Arthritis Today - Spring 2009

Arthritis Research UK’s greatest achievement in its seventy years of existence has undoubtedly been its development and pioneering of anti-TNF therapy for rheumatoid arthritis (RA). Since this new class of drugs first appeared in the late 1990s, others are now following, prompting the possibility of - if not a cure as such - then the prospect of doctors being able to induce and maintain patients in a state of remission.

Articles in leading journals like The Lancet excitedly talk about how remission has become the goal of managing early RA, and that this aim needs now to be included in the design of clinical trials. The same article also concedes that there are several definitions of what remission actually means.

Paul Emery, who has been the lead investigator in a number of international Phase III, multi-centre clinical trials of new RA drugs, explains:
“For the first time it is feasible to talk realistically about remission as the primary outcome for people with newly diagnosed arthritis. However with more patients achieving a remission state the definition of remission itself has been re-examined.

“If we were talking about remission in cancer, it would mean that you have no detectable disease and eradication of the tumour.  In RA we conventionally define remission as clinical remission where there may still be underlying disease, so we are now discussing true remission, which is defined by sensitive imaging (ultrasound or MRI) and no disease progression over time. It is still possible to have no symptoms but yet have significant sub-clinical disease. Conversely some patients still have pain but no underlying disease; this is often the case with patients who are treated late.” 

Could the term “being in remission” ever mean that a patient remains free of disease - once they have come off drugs?  At the moment, the standard way of inducing remission is to step up drugs in order to suppress inflammation.  More recently there has been a change to remission-induction using anti-TNF as first therapy in controlled studies and subsequently to stop it when patients are in remission reducing to a maintenance dose of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate.

To Professor Emery, the mere suggestion that being in remission could mean being off medication is evidence of how far treatments for RA have come in the past few years. “Until recently it would never have occurred to doctors that remission would mean that a patient can come off drugs. That is a huge step forward, but that’s the way we are going, so there’s now an evolving definition of the term remission. At some point it might mean that a patient is completely well and the therapy can be stopped.”

The results from several recent clinical studies have provided evidence of the effectiveness of anti-TNF in early RA, and that people with early disease respond much better than patients with late-stage RA. The multi-centre COMET trial of patients who had had RA for between three months and two years showed that 50 per cent of them, on a combination of etanercept and methotrexate, attained clinical remission after a year, compared to 28 per cent of patients on methotrexate. Another trial, called TEMPO, showed that 40 per cent and 19 per cent of patients respectively were in remission after taking etanercept and methotrexate, but these patients had had RA for on average seven years.

“Anti-TNF works in most patients if they are treated early enough.”

Of course, in the UK, such discussion of inducing remission or treatment of early RA with anti-TNF therapy remains entirely hypothetical outside clinical trials.  TNF blockade works in more people with arthritis when they are treated early enough, but current guidelines from the government’s health watchdog the National Institute for Health and Clinical Excellence (NICE) mean that only those people with severe RA who have failed on at least two DMARDs are eligible for this class of drugs.

“If cost was not an issue we would be treating most patients with early RA with anti-TNF therapy, as the effect is greater than with standard DMARDs,” says Paul Emery. “Anti-TNF works in most patients if they are treated early enough.”

This is not a universal view, and also begs the question whether it would be appropriate for all patients with early RA who have the condition fairly mildly and whether they would actually benefit from such an approach.

Professor Emery has little doubt what most patients would choose. “If you were given the opportunity to go into remission and have a chance to stop your therapy, but had to take more powerful drugs at the beginning, would you take it?  This becomes especially relevant when COMET shows no increase in toxicity. It’s a question of relative benefit, and RA, true RA, is a really nasty disease. Anti-TNF makes a make difference to people’s quality of life.”

“Inducing remission in late stage RA is a real possibility”

Treatment could be even better than it is and clinical trials have produced better data than seen in routine clinical practice, he believes; in other words, there’s a big lag between trial results and what patients actually get. However, it should be stressed that with more than 70 per cent of people with RA responding well to anti-TNF therapy in early disease, the possibility of inducing remission in patients with late stage as well as early RA is also very real (see case study).

The argument that putting all new cases of RA onto anti-TNF therapy would be eye-wateringly expensive (the drugs cost about £12,000 a year per patient) is countered by the fact that many of these patients would be able to stay in employment. At the moment, four out of ten people in work with RA lose their jobs within five years, and one in seven give up work within a year of diagnosis.

Keeping people with RA in work is now the basis of campaigning by patient groups, pharmaceutical companies and professional bodies in the UK, and almost 50 nursing and medical organisations have pledged to consider supporting people of working age to stay in employment, using job retention as a critical outcome measure. Paul Emery, as next President of EULAR (from June 2009), (the European League Against Rheumatism) a European-wide organisation representing patients, health professionals and research bodies, is very much involved in this.

He adds: “Anti-TNF is used more widely in mainland Europe and also in the US, where there is private medical insurance and greater freedom for doctors to prescribe, and certainly NICE is having a major impact on the use of the therapy in the UK. But the success of clinical studies showing the effectiveness of anti-TNF on early RA will put pressure on NICE to look at this issue.”

The sheer number of new RA drugs currently in the pipeline could also pressurise NICE into looking afresh at how people with early RA should ideally be treated.

The imminent licensing of another very promising new RA drug, tocilizumab, aimed not only at people who have either failed on or not responded to not only to anti-TNF therapy but also a DMARD such as methotrexate or sulfasalazine, raises more interesting questions for NICE. What will be the pecking order of drugs if tocilizumab and anti-TNF therapy are the same price, for example?

Another unresolved issue is the so-called sequential use of anti-TNF drugs. NICE has decided to review its controversial guidance on the “sequential use” of anti-TNF therapy. Its previous draft guidelines had recommended that RA patients who failed on anti-TNF should not be allowed to try a second, but the watchdog is now re-considering the decision in the light of outcry from campaigning groups.

Paul Emery believes that rheumatologists should be able to decide on sequential prescribing. “I wouldn’t try it on everyone, but we have treated people who had no response after the first anti-TNF but then went into remission with another. However, if you have a patient that has failed on two anti-TNF therapies you would be less inclined to treat with a third….”

Whatever the current inadequacies of the treatment of RA, the strides made improving it have been massive over the past 20 years. “Then, if you failed on two DMARDs, there was nothing else, you just ran out of drugs,” points out Paul Emery. “Now we have a greater understanding of how we can use methotrexate in larger doses, and of course we have now more effective treatments like anti-TNF, which has been the stimulus for other new drugs.”

Professor Emery predicts that in another 20 years time all new cases of inflammatory arthritis will be rapidly assessed and the concept of “individualised medicine” will come into play, with treatment more targeted and tailored towards individual needs. In the meantime, he concludes: “We’ve come a long way!”

New RA drugs in the pipeline

Tocilizumab: expected to be licensed in the UK in October 2009, the drug is also currently awaiting NICE approval. Brand name RoActemra, it is the first interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody developed for the treatment of RA, and has a different mode of action to anti-TNF therapy.  Following several multi-centre Phase III trials which demonstrated impressive effectiveness, it is expected to be licensed for RA patients who fail on other drugs, including methotrexate and anti-TNF therapy.

Certilizumab-pegol: brand name Cimzia, it is a new anti-TNF therapy currently going through the NICE approval process, with a decision expected by February 2010. Phase III trials have shown the drug effectively prevents joint damage when combined with methotrexate. It is already approved in the US for Crohn’s disease.

Golimumab: following positive Phase III trials results, it is now awaiting licensing in the USA and Europe for the treatment of RA, psoriatic arthritis and ankylosing spondylitis.It has recently been referred for review by NICE for methotrexate-naïve RA patients.

Ofatumumab: Phase III clinical trials into this B-cell therapy also known as Humax-CD20 are underway, for both methotrexate and anti-TNF failures. It is also in long-term trials for non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.

Ocrelizumab: this drug, which also targets B-cells, is currently in Phase III trials for rheumatoid arthritis, lupus and multiple sclerosis.

Case study

Allison Morsali, now 52, developed severe RA 12 years ago, and after her condition failed to respond to methotrexate, she was put on infusions of infliximab, which also proved unsuccessful.

A patient first at the early arthritis clinic in Leeds, then the remission clinic, Alison’s doctors pushed to get her onto a second anti-TNF therapy, etanercept. It has been so effective in controlling her RA that she and her medical team are now reducing the dose so that she can come off the drug completely by May – and be in drug-free remission.

“I’ve gone from being extremely ill: taking lots of painkillers and anti-inflammatories, wearing splints on both wrists and having to give up work for six months, to going back to work full time, and even going to the gym, so I’m a shining example of what these drugs can do,” says Allison, a manager at a further education college in Leeds.

“I’ve been left with some joint damage and have restricted mobility, but it’s been a massive turnaround. Etanercept is the only thing that has controlled my RA. For the past three years I have been living a reasonably normal life with the odd flare.”

Allison has tried once before to give up medication but flared up after a few months. However, she feels there has been such a drastic improvement in her condition that it’s worth another try.

“I now feel so well and have done for more than a year – there’s absolutely nothing wrong with me – and I don’t think you should keep taking drugs if you don’t need them.”

• Arthritis Research UK’s new clinical studies group into inflammatory arthritis is currently discussing the optimal strategy for patients who fail on their first anti-TNF therapy, the best choice of the first biological drug for RA patients, and how these drugs can be used most effectively. A resulting clinical trial investigating some of these questions is expected to be awarded shortly.

Forty-six per cent of the UK population use complementary medicines at some point in their lives, spending more than £450 million a year on non-conventional treatment.

Among people with arthritis the figure is even higher – 60 per cent of patients try such treatments as green-lipped mussels, homeopathy and rosehip – in a desperate bid to relieve their pain.

But despite the vast numbers of products available in health food shops and via the internet, it can be very difficult for people to know if what they are taking actually works – or whether they are simply wasting their money.

It was in response to this that Arthritis Research UK decided to produce the first evidence-based report dedicated to complementary medicines in arthritis. The aim was to inform the public whether there is scientific evidence to support the clinical effectiveness and safety of a range of products for which claims have been made, but in many cases are unsubstantiated by hard evidence.

And despite the vast number of complementary and alternative medicines on the market, the report found that evidence from randomised controlled trials was available for only 40 of them.

Professor Alan Silman, Arthritis Research UK medical director, explained: “Complementary medicines are widely used by people with arthritis as they seek to avoid taking potentially harmful drugs, preferring natural products. However, natural does not mean they are either safe – or effective. Many people spend hundreds of pounds on these products and they need to know that there is a strong chance of benefit.”

Guidance is important

The report covers medicines taken by mouth or applied to the skin, rather than therapies such as acupuncture and chiropractic. It scores medicines according to their effectiveness with 1 indicating that the available evidence suggests that the compound is not effective and 5 indicating that the compound is effective. It also grades the medicines according to safety, providing traffic light classifications for each.

Professor Gary Macfarlane, who led the research, said it was important that people with arthritis had some guidance on the complementary medicines available. “While over 60 per cent of people with arthritis or other aches and pains use some form of complementary and alternative medicine - and find different things work for them - it is useful to also have the scientific evidence available and just as important to know how safe we think they are to use,” said Professor Macfarlane. “All of the evidence can now be accessed in this definitive report.”

Fish body oil scores highly for rheumatoid arthritis

The report throws up several surprises. For nearly two thirds of compounds used for rheumatoid arthritis, for example, the data in the report suggests they don’t work, while the effectiveness of glucosamine sulphate, a supplement popular with people with osteoarthritis, is again called into question, scoring only three.

The two highest-scoring products in terms of reducing pain, movement or general well-being were fish body oil for rheumatoid arthritis and capsaicin cream for osteoarthritis.

Products for osteoarthritis scoring four were herbal extract phytodolor and nutritional supplement SAMe (although these products are not available in the UK), while fish liver oil only registered a one.

What does the report say?

For rheumatoid arthritis (RA):

• Nearly two thirds (13 out of 21 complementary medicines [62 per cent]) were shown to have no or little effect based on the available evidence (scoring 1 out of 5 on the effectiveness scale)
• The 13 are: antler velvet; blackcurrant seed oil; collagen; eazmov herbal preparation; feverfew; flaxseed oil; green-lipped mussels; homeopathy; reumalex herbal mixture; selenium; Chinese herb tong luo kai bi; vitamins A,C and E anti-oxidant vitamins; and willow bark.
• By contrast fish body oil scored 5 out of 5 for people with RA, reducing joint pain and stiffness.

For osteoarthritis (OA):

• Nearly one fifth (6 out of 27 medicines [22 per cent]) were shown to have little or no effect based on the available evidence
• Glucosamine one of the most widely taken products showed mixed results with glucosamine sulphate scoring 3 and glucosamine hydrochloride scoring 1
• Capsaicin gel (available on prescription), made from chilli peppers, proved most effective in relieving pain and joint tenderness, scoring the full 5.

For fibromyalgia:

• Only four products were assessed
• None of them highly effective with three medicines scoring 2 out of 5, and the fourth an ineffective 1.

Safety:

• One quarter of the compounds were given an “amber” safety classification indicating there were important side-effects which had been reported, although there is much less safety information available for complementary medicines in comparison to conventional medicines.
• Only one “red” safety classification was issued against thunder god vine for RA.

Case study

Margaret Fisken from Aberdeen was 40 when she was diagnosed with rheumatoid arthritis (RA). For five years she tried a large number of complementary medicines to try and relieve her increasingly deteriorating condition, spending around £200 in the process.

“The RA started in my feet and spread through my body within a few months,” explains Margaret. “At that time I wasn’t given any strong medication, and the disease took hold - the joints became quite deformed.”

One of the first complementary medicines she tried was cider vinegar when she was first diagnosed on her 40th birthday. “Someone said to me: ‘I hear such and such works so you should try it,’ ” says Margaret. “However, I didn’t find that anything worked at all.”

Over the years Margaret tried the following products – without success:

Blackcurrant seed oil, capsaicin gel, chondroitin, devil’s claw, evening primrose oil, feverfew, fish oil, ginger, rosehip, glucosamine, homeopathy, selenium, vitamins (all), aloe vera, cider vinegar, echinacea, garlic, green tea, ginseng, zinc and copper.

What she found the most helpful have been conventional drugs, in particular the standard therapy for RA, methotrexate. “When the methotrexate kicked in, I didn’t feel I needed anything else so gave up trying the complementary medicines,” she says. “Standard drugs are the only medicine that has worked for me.

“I was diagnosed in 1992 and between then and 1998 I was trying everything. I was virtually chair bound, and movement was so painful.  On occasion, if going out I had to go around in a wheelchair and I couldn’t move without assistance. I was also in severe pain. Methotrexate revolutionised my life compared with how I was before.  Within a few months of starting the medication I improved fairly dramatically, and it gives me a reasonable quality of life with just the odd blip.”

Margaret was a member of the expert panel convened by Arthritis Research UK to assess products for the complementary medicines report.

She says she thinks Arthritis Research UK’s report is long overdue and much needed, and is happy to have been involved. “There are many people looking to spend large amounts of money on all this stuff and people trying to sell it are hugely hyping it up, and yet until now no-one has been able to say with any authority if it works or not,” she adds.

• Copies of the full 80-page report which is free of charge, are available on 01904 696994, by emailing mailto:arc@bradsawsdirect.co.uk or by accessing the PDF on our website.

Research into developing new treatments for osteoarthritis have so far failed to produce anything remotely effective or safe, as the recent vioxx drug scandal showed when a popular painkiller for osteoarthritis had to be withdrawn worldwide after a number of related deaths.

While basic science attempts to chip away at the many possible causes, hampered by the fact that essentially osteoarthritis is not just one disease but several - involving cartilage, bones, joints and inflammation - patients struggle to find satisfactory pain relief, often turning in desperation to unproven supplements when conventional medicines fail to work. And while there are now many drugs on the market that slow down disease progression in inflammatory forms of arthritis such as rheumatoid, and which may even lead to remission in the not too distant future, a similar drug for osteoarthritis is acknowledged to be years away.

So is a completely new approach to treatment needed? Step forward David Felson, Professor of Medicine and Public Health at Boston University, leading world authority on musculoskeletal diseases, particularly osteoarthritis, regularly published in leading journals, principal investigator of the Framingham Study, one of the biggest epidemiological studies in the world, and a practising clinician.

And now he’s heading up research in the form of a £1.4m special strategic award for arc looking at ways of developing new treatment approaches for osteoarthritis.

One of the last unconquered musculoskeletal diseases

Although the nuts and bolts of Professor Felson’s research is not due to start until the summer, he is already spending one week a month at Manchester University, where he holds an academic post, and which he plans to do for the next five years, overseeing a large multi-disciplinary research programme and three planned clinical trials.

“Osteoarthritis remains among the last unconquered musculoskeletal diseases and one of the few chronic diseases of ageing for which there is no effective strategy to prevent disease progression,” he says. “And in order to conquer it more successfully, it needs to be addressed in a multi-disciplinary fashion.  I would never pretend to study it just by myself, just as a rheumatologist, I’d only study it if there were enough folks who have the interest and the expertise  to compliment my own – radiologists, engineers and biomechanics, physiotherapists, people who know about bone and muscle. If you assemble all these people and pose the right questions and encourage them to interact and talk with each other, we can hopefully answer those questions.”

Moving away from cartilage

What marks out Professor Felson’s approach as unusual is that he is moving away from concentrating on cartilage repair as a central treatment target.

“My own predilection is that cartilage is maybe not so important in dealing with and treating osteoarthritis,” he says. “I don’t say that it’s not important in the creation of disease, but once it’s developed, other changes occur in the joint and these then drive the process, and cartilage takes a back seat. It’s a radical position, and not generally accepted at all. One of the reasons I came to England is that some of the ideas that underline that position really emerged here.”

David Felson has reached his position by watching, with increasing frustration, a number of treatments that have been tested and have failed. “For example doxycycline, (an antibiotic in the tetracycline family) which ought to work if cartilage was the problem, but doesn’t; a trial of risedronate (a bisphosphonate drug used to reduce bone loss in osteoporosis) and a large number of compounds developed by the pharmaceutical industry that appear to stop cartilage loss, but don’t work in clinical osteoarthritis. We know that there is no correlation between cartilage damage on x-rays and pain, because cartilage has no pain fibres. The research road is littered with cartilage studies, and it’s reached a dead end.”

What Professor Felson proposes to concentrate on instead are treatments that may both relieve the pain of osteoarthritis and alter the structures in the joint that are the sources of this pain, bone marrow lesions, and synovitis – inflammation of the synovium, the fluid that surrounds the joint to keep cartilage slippery.

Bone marrow lesions may be a cause of pain

The advent of magnetic resonance imaging (MRI) which can detect changes in the joint more accurately than ever before, has shown that these bone marrow lesions - areas of bone damage which show up on MRI as white blotches - are seen more frequently in people whose knee osteoarthritis is painful than those whose knee osteoarthritis is not painful. And the lesions get bigger when pain gets worse, suggesting that they are a cause of pain.

Professor Felson and his group were among the first researchers to suggest that despite osteoarthritis being known as a degenerative condition, mild inflammation also plays a part in the development of osteoarthritis (which is why anti-inflammatories and steroid injections can be effective). Synovitis is seen in at least 50 per cent of patients with painful knee osteoarthritis, and previous studies have shown that if synovitis decreases, so does pain. So targeting synovitis is another important strand of the forthcoming research.

The aim of the research programme is to evaluate treatments that may affect bone marrow lesions and synovitis to see if they alleviate pain, and hundreds of people with osteoarthritis of the knee from the Manchester area are to be recruited over the next three years to take part in related studies.   

The other novel idea to be pursued is that all patients with osteoarthritis do not need the same treatment, but rather subgroups of patients with knee osteoarthritis can be identified who will respond to targeted treatment. There are three different subgroups to be studied. First are those with patellofemoral osteoarthritis (affecting the joint between the undersurface of the knee cap and the femur). Second, there are those with disease localised to the inside of the knee and lastly, the team will evaluate people whose osteoarthritis includes prominent fluid swelling in their knees.

Targeting people with particular types of knee osteoarthritis into specific sub-groups is an important feature of the research, although there is inevitably some cross-over. “I think another reason why there may be a failure in the development of treatments is that people have thought it is a single disease,” adds Professor Felson. “There are similar elements in many patients but for treatment purposes we need to think of osteoarthritis as a different group of illnesses that needed to be treated differently.”

A need for urgent progress

In his osteoarthritis clinic in Boston, Professor Felson takes a multi-disciplinary approach to treatment, offering specific physical therapy depending on patient’s particular problems. With ageing and obesity an even greater crisis on the other side of the Pond than in the UK, he is acutely aware of the need for urgent progress. “I understand why people take supplements like glucosamine, even though they probably don’t work. I don’t try and stop people from taking supplements because we need something that helps people and if they think it helps, then who am I to know better?”

At the age of 56 Professor Felson is finding that the subject that has occupied him professionally for more than 30 years is also starting to affect him personally. “I don’t have knee osteoarthritis but I probably have a mild case of it   in my hips,” he says. “I don’t want to have an x-ray because I don’t want to know. I know too much!”

Many people will experience knee pain related to osteoarthritis and the numbers are set to rise, explained in part by our ageing population and increasing prevalence of known risk factors such as obesity and poor physical fitness.

The vast majority of knee problems are managed in primary care by GPs and other health care professionals such as physiotherapists, and yet many people with knee pain find that the current NHS services are frustratingly limited. As a result, researchers at the Arthritis Research UK National Primary Care Centre at Keele University, through a series of clinical trials, are trying to find new ways in which the treatment of knee pain problems can be improved.

Teams of researchers at Keele led by Professor Elaine Hay and Dr Nadine Foster have conducted two large clinical trials (funded by Arthritis Research UK) of different types of treatment for people aged 50 and over who have a clinical diagnosis of knee osteoarthritis.

Both studies have investigated the benefits of advice and exercise, which recent National Centre for Health and Clinical Excellence (NICE) guidelines for osteoarthritis (www.nice.org.uk/CG59) recommend as core treatment, available to everyone irrespective of age or level of disability. In the two trials, NHS physiotherapists provided education, advice about self-help strategies and pacing of activities, and exercise therapy. The exercise treatment was based on a clinical assessment of the knee problem and included exercises to strengthen muscles around the knee, increase patient’s balance and improve the ease with which everyday activities can be completed.

NHS network

Since 1999 Dr Jonathan Hill, an Arthritis Research UK lecturer in physiotherapy research at the Keele centre has helped to establish a network of NHS physiotherapists who are keen to collaborate in high quality research such as large randomised clinical trials. This partnership between Keele researchers and clinical physiotherapists has made these trials possible, and more than 125 physiotherapists from 23 NHS Trusts across the West Midlands region are now involved.

The physiotherapists not only helped to recruit and treat patients but were actively involved in helping to shape the research questions, develop the treatment protocols, interpret the results and disseminate the study findings into NHS practice.

Comparing different trials

The first of these two knee pain trials called the TOPIK trial (Treatment Options for Pain in the Knee) evaluated the clinical effectiveness of two treatment approaches. The first was a treatment delivered by a pharmacist working in an enhanced role, reviewing patients’ medication to ensure they were taking appropriate tablets for their pain. The second approach was an advice and exercise package delivered by NHS physiotherapists. These two approaches were compared to a control treatment that consisted of usual GP care, written advice and information followed up by one telephone call by a practice nurse. The results demonstrated that both the enhanced pharmacy and exercise package significantly improved patients’ knee pain compared to the control treatment. In addition, the exercise package also significantly improved patients’ knee function.

The second knee pain trial known as the APEX trial (Acupuncture, Physiotherapy and Exercise for Knee Pain), investigated the clinical effectiveness of acupuncture in addition to an advice and exercise package delivered by NHS physiotherapists. Although no additional benefit from acupuncture was found in terms of pain on activity at the follow-up time points of six and 12 months, the results for the advice and exercise package were striking, as the improvements in patients’ knee pain and function were greater than those seen in the TOPIK trial.

The researchers presented these results to their physiotherapy collaborators who had delivered the treatments in order to explore the reasons why the advice and exercise package in the APEX trial was more effective than in the TOPIK trial. The clinicians suggested that the key difference between the treatment was the extent to which they focused attention on making the exercises more specific and progressive for the individual and the way in which, overall, they ‘sold’ the exercise to patients. This finding suggests that older adults with knee pain could have a better clinical outcome if greater attention was given to the quality, intensity and progression of the exercise programme.

Arthritis Research UK went on to fund Mel Holden through an Allied Health Professional training fellowship to work on the Keele ABC-knee study (Attitudes and Behaviours Concerning knee pain). This PhD programme aims to investigate the attitudes and behaviours of older adults and of physiotherapists to exercise for knee problems. This research, alongside other research studies, has provided useful information that has identified strategies to improve both the quality of exercise interventions and ways to help ensure individuals are supported to adhere to increased physical activity levels over the longer-term.

Now recruiting

So NHS physiotherapy partners with Keele are now being approached by the research team to collaborate in a third randomised clinical trial for older adults with clinically diagnosed osteoarthritis of the knee. This study is funded by Arthritis Research UK and the National Institute of Health Research (NIHR) and is called the BEEP trial (Benefit of Effective Exercise for Knee Pain). The new trial will investigate the benefit to patients of identifying ways of improving the quality of, and adherence to, exercise and physical activity in general. Patients will be recruited from participating NHS physiotherapy centres initially for a pilot study in 2009 and then for the main clinical trial in 2010-2011.

So if you have knee osteoarthritis what should you be doing about it?

Dr Mark Porcheret, a GP whose research has focussed on the treatment of knee osteoarthritis, recommends that firstly you should be provided with clear advice about how to manage your condition from your doctor, and that you should actively be seeking to improve your muscle strength and general physical fitness wherever possible. You may need the advice and support of a professional such as a physiotherapist to do this confidently.

Other useful treatments include losing some weight if you need to (as weight has been shown time and time again to be linked to the amount of pain people get in their knee joints), taking paracetamol (up to two 500mg tablets four times a day) or using one of the widely available (from the pharmacist or your GP surgery) non-steroidal anti-inflammatory gels such as ibuleve. If pain, or problems with mobility continue, there are a number of other treatments your GP or physiotherapist can try, such as acupuncture, stronger painkillers, local steroid injections, capsaicin (a cream containing a product of chilli peppers that gives a numbing effect) and local heat or cold. If these are not successful and the problem is getting a lot worse then surgery may be the answer.

Joint replacement, though involving major surgery, is very effective but arthroscopy (where the surgeon looks inside the joint with a special telescope) has been shown to only help a small proportion of people with knee osteoarthritis: those who have problems with mechanical locking of the knee. So remember, even though knee osteoarthritis is not curable there are many treatments that can help reduce pain and increase mobility.

• Dr Jonathan Hill is an Arthritis Research UK lecturer in physiotherapy research, and Dr Nadine Foster is a senior lecturer and Department of Health primary care career scientist at the Arthritis Research UK national primary care centre.

This innovative research hub has established itself as a highly efficient, patient-focussed centre that places teamwork and innovative collaboration at the forefront of its work ethos. Arthritis Today looks at how the first tier of this thriving academic group, the postgraduate students, are progressing across a range of arc-funded PhD projects.

An impressive reputation

Newcastle University’s Faculty of Medical Sciences boasts an impressive reputation for its achievements in strategic planning, translational research, and academic teaching. Rated very highly in the recent 2008 Research Assessment Exercise, and awarded prestigious National Institutes for Health Biomedical Research Centre status, the faculty attracts extensive funding from Arthritis Research UK and other bodies, and enjoys expanding research and clinical research facilities.

Tim Cawston, Dean of Research and William Leech Professor of Rheumatology, sums up a major research emphasis of the faculty: “It has been said recently that life expectancy is increasing by five hours for every single day that passes. What we need to focus on is: how good will those five hours be, and how can we make them better?”

The Musculoskeletal Research Group certainly rises to this challenge by promoting a collaborative mix of basic science and clinical research projects to address the problems of arthritis and age-related musculoskeletal diseases, alongside other specialist areas in paediatric rheumatology and education research. Strong interactions between laboratory and clinical sectors ensure a good supply of vital clinical samples and excellent communication links that support their translational approach to disease research.

Up and coming research in focus

For the PhD students, research is set against a background of investigative excellence in a range of disciplines: immunotherapy, stem cell transplantation, molecular genetics, and orthopaedic science, to name just a few. This expertise and technology supports their approach to tackling key arthritis issues - identifying susceptibility and early disease, and preventing or slowing disease progress.

Immunotherapy and matrix biology are the main research areas. Immunotherapy investigates the functioning of the immune cells in health and disease and exploits this knowledge to develop therapies that can restore normal functioning or block destructive pathways. Matrix biology is concerned with the functioning of the cartilage and bone environment and how molecular interactions within this dynamic medium are responsible for cartilage and bone damage.

Reduced enzymes in osteoarthritis

Christos Gabrielides is investigating how cartilage problems in osteoarthritis (OA) may be caused by defects in cartilage cell mitochondria. Mitochondria are small organelles within the cell that are described as ‘power houses’ because they generate the chemical power for cell metabolism. As well as energy, their chemical reactions produce toxic substances called free radicals, which are very reactive and can damage other molecules.

Christos explains: “We know that mitochondrial dysfunction plays a role in OA and other diseases such as Alzheimer’s. Normally, free radicals are neutralised by powerful enzymes but we’ve discovered that in mitochondria from OA individuals, these enzyme levels are significantly reduced. We think that free radicals accumulate and damage mitochondrial genes, causing cellular malfunction and eventually cartilage breakdown. Accumulation of genetic mutations is believed to be the reason why we age and since OA and Alzheimer’s generally affect older people, this may be the cause of tissue malfunction.”

He aims to investigate the development of these mutations by studying mitochondria sourced from OA clinical samples. If the research confirms that enzyme depletion increases genetic mutations and OA progression, it may reveal new targets for therapy development.

Understanding molecular recognition

A specific division of immune cells, called B-cells, are known to play an important role in the recognition of microbes when infection occurs in the body. Recent research suggests that in rheumatoid arthritis (RA), this defence system malfunctions and B-cells may mistakenly recognise some of the body’s own molecules as ‘foreign’. This results in the immune system attacking the body - the autoimmune response.

Caroline Wilson, now in her final PhD year, has been investigating how B-cells respond to one of these body molecules, aggrecan, that makes up much of the joint cartilage matrix. Aggrecan is an important component of healthy cartilage and if it’s attacked by the immune system, cartilage structure is destroyed.

By investigating the cellular mechanisms that cause this recognition system to go wrong, Caroline hopes to produce data that will contribute to the development of drugs designed to block or even prevent disease. “We have generated a line of B-cells that recognise only aggrecan molecules so that we can study the detail of the recognition system. The aggrecan-specific B-cells are 10,000 times more efficient than ordinary B-cells at inducing an immune response. We’re using these to characterise the molecular events that promote autoimmunity.”

Achieving the aggrecan-specific model has been a large part of her research and represents a major advance in autoimmune investigation techniques that will benefit RA research as well as other autoimmune disease studies.

Vaccine possibilities for rheumatoid arthritis

Dendritic cells feature high on the list of ground breaking research topics. These are the immune cells that act like army generals, issuing orders to the army of white blood cells and coordinating the immune response. Some can order an attack whilst others can suppress an attack, and it’s this controlling ability that makes them a key focus for research purposes.

Media coverage has had the global research community reverberating with the news that the Newcastle team, headed up by Professor John Isaacs and Dr Catharien Hilkens, had achieved the first steps in vaccine development for RA using these unique cells, with Arthritis Research UK funding.

Dendritic cells can develop into either the mature cells that promote the immune response, or the so-called tolerogenic cells that prevent immune system activity. Newcastle researchers take white blood cells from the patient and subject them to a novel in vitro technique that manipulates their differentiation into tolerogenic dendritic cells. These will be introduced back into the patient in vaccine form, by injection directly into an inflamed knee joint.

It’s hoped that this vaccine system will suppress or down-regulate the autoimmune response - using the patient’s own cells guarantees immune specificity and there are high hopes for positive outcomes. Once pilot studies are complete, larger scale clinical trials will be initiated.

Switching off inflammation

Both postgraduate and postdoctoral students are engaged in research projects focusing on this exciting research strand. One of these students, Harriet Purvis, is investigating how the tolerogenic dendritic cells suppress the immune system in RA. The cells that launch the attack in an immune response are called T-cells and recent research has identified a new subset of these, called Th17 cells. These produce powerful inflammatory chemicals, or cytokines, including IL-17 (interleukin-17), that destroy synovial tissue and enhance bone destruction.

IL-17 is found in high concentrations in the synovial fluid of RA joints and it is suggested that switching off or slowing down the activity of these ‘bad’ Th17 cells could prevent or inhibit RA. Harriet explains: “The aim of the project is to learn how the tolerogenic dendritic cells affect Th17 cell function. If we can understand the underlying molecular mechanisms involved, we may be able to identify new targets for therapy options. In addition, we want to identify biomarkers, that is, molecules that give us some measurable indication of how well this dendritic therapy is achieving Th17 cell suppression. Then we’ll be able to measure treatment efficacy prior to overt clinical benefit.

Dr Bahaa Seedhom

About Bahaa

I enjoy listening to classical music; both live performances and at home, including much contemporary music, but I stop when it begins to hurt the ears. Reading; literature and theological books. I immensely enjoy constructing rock and water gardens in the Japanese style and have built a few. I take interest in Persian carpets. Renovation of buildings; trying but the results can be rewarding at times. Entertaining; I am reasonably competent at cooking.

What does your work involve?

I must explain that I am now semi-retired but work on a part time basis. My group, which formerly belonged to the musculoskeletal section led by Professor Paul Emery has now merged with the tissue engineering group of the department of oral biology in the Leeds Dental Institute. The merger has been a most logical step; collaboration between our two groups over the past 15 years has been fruitful, and resulted in Master and Doctoral theses, and joint publications in peer reviewed journals. The collaborative work continues in exciting translational research in the areas of tissue engineering (primarily of ligaments and cartilage) and computer assisted surgery of joint replacement.

How long has Arthritis Research UK been funding you?

Arthritis Research UK has generously funded my research since 1968 – some 41 years, for which I am most grateful.

What’s the most important thing you have found out in the past 12 months? And why?

The most important finding was an observation about the arrangement of cells in cartilage. Chondrocytes (cartilage cells) were thought to occur in groups of different numbers, but the observation, which we made in bovine cartilage, and published last year, was that chondrocytes generally occurred in pairs. The significance of this pairing may lie in that the cells in a pair could well be functionally interdependent. Should this be the case in cartilage of different species, especially in human cartilage, it should influence the methods developed to study of the metabolic activities of chondrocytes. These studies are generally undertaken on isolated chondrocytes, and our understanding of their behaviour could therefore be incomplete, or even incorrect. As our understanding of chondrocytes' behaviour is central to the cell based therapies of cartilage defects, a limited or incorrect understudying of chondrocytes' behaviour would render such therapies less effective.

What do you hope or expect to achieve as a result of your Arthritis Research UK funding?

Arthritis Research UK funding is vital for the continuation of employment of research colleagues and of maintaining research projects – without the flow of finance, projects come to a grinding halt.

What do you do in a typical day?

As I am not now shackled with any administrative activities, my work is mostly research related – supervising research, participating in writing/editing colleagues’ documents – whether these be papers, scientific reports or grant applications.  

What is your greatest research achievement?

In the area of prosthetics: a system for reconstruction of ruptured ligaments. In the area of applied research: formulation of a hypothesis on the role of mechanical factors in the development of osteoarthritis.

Why did you choose to do this work?

The choice was driven by a desire to put my engineering skills into use in the medical field. Human joints and their constituent structures were an appropriate starting point; joints are engineering bearings in every sense except for being living structures and hence much more complex. Like many of my fellow bioengineers I received immense encouragement from my boss, the late Professor Verna Wright, who was an innovator and among the most adventurous in his generation of medical professionals.  

Do you ever think about how your work can help people with arthritis?

Actually this is what you would habitually do if you work in this area of research – nearly all the studies undertaken by my group have been set up to tackle an arthritis-related issue. For instance prosthetic joints are designed to treat folk at the end stages of the disease with virtually destroyed joints. Prosthetic ligaments, as another example, are intended for the reconstruction of ruptured ligaments in order to restore stability to joints. This would hopefully prevent further damage and degenerative changes to the joint that could lead to the development of the disease. Other studies could help by suggesting modification to the lifestyle of folk to keep the joints healthy. 

What would you do if you weren’t a bioengineer?

A profession, which if it did not alleviate pain would bring joy to people – may be I would aspire to be a musician, but I would like to be a consummate one; the life of a second rate musician is a misery (whereas that of a second rate scientist is perhaps more tolerable)

• Bahaa Seedhom is a reader in bioengineering at the University of Leeds

Professor Vic Duance

About Vic

Sport has always played a major part of my life, football, squash and running. Football watching (season ticket holder at Old Trafford) limit active participation as much these days, that’s my excuse. I have run six marathons, and collected sponsorship for Arthritis Research UK on several occasions. However, I don’t think I could ever run enough marathons to repay my debt to Arthritis Research UK.

What does your work involve?

Cartilage, a tough but flexible tissue, helps the ends of our bones to glide smoothly over each other during movement of the joints, and acts as a ‘shock-absorber’, protecting the joint from damage during normal daily life. Collagen molecules are important to the form and function of healthy joint cartilage, and damage to these molecules contributes to the failure of cartilage in arthritic disease. A large part of my research career has been devoted to understanding the structure and function of the collagens in cartilage, muscle and the intevertebral discs; tough tissues that cushion the bones of the spine.  In particular, my research group has been investigating how collagens change with age and disease, and how they may also be involved in the repair of damaged cartilage. In recent years, our research emphasis has shifted from collagen itself to the activities of the cells that make collagen (and other molecules that form cartilage). We are interested in how the complex series of molecular events that occurs in the cells in response to mechanical loading during movement of the joint may sometimes lead to damage of these molecules, and degeneration of cartilage. Using this knowledge, our ultimate aim is to devise strategies for enhancing cartilage repair in arthritis.

How long has arc been funding you?

Since 1975, I think I have had continuous Arthritis Research UK support for my research, culminating in the recent award of a £2.5 million grant to establish the Arthritis Research UK Biomechanics and Bioengieering Centre here in Cardiff.

What’s the most important thing you have found out in the past 12 months? And why?

We have made significant progress in two areas. We have investigated the cytoskeleton, a kind of internal framework that gives the cartilage cell shape and structure, as well as acting as a ‘telegraph line’, through which the cell detects and responds to mechanical loading when the joint is under pressure. We have found that vimentin, one of the proteins that forms the cytoskeleton, differs significantly between osteoarthritic and normal cartilage, and that this difference may influence the way that that the ‘telegraph line’ responds to loading in osteoarthritic cartilage. Understanding this complex process will help us to tease apart the relationship between mechanical loading, cartilage damage and the development of osteoarthritis. We have also been active in the area of tissue engineering. Repairing damaged cartilage by implanting new, healthy cartilage cells from the patient’s own body is showing some success. Prior to the repair, some of the damaged cartilage is first removed; this process causes death of some of the cells at the removal site, and we believe that this hinders successful repair. We have shown that inhibiting cell death enhances cartilage repair; this treatment may improve the success rate of cell implantation procedures.

What do you hope or expect to achieve as a result of your Arthritis Research UK funding?

A better understanding of the biological processes that lead to the development of osteoarthritis, which will enable the development of better/new targeted drugs and/or treatments. At present we have very limited interventions at our disposal to treat patients. This will be a major drive of the new centre.

What do you do in a typical day?

It would be very nice to say that I go into the lab and set up experiments on a regular basis, unfortunately those days are long gone. I am Director of Postgraduate Research for the School of Biosciences. I also have a teaching commitment involving lectures generally related to my expertise in connective tissue biology.

What is your greatest research achievement?

Work over many years from my labs (Bristol and Cardiff) has made a significant contribution to our understanding of the structure and function of cartilage collagens.

Why did you choose to do this work?

After my PhD in enzyme kinetics I had a number of options but the opportunity to investigate the role of collagens in arthritis was my choice which I have never regretted.

Do you ever think about how your work can help people with arthritis?

It is easy to forget the over-riding purpose when undertaking basic research as you rarely come into contact with patients. I have always had close association with clinical colleagues so I don’t believe I have ever lost sight of “why am I doing this”. How our research can help patients was a major consideration in our bid for the Centre of Excellence for Biomechanics and Bioengineering, which is an association of basic scientists from a wide range of disciplines in collaboration with our clinical colleagues from rheumatology, orthopaedics and physiotherapy with both short and long term goals to help sufferers of arthritis.

What would you do if you weren’t a scientist?

Biology was always my main interest in school and I find it difficult to think what else I would want to do. Dreams of course were (and still are) to be a footballer playing for Manchester United.

• Vic Duance is Professor of Biochemistry at the University of Cardiff, and director of the new Arthritis Research UK Biomechanics and Bioengineering Centre.

There’s nothing modest about Andy Cope and Frederic Geissmann’s ambitions. The pair, both newly appointed as Arthritis Research UK professors at King’s College London (KCL), have big plans for the future of research into inflammatory forms of arthritis.  In a nutshell, by combining their clinical and scientific expertise, they are planning new ways of tackling inflammation that could lead to improved treatment - and even prevent inflammatory disease from happening in the first place.

With a £4.1m endowment from Arthritis Research UK and input of £2.6m from KCL and Guy’s and St Thomas’ charity, a new research centre is being constructed at the heart of the Guy’s campus where a large group of scientists and clinicians will collaborate in a multidisciplinary programme of research on inflammation and inflammatory diseases.

The new Centre for Molecular and Cellular Biology of Inflammation is opening in a phased way through the year, and should be fully up and running towards the end of 2009.

Frederic Geissmann, a world authority on immune cells called phagocytes, was lured to KCL with the promise of funding and freedom to pursue his research interests. With his impressive CV and research track record, new colleague Andy Cope describes him as a “superstar”.

A stimulating environment

Professor Cope in his turn could hardly resist the offer of being a part of this new centre from its inception, leaving his long-time base of the Arthritis Research UK Kennedy Institute of Rheumatology for the promise of new opportunities for making important contributions to arthritis research. Showing visitors around the fledgling unit, both men are openly excited about the opportunities that the centre offers them and their team of up to 70 researchers.  It will provide a stimulating environment for the next generation of trainee scientists and clinicians, including the PhD students soon to be recruited as part of the Oliver Bird Rheumatism Programme.

They are also keen to stress that the two of them are very much a package. It’s the first time that two Arthritis Research UK professors have been appointed at a single institution; Frederic Geissmann as professor of inflammation biology, Andy Cope as professor of rheumatology. They fill a post left vacant since the retirement of previous incumbent Professor Gabriel Panayi a few years ago.

Andy Cope explains the reasoning behind this: “If you were to go back 20-30 years, senior academics served multiple roles, being responsible for the clinical service and at the same time running a laboratory dedicated to clinical or basic research. This would involve significant administrative duties in the hospital and university setting, and a big commitment to teaching and training.  It was a challenging job, even back then.  The landscape has changed in recent years with growing pressures on clinical service delivery and a highly competitive research environment.  This has made it very difficult for a clinician to make major contributions in clinical medicine and in the laboratory.  In fact, clinical and laboratory-based career paths in medicine have diverged, and so in recent years it has become increasingly difficult for universities to recruit individuals who can deliver excellence in all three domains - clinical service, research and teaching.”

A great opportunity

Frederic Geissmann adds: “This is not only about spreading responsibilities or workload. Over the past 30 years, science has become a major force that has driven progress in clinical medicine, and there is a real opportunity today to build a better clinical medicine based on an in depth knowledge of the precise, molecular, mechanisms of diseases. However, only relatively few universities in the world have the will and means to lead this process. So when Adrian Hayday, chairman of the Division of Immunology, Infection and Inflammatory Disease (which includes the academic department of rheumatology) at KCL, told me that that Professor Alan Silman, the medical director of Arthritis Research UK, and KCL were keen to give financial support to create a basic science centre working on the mechanisms of inflammation - that would work together with the rheumatology department to improve our understanding of chronic inflammatory diseases, and to develop new diagnostic markers and better treatments - I decided it was a great opportunity for me, and I accepted to be the head of this centre.”

There are obvious synergies between the new professors. Professor Cope has been interested for many years in understanding how the immune system, in particular the T lymphocyte, becomes activated in inflammatory disease, and why the joint becomes the focus of this activity in patients with arthritis.  Monocytes and macrophages, the cells whose function is the focus of Professor Geissmann’s research, play a central role in immune activation and are likely to drive the inflammatory process that attracts T-cells and other cell types to joint tissues during the very early stages of disease. 

Working towards the 'Holy Grail'

Another of Professor Cope’s clinical research interests focuses on what he believes is the “Holy Grail” for researchers and clinicians working in rheumatoid arthritis research – identifying healthy people in the community who are most at risk of developing the condition – and actually then being able to carry out studies that might even prevent RA in the first place.

“The research groups that have made the biggest impact on patient care have been those who have invested in building up large cohorts of patients,” explains Andy Cope. “A cohort is a large collection of patients with the same or closely related disease.  By capturing detailed information from patients and comparing this with data from healthy control subjects you can learn a lot about the disease at the population level.”  

“The question we now want to ask how is: can we establish a cohort of apparently healthy individuals who are at high risk of developing RA?  This would be a great opportunity to study the interactions between genes, environmental factors, and the immune system, and how they interact to cause disease.”

Treating the high risk group with cheaper, safer drugs

With collaborators at the arc epidemiology unit in Manchester and at Imperial College, Professor Cope is setting up the first stage, looking to recruit a substantial cohort of subjects at high risk of developing RA – for example women smokers, who may be overweight, and also carry the genes associated with susceptibility for RA. The team will then watch these individuals very closely to see if they go on to develop the disease, and compare the results from a low risk cohort of the same gender and age but who don’t carry the susceptibility genes. Cope believes that the population in south east London is an ideal setting for such studies. The ultimate goal would be to treat the high risk group with cheaper and safer drugs before showing signs and symptoms of the disease and so prevent it from occurring.

Professor Geissmann has already gained valuable new insights into the vital role that phagocytes play in the inflammatory response to disease. These cells patrol our body in the bloodstream and move into infected tissues when required, engulfing invading microbes and secreting chemicals that stimulate other immune cells and cause inflammation. How they do this and why don’t they stop doing this in arthritis?

To answer these questions, Professor Geissmann has developed a novel technique that reveals cell behaviour in a totally new way. The cells are made to fluoresce so that they glow when viewed under a powerful microscope, and are viewed in real time, in living tissue. The images are fascinating - the cells can be seen as blobs of colour moving around the tissues and interacting with other cells.

Cutting edge imaging

“The methods we use to investigate the cells are technically very demanding,” says Professor Geissmann, “and that’s why it’s so important to have good collaboration with our imaging department specialists. We’re using cutting edge imaging and cell targeting techniques that allow us not only to view the cells but to investigate how their development and actions are controlled.”

Advanced imaging is also generating new knowledge at the molecular level as well. Within immune cells, genetic material is responsible for programming the manufacture of inflammation chemicals, such as tumour necrosis factor (TNF) and other cytokines. Understanding this control is crucial to inflammation research.

Professor Geissmann explains: “We want to find out which genes are responsible and how they affect the metabolic pathways that start and stop cytokine manufacture after infection. In arthritis, cytokine production is excessive and sustained. We may be able to design therapies that interrupt or stimulate the relevant pathways to prevent this. The goal is to correct the imbalance without compromising the body’s ability to fight infection.”

The role of the humble fruit fly, Drosophila

The research model for these studies is the humble fruit fly, Drosophila. This may seem a surprising model but in fact the genes responsible for cytokine production in the fly are similar to those in the human - over 90 per cent of our genetic material is the same - and the research will eventually translate into human studies. The fly is a very convenient experimental model - easy to reproduce quickly in large numbers and without the ethical constraints of rodent models.

The relevant Drosophila genes are tagged with fluorescent proteins so that once they are activated, the fluorescence can be tracked using advanced imaging techniques able to monitor living systems, and the images are simply stunning.

Christine Wong and Celine Trouillet, PhD student and laboratory manager respectively, have been establishing this novel technique and preparing the genetic material in preparation for the studies: “We can’t wait to move into the new research centre facilities. The new laboratory facilities have been purpose-built to our particular research specifications and will make a huge difference to our operational ability and throughput.”

The flies will be infected with microbes to stimulate an immune response and the resulting gene activity tracked in real time. “We already know,’ says Christine Wong, “that the genes responsible are active in the joints in humans and interestingly, this has been found to be the case in Drosophila too. We are going to study each gene in turn and map the outcomes of the immune response for each one.”

Professor Geissmann agrees: “During infection the body fights to restore health, and the cytokine system relies on a finely-tuned control mechanism. We’ll investigate how this control is achieved, why the joint is a focus of activity, and potential avenues for manipulating the system to block excessive inflammation in arthritis. The analysis will be challenging, but we should achieve the first detailed genetic blueprint of inflammation control in Drosophila - a world first."