherapy departments, leisure and community centres and places of work.
Next in the pipeline is the development of a patient-facing website that will allow people with arthritis to do the programme at home. This will massively increase the number of people with joint pain who will be able to ESCAPE-pain.
Intensive treatment for inflammatory arthritis
A new approach to treatment
The development of biological therapies transformed the treatment of rheumatoid arthritis, but there’s still much debate about how and when to use these drugs. Our researchers highlighted the importance of starting early, intensive treatment within 12 weeks of symptom onset.
Traditionally the approach with biological therapies had been conservative. Treatment was escalated as symptoms progressed.
But research at the University of Leeds, led by Professor Paul Emery, transformed the standard management of rheumatoid arthritis. The focus changed to early diagnosis and aggressive treatment with the aim of disease remission, as opposed to symptom management.
This is the result of findings that treating patients within 12 weeks of symptom onset is crucial to prevent pain and reduce the risk of long-term joint damage and disability.
Biological therapy was shown to be safe and effective for patients with very early disease, with significant benefits observed after eight years without the need for continued treatment. A similar aggressive approach is also effective for psoriatic arthritis.
Identify reasons for delays
Subsequent research led by Professor Karim Raza at the University of Birmingham reinforced the importance of starting treatment for rheumatoid arthritis within 12 weeks of symptom onset.
Studies highlighted the delay in patients receiving specialist care and identified underlying reasons for the delay, including:
- patient delay in seeking help from their GP – particularly for patients of South Asian origin
- GP delay in referring the patient.
This line of research was supported in part by grants from us, with funding also coming from the National Institute of Health Research (NIHR), European Commission, Medical Research Council (MRC) and others.
Together, these key findings have informed guidelines for treating rheumatoid arthritis developed by national bodies including the National Audit Office, the National Institute for Health and Care Excellence (NICE), and the Arthritis and Musculoskeletal Alliance. All of these bodies recommend early referral and early and aggressive treatment.
Outside of the UK, the evidence has also informed the joint European and American Guidelines.
Introduction of a best practice tariff
In 2013, our policy team and the British Society for Rheumatology, worked with the Department of Health to develop a best practice tariff for people with rheumatoid arthritis.
As a result, people with inflammatory arthritis should expect to:
- be seen by a rheumatologist within three weeks of being referred by their GP
- receive diagnosis and start treatment within six weeks of GP referral.
It’s estimated that early treatment of rheumatoid arthritis is associated with annual productivity gains to the UK economy of £6.2million. This more than outweighs the estimated additional annual cost of £2.2million to the healthcare system.
Targeted treatment for back pain
What is back pain?
Lower back pain is a major health problem in the UK, affecting four out of five people at some point in their lifetime.
For most people, back pain is caused by a simple muscle, tendon or ligament strain and they’ll recover within a few weeks. However, around three quarters of people continue to experience back pain and disability a year after first seeing their GP.
Ongoing severe back pain can impact on a person’s ability to work and carry out daily activities, as well as affecting relationships, sleep and mood.
Back pain is estimated to make up 20% of total health spend in the UK and was responsible for almost 10 million lost work days in 2014.
There are a range of treatments available for back pain – including painkillers and other drugs, physiotherapy, occupational therapy and surgery – but previously it was unclear which patients would benefit most from which treatment.
Developing the STarT Back Tool
We funded Professor Elaine Hay and her team at the Arthritis Research UK Primary Care Centre at Keele University to address this problem by developing a new way of grouping patients according to the treatment most likely to work best for them.
The team developed the STarT Back Tool, which is a short questionnaire that GPs can use to assess an individual’s physical, psychosocial and psychological risk factors for chronic back pain that can be improved with treatment.
The patient’s responses are then used to categorise them as being of either low, medium or high risk of experiencing chronic pain.
Those considered to be at low risk can be given reassurance and advice to self-manage their condition, whereas those at medium or high risk of chronic back pain can be referred for further treatment.
Testing the effectiveness of targeted treatment
Using a randomised controlled trial, the research team compared the effectiveness of a targeted treatment approach using the STarT Back Tool with current best practice physiotherapy for patients with low back pain.
In the trial, 851 patients visiting their GP for low back pain were referred to community-based physiotherapy clinics, before being randomised to receive either targeted treatment or current best practice.
All patients attended a 30-minute session with a physiotherapist, which included:
- advice on pain relief and activity
- self-help information.
Those in the targeted treatment group were then assigned further care depending on which risk category they were classified as:
- Low risk – no further intervention.
- Medium risk – physiotherapy using a physical approach.
- High risk – physiotherapy using a combined physical and psychological approach.
This trial, along with a subsequent trial funded by the Health Foundation, identified significant improvements in symptoms when using the targeted treatment approach compared to usual care.
Specifically, a targeted treatment approach led to:
- a reduction in patient-reported disability at 4 and 12 months
- 50% fewer days off work
- 30% fewer sickness certificates issued
- cost savings to the NHS of £34 per patient
- wider societal cost savings of over £400 per patient due to reduced time off work.
Changes in practice
Use of the STarT Back Tool is now recommended by the Royal College of General Practitioners, the Department of Health National Spinal Taskforce, and the British Pain Society, among others.
Free access to the tool and information on how to implement the tool into clinical practice is provided at www.keele.ac.uk/sbst
The site has had 30,000 unique visits since 2009.
More than 20 healthcare organisations in the UK have adopted the tool. Further afield, over 85 clinical services worldwide are using the tool to stratify patients and inform them of the probable progression of their pain.
Osteoarthritis as an occupational disease
What is osteoarthritis?
Osteoarthritis is the most common form of arthritis, affecting around 8.8 million people in the UK. The causes of osteoarthritis are complicated, with a person’s risk of developing osteoarthritis depending on both genetic and environmental factors.
We still have much to learn about how these two components work together to cause disease. However, research into lifestyle factors contributing to osteoarthritis – supported by funding from us – identified a number of occupations associated with a high risk of osteoarthritis.
- coal mining
- carpet fitting
- carpet and floor laying.
Linking heavy lifting with osteoarthritis of the hip
Professor Peter Croft at the University of Keele, in collaboration with Professor David Coggon and Professor Cyrus Cooper at the University of Southampton, conducted a study in which they compared 611 people with hip osteoarthritis awaiting hip replacement surgery with 611 healthy individuals.
Detailed lifestyle information was collected from both groups including:
- occupational and leisure activities
- body build
- smoking status
- alcohol consumption.
In men, an association was found between occupational heavy lifting, defined as regularly lifting 10 kg or more for prolonged periods, and hip osteoarthritis.
The risk of hip osteoarthritis was even higher in men lifting 25 kg or more, with farmers most frequently reporting lifting the heaviest loads among the hip osteoarthritis group. The researchers suggested that the high rate of hip osteoarthritis seen in farmers was due to the amount of heavy lifting done as part of their job.
Kneeling and squatting linked to osteoarthritis of the knee
In a separate study, people with painful knee osteoarthritis were recruited from a large general practice and compared to another group without knee osteoarthritis. The results suggested the risk of knee osteoarthritis was increased by prolonged occupational kneeling or squatting.
A larger investigation was later carried out which compared 518 people with knee osteoarthritis awaiting surgery with 518 healthy individuals. The risk of knee osteoarthritis was highest among people whose occupations involved prolonged kneeling or squatting, in particular when the occupation also involved heavy lifting.
Osteoarthritis as an occupational disease
The evidence from these studies contributed to reports produced by the Industrial Injuries Advisory Council (IIAC) reports on knee osteoarthritis and hip osteoarthritis. The IIAC is an independent scientific advisory body who review scientific and medical evidence and advise the Department for Work and Pensions on proposed changes to the Industrial Injuries Scheme.
The IIAC’s reports resulted in legislation being changed to include knee osteoarthritis in coal miners, carpet fitters and carpet/floor layers – and hip osteoarthritis in farmers – in the list of prescribed industrial injuries.
This meant that people who had developed knee or hip osteoarthritis as a result of working in one of these occupations were able to claim Industrial Injuries Disablement Benefit.
Depending on their level of disability, people eligible for the benefit receive between £33 and £168 per week. By 2011, over 16,000 former coal miners had successfully made a claim since the change to the legislation in 2009.
This research also contributed to the recognition of knee osteoarthritis as an occupational disease in other countries, including Germany and Denmark.
Reducing miscarriage in women with APS
What is APS?
Antiphospholipid syndrome (APS), sometimes called ‘sticky blood syndrome’ or Hughes syndrome, can cause blood clotting in the arteries and veins.
APS can occur on its own or alongside an autoimmune condition called lupus, and is a major cause of recurrent miscarriage as well as being one of the most common causes of stroke among people under the age of 40.
APS and pregnancy
In people with APS, the immune system produces harmful antibodies called antiphospholipid antibodies (aPL), which attack proteins in the body and cause the blood to become sticky and more likely to clot. This can cause problems in pregnancy:
- In early pregnancy, these antibodies can stop the embryo embedding in the womb properly, increasing the likelihood of miscarriage.
- In later pregnancy, the antibodies may cause blood clots in the placenta, which can result in poor growth, pre-eclampsia or still birth.
aPL are detected in approximately 15% of women who experience recurrent miscarriages, defined as three or more miscarriages.
Without treatment with drugs, the live birth rate among women with recurrent miscarriages with aPL is estimated to be as low as 10%.
Aspirin and heparin to prevent recurrent miscarriage
During the 1980s, treatment to prevent recurrent miscarriage was largely based on anecdotal evidence. Several case studies from the late 1980s reported the successful use of aspirin either alone or in combination with steroids to prevent miscarriage in women with APS. However, the use of steroids in pregnancy was associated with a range of side-effects including:
- high blood pressure
- premature birth.
At this time, Professor Lesley Regan was running the Recurrent Miscarriage Service at St Mary’s Hospital in London. She treated one patient who had aPL with aspirin and heparin, which resulted in a successful pregnancy. She then treated several other women – successfully – with aspirin and heparin.
In 1992, we awarded a project grant to Professor Regan to conduct a clinical trial to compare the impact of aspirin with aspirin plus heparin on preventing miscarriage in APS.
The trial included 86 women who had experienced three or more miscarriages in their first or second trimester and tested positive for aPL. All women took aspirin following a positive pregnancy test. After an ultrasound to confirm the viability of the foetus, women were randomly allocated to receive either aspirin alone or aspirin plus heparin up until 34 weeks’ gestation.
The trial found that women taking aspirin plus heparin had a 71% live birth rate compared to a live birth rate of 42% for women taking aspirin only.
Changing the guidelines
The findings of the trial led to the UK Royal College of Obstetricians and Gynaecologists (RCOG) asking Professor Regan to write its guidelines on the investigation and treatment of couples with recurrent miscarriage. These guidelines recommend the use of aspirin plus heparin for women with recurrent miscarriage with aPL.
The trial findings – along with those of similar clinical trials – also informed guidelines in the US, Netherlands, and Australia, all of which recommend the use of aspirin plus heparin for women with recurrent miscarriage with aPL.
Many women with APS who would previously been unable to have children have now had successful pregnancies as a result of this research. Professor Regan’s clinic at St Mary’s Hospital is now the largest recurrent miscarriage clinic in Europe and receives approximately 1,000 referrals a year for couples from across the UK.
It’s estimated that 1% of couples trying to conceive – equivalent to 6,000 couples in the UK – suffer experience recurrent miscarriage. As 15% of women with recurrent miscarriage test positive for aPL, this suggests that hundreds of couples in the UK may be benefiting from this treatment each year.