Arthritis Today - Winter 2009

Do you come out your GP surgery feeling that you haven’t really got anywhere? Dr Christian Mallen offers expert advice on people with knee osteoarthritis can get the most from their GP consultation. 

If you are reading this and you are suffering with knee pain, don’t be alarmed - you are not alone. Around one in four people over the age of 50 experience knee pain yet only half of these people will seek medical advice about their pain. The commonest diagnosis given to older people with knee pain is osteoarthritis. For many people getting a diagnosis of osteoarthritis from their doctor is worrying, yet there is much that can be done for people suffering from this very common condition.

When you visit your doctor for the first time they will take a history from you (talk to you about what has been going on) and usually examine your knees.

As well as asking about your joints, your doctor will also ask questions about how you are feeling in general and how the knee pain impacts on your day to day ability to do things. Don’t be surprised (or offended) if they also ask you about your mood, as depression and anxiety are both very common in people with knee pain (about one in three older people with pain in their joints or muscles also have a low mood). Treating your low mood can also be beneficial to your knee pain.  If you feel low, or need extra help doing your usual activities, do let your doctor know. They can’t help you with what they don’t know about! They will also want to know about other conditions you may suffer with, such as diabetes and high blood pressure, as this will affect which treatments you will be offered. If they don’t ask directly about this, don’t worry, as they may have this information about you already.

It is often possible to make the diagnosis of osteoarthritis without looking at the knee, although it is good practice to perform an examination. This doesn’t hurt and only takes a few minutes to do. Typically the doctor will start by looking at your knee. In particular they look for any swelling, deformity, or any redness, and at the muscles surrounding the joint. They will then go on to do more specific tests which involve moving the joint around and testing how stable your knee is.

The diagnosis of osteoarthritis can usually be made on the history you tell your doctor and on the results of the physical examination. X-rays are seldom needed and usually do not change the management of your problem. Likewise, for osteoarthritis, which tends to be related to ‘wear and tear’, blood tests do not provide any additional useful information.

Most people with osteoarthritis can be successfully managed by their GP, with the help of the primary care team. Other professionals that can provide useful information and support include the practice nurse, local pharmacist and physiotherapist. Make use of this team, as everyone contributes different skills and have different areas of expertise. Referral to a specialist, such as a rheumatologist or orthopaedic surgeon, is not necessary for the majority of people with knee pain, although some people with more severe and longer lasting problems may benefit from a visit to the hospital.

There is a range of core treatments that are recommended for everyone, the most important of which is exercise. This troubles many people, as it may not make sense to exercise when it causes pain. However, joints like to be used and long periods of rest may cause worsening of your pain and disability. Your GP or physiotherapist can offer advice on doing the right sorts of exercise, but try to keep as active as you can. Arthritis Research UK provides useful information on doing the right kind of exercises for your knee. Weight loss is also important as it takes pressure off the knee joint. Most people find losing weight difficult, particularly if they find exercising difficult. Ask your doctor or practice nurse about this. Many surgeries provide weight loss clinics and can refer you to a range of exercise programmes, including water-based activities that make exercising easier and more enjoyable.

GPs also frequently prescribe medication that you can also buy from the pharmacist or supermarket. These include simple painkillers such as paracetamol and topical applications that you rub into your knee (such as ibuprofen gel). If your doctor recommends using these, give them a try, even if you have used them before. They are very effective for many people with knee pain but may need to be taken regularly to notice a real benefit. If these treatments don’t help, go back to your doctor, as there are still lots of alternatives you can try, such as a steroid injection and other types of pain relief. Many people now buy preparations such as cod liver oil, glucosamine and chondroitin sulphate from their pharmacist or herbal shop. Whilst the National Institute of Health and Clinical Excellence (NICE - the organisation that advises doctors on what treatments to use) does not specifically recommend using these treatments, some people do notice a benefit from them and they are unlikely to cause you any harm.

Successfully managing knee pain requires an ongoing partnership between you and your doctor. There are some things that a GP can do for you, but many successful treatments, such as exercise and weight loss, can only be done by you. Below I have listed a few tips to help you get the most out of your visit to the GP.

Many new drugs to counter the worst effects of osteoporosis are coming onto the market, yet for many older women it’s a struggle to get either a diagnosis or even basic treatment. 

It’s an irony not lost on campaigning bodies and concerned clinicians that at a time when exciting new drugs for osteoporosis are more common than the proverbial No 53 bus, many women at serious risk of fracture remain undiagnosed and untreated.

In an ideal world, post-menopausal women considered to be likely to develop osteoporosis (risk factors include heavy smoking and drinking, family history, steroid use, and poor diet) would have a bone density scan known as DXA.

If the scan showed thinning bones they would be put on a bisphosphonate drug such as alendronate or risedronate, and offered calcium and Vitamin D to help to prevent or reduce further bone loss. Other, more expensive drugs would be available for those women who needed them.

However, numerous factors conspire to prevent this from happening. One major factor is a very poor level of awareness verging on downright ignorance about the significance of the condition – both among people with osteoporosis themselves and those who treat them.

This was recently thrown into sharp focus by the appearance of some worrying findings from a global study which revealed that 55 per cent of 60,000 women with osteoporosis did not believe they were at a greater risk of fracture than their healthy peers. Related research showed that less than half of osteoporosis patients were taking calcium and Vitamin D alongside their drug treatment – which is essential in order to get the maximum heath benefit.

Poor awareness

These findings prompted Professor Cyrus Cooper, one of the investigators and a leading osteoporosis expert from the University of Southampton to comment that it was to be hoped that findings would highlight the deep impact that a fracture could have on a patient’s life. “It should create an awareness among health professionals that preventative therapy should be commenced urgently in patients with osteoporotic fractures,” he added.

Professor David Reid, a rheumatologist at Aberdeen University and another leading expert on osteoporosis, agrees that both patients and their doctors need to take osteoporosis much more seriously. “In Aberdeen we offer a DXA scan to anyone over the age of 50 who has had a fracture but a large proportion of people simply don’t turn up,” he says. “And whether or nor someone gets treated for osteoporosis depends very much on the will and the willingness of the GP. There’s very little financial incentive for them to do so.”

Rheumatologist at Salford Royal Hospital Dr Terry O’Neill says the system doesn’t abet swift diagnosis. He adds: “Many GPs lack awareness of osteoporosis, and a lot more needs to be done in terms of identifying the condition, and raising awareness of why it is so important.”

When a patient has a fracture they typically go to Accident and Emergency, may be referred to an orthopaedic surgeon, and then on to the fracture clinic. Continues Dr O’Neill: “Their details are processed but no-one realises that these patients then need to be “red-flagged” for their GP – in other words the GP doesn’t get a letter about their fracture so doesn’t put them on a bisphosphonate drug. Those hospitals that have a fracture liaison service can offer better more joined-up provision, but only 20- to 30 per cent of hospitals have this kind of service and large areas of the country don’t have it.”

Most vertebral fractures go undetected

The situation is equally gloomy for people whose osteoporosis causes a vertebral (spinal) fracture. According to Arthritis Research UK clinician scientist fellow at the University of Bristol, Dr Emma Clarke, up to 90 per cent of all vertebral fractures go undiagnosed. Because back pain is common, most GPs will not refer a patient with a possible fracture of the vertebrae for an x-ray or a scan and therefore the patient remains undiagnosed and without the treatment they need.

Another reason why osteoporosis is not always properly treated is the immensely complicated guidelines that cover both tried and tested and brand new drugs. Sensible, national guidelines that all medics understand and adhere would clearly be a big step forward but are currently lacking. Something that that has angered and frustrated campaigners in equal measure has been the failure over a six-year period of the government’s health watchdog body the National Centre for Health and Clinical Excellence (NICE) to produce what they regard as workable, ethical guidelines on the prescription of drugs for the primary prevention of osteoporosis. During this time, they point out, 420,000 people have suffered hip fractures, and 80,000 of whom will have died as a consequence.

According to the new NICE guidelines that were finally published in October 2008, patients at risk of fracture or who have had a fracture, may be prescribed alendronate, which is now off patent and in Professor Reid’s words is now: “cheap as chips, if not cheaper.” It costs between £50 and £108 a year, depending, depending if patients have a daily or weekly dose.

However, about a quarter of patients are unable to tolerate alendronate, which can result in unpleasant gastro-intestinal side effects, or it simply doesn’t work for them. But although the guidelines allow patients to switch to another bisphosphonate, such as risedronate or etidronate (both slightly more expensive) it is on the basis of a list of complex criteria involving a patient’s age, bone density, risk factors and fragile bone indicators that the average GP or patient would find completely baffling and largely incomprehensible.

“Unworkable” NICE guidance

This has enraged the National Osteoporosis Society, which led an unsuccessful appeal against the NICE guidance on the basis that the guidelines effectively mean that patients’ bone density has to worsen before they can access a second bisphosphonate.

Health sector relations officer with the NOS Anne Thurston says: “We’re very unsatisfied with the guidance which states that you have to get worse before you get better – it flies in the face of medical practice and is unworkable. We are talking about everyday GPs in their surgeries, not experts in osteoporosis, trying to make the best judgments they can. We know awareness of osteoporosis is not what it should be, and having unclear guidelines does not help.”

David Reid goes further: “The current clinical guidelines are not only clinically unworkable but I think they encourage doctors to go against the Hippocratic Oath to do the best for their patients. It’s bad practice and complete and utter nonsense – and it’s purely about costs.”

In anger and frustration at the NICE guidelines, Professor Reid and other experts within the National Osteoporosis Guidelines Group have drawn up their up own guidelines, aimed at improving the assessment of fracture risk ad to identify the most appropriate treatment. They are using an online fracture risk assessment called FRAX developed by the World Health Organisation that can be used by interested GPs which has guidelines on the treatment of men and pre-menopausal women, and includes some the newer treatments for osteoporosis. But again, it depends on the willingness of GPS to use it.

Meanwhile the NOS will continue to lobby for a new NICE appraisal of new and existing drugs in 2010.

So is there any light on the horizon for the thousands of people with osteoporosis at real risk of fracture? One small chink appears to be the decision to include osteoporosis in the GP contact as a new Directed Enhanced Service (DES) This means that GPs will be paid extra to diagnose and treat patients with osteoporosis. However, the relatively small amount of money allocated to the DES (£5m this year and £5m in 2010; just £588 per year per GP practice) will limit its effectiveness.

Osteoporosis facts

• There are around 180 osteoporosis-related fractures in England and Wales every year: 70,000 hip fractures, 41,000 wrist fractures and 25,000 vertebral fractures.

• The combined cost of hospital and social care for patients with a hip fracture is more than £1.73bm.

• Generic alendronate costs between £53 (for a once weekly dose) and £100 a year (a once daily dose). Etidronate costs £85 a year, and risedronate (Actonel) between £250 and £265 a year.

• New osteoporosis drugs in the pipeline: denusomab, a promising biologic agent which appears to be at least as effective as another recent addition to the market, zoledronic acid (brand names Aclasta and Zometa). Slightly further on the horizon is odanacitab, currently undergoing Phase II trials.

How research is helping

The situation may improve in the medium to long-term if a major clinical trial funded largely by the Medical Research Council, with additional support from Arthritis Research UK, shows that mass screening of women over the age of 70 – through a combination of self-reported risk factors and a bone scan can help to reduce the numbers who suffer fractures. Importantly, it will also assess if screening is cost effective. The SCOOP trial started in January 2008 and will run for seven years.

An earlier Arthritis Research UK-funded pilot study indicated that a systematic, community-based approach to screening older women for the disease could be effective.

Several other Arthritis Research UK-funded research projects may also lead to more efficient means of detecting the condition.

A team led by Professor Tim Cootes at the University of Manchester’s Imaging Science and Biomedial Engineering Research Division is aiming to devise a quicker and more accurate means of identifying vertebral fracture and diagnosing osteoporosis than the current DXA screening. The new diagnostic tool is a computer programme which will be able to detect each vertebra in each x-ray and DXA image, and indicate whether it is fractured a how badly.

Dr Clarke in Bristol is using her three year Arthritis Research UK fellowship to recruit up to 4,000 women between the ages of 65 and 80 to take part in a screening programme to detect vertebral fractures by having a simple x-ray. She hopes that if it is proven to be clinically and cost effective, it could lead to a big change in the way older women are treated nationally by GPs.

With his three-year clinician scientist fellowship from Arthritis Research UK, Dr Ken Poole at Addenbrooke’s Hospital in Cambridge hopes to develop new methods of assessing and preventing thinning of bones in the neck of the femur, using new high resolution scanning techniques called CT scans.

Dr Poole is all too aware of the devastating consequences that a hip fracture can cause in older women, and which so easily could be avoided. He adds: “Hip fractures in older adults annually account for more than 85,000 hospital admissions, and up to a third of sufferers die within a year, with survivors facing pain, reduced mobility and lack of independence.”

Ultrasound imaging has become an increasingly visible feature in UK rheumatology departments in recent years. In the 1990’s, improvements in technology allowed clearer images and better differentiation between different joint-related tissues. In addition, the cost of machines fell, making it a more affordable and accessible technology than MRI. One significant advantage of ultrasound is that it can be performed immediately in clinic providing instant information to the clinician and avoiding the need for a patient to return for a further appointment.

What is ultrasound and how does it work?

The technique uses supersonic waves which are emitted from a hand-held probe and penetrate the skin.  These then bounce off structures in the body and are re-captured by the probe and converted into an image. To what extent they bounce back depends on the type of tissue – each tissue, such as bone, synovium (joint lining tissue), joint fluid, tendon, ligament, and fat, has a different density. Some structures transmit sound (for example fluid appears black) whilst other reflect it (bone appears white). There are two basic types of imaging: Grey scale and Doppler. Grey scale is what is meant by the black and white image and gives us information on the structure and amount of tissue.  In contrast, Doppler gives us information about blood flow and may assist in the demonstration of active inflammation. Using both techniques gives us a unique insight into the development of musculoskeletal conditions and allows greater accuracy than just feeling and moving joints with our fingers - the standard method of assessing joints.

Why has ultrasound become popular?

In recent years it has become increasingly recognised that early identification and treatment of disease, in particular joint inflammation, can prevent joint damage and increase patients’ quality of life. In addition, new (but potentially toxic) therapies have driven a desire for more accurate diagnoses. Imaging techniques such as ultrasound may not only help with diagnosis but have the potential to help predict which patients will do badly (hence require stronger treatments), allow more accurate disease monitoring and allow direction of needles into joints.

Who can perform ultrasound?

Ultrasound can potentially be performed by any practitioner as long as they are adequately trained.  Traditionally, the radiologist was the one who fulfilled this role but due to the fact that there is a preference to have the information at the time of clinical assessment, the clinicians themselves have begun to learn.  As a result, it is now possible that such an investigation will be performed by your rheumatologist, sports physician, podiatrist, physiotherapist or clinical nurse specialist. This increase in demand has meant that the development of training has become even more important.

Why isn’t ultrasound provided in all hospitals?

One major reason for ultrasound not being provided in some hospitals is a lack of training facilities in the UK. This reflects the relatively few trainers and a current lack of infrastructure. Providing training is a costly and time consuming business. Another reason is a lack of expertise amongst clinicians as it is still a relatively new technique in the UK. Additionally, there is a general lack of musculoskeletal radiologists in the UK and in particular ones who are trained at looking for signs of inflammation, which is what rheumatologists particularly want. Currently most musculoskeletal ultrasound imaging is performed in teaching hospitals but it is likely that this will change over time.

Ultrasound research

Researchers and medics in Leeds have been actively investigating the role of ultrasound for the management of arthritis since 1997. It was one of the first centres in the UK and Europe to establish a dedicated ultrasound unit within a rheumatology department. There are two main strands to our work in Leeds - clinical research and training and education.

I joined the Academic Section of Musculoskeletal Disease in Leeds as a research fellow in 1997 and now lead the ultrasound research within the department, developing the technique with Professor Paul Emery and the musculoskeletal radiologists. At that time, there were no guidelines to follow.  As ultrasound was such a new tool much work had to be done in order to validate it, (ie provide what we were seeing represented true picture of what was happening in the joint.) This meant comparing it with other imaging methods (like MRI) and tissue samples and testing its reliability. As a result, the group has made important contributions to the field by demonstrating the accuracy of the tool for detecting synovitis, tendon disease and bone damage in a number of joints such as the hand, knees and feet. This work was fundamental to the development of the first international consensus-derived pathological definitions of US detected pathology which the Leeds group has led. Further work with European and American researchers is currently underway to develop guidelines for acquiring and reading images.

How ultrasound is helping patients

One of the great strengths of the Leeds group has been the application of ultrasound in clinical practice. Much work has focussed on the better characterisation of early inflammatory disease. We have uniquely demonstrated that ultrasound can be used to detect inflammation not found on clinical examination (so called subclinical disease) such that it might change a specific diagnosis, for example, demonstrating that diagnoses may change in up to 50 per cent of patients after using ultrasound. Recently, we have also shown that ultrasound may be helpful in predicting which patients will go on to have a more serious disease. Our group has recently investigated the role of imaging of arthritis patients’ joints in remission. They have shown that ultrasound and MRI continue to show signs of inflammation in many patients even when they feel well. This implies that treatments should not be immediately stopped even if the examination or blood tests are normal.

Further clinical research

Much of our original work has concentrated on rheumatoid arthritis but work has also been done in collaboration with Professor Philip Conaghan and Dr Helen Keen in osteoarthritis and Professor Dennis McGonagle and Dr Ai Lynn Tan in spondyloarthropathies (such as psoriatic arthritis and ankylosing spondylitis).  The team has also successfully collaborated with the academic podiatry department through Arthritis Research UK senior lecturer Dr Tony Redmond and Arthritis Research UK PhD fellow Heidi Siddle. As a result we have set up an inter-disciplinary group to allow better clarification of disease processes in the foot and potentially more tailored management plans. 

Another important area that the group has recognised as important is the development of a training programme for aspiring rheumatology sonographers. My colleague Dr Andrew Brown, through an Arthritis Research UK educational fellowship, developed the first ever consensus-derived curriculum which will become a standard to work by.  These have been influential in the formation of UK and European training guidelines.  Further work is currently planned to develop future teaching strategies.

Arthritis Research UK has recently given an equipment grant for a new ‘state of the art’ ultrasound machine. This will enable our group to continue in their scientific work across a number of projects and provide further opportunities for training. We hope that ultrasound will further improve our understanding of early disease processes and the potential methods by which the disease processes will be managed.  High quality research using state of the art ultrasound equipment will encourage the refinement and provision of improved clinical care for patients with a variety of musculoskeletal disorders.

• Dr Richard Wakefield is a senior lecturer in rheumatology in the Academic Section of Musculoskeletal Disease at Leeds University

Alice Peterson’s moving story of how she was diagnosed and finally came to terms with rheumatoid arthritis as a talented teenage tennis player, was featured in Arthritis Today nine years ago. To mark the re-publication of her book, Alice, now a full-time novelist, whose condition is controlled by anti-TNF therapy, explains how she came to write it. 

How many of you have written things down to make sense of a problem? If you are worrying about something, do you find writing helps you to feel better? Aren’t lists a great way to remind you of the things you need to do? And how satisfying it is when we can tick the things off! Writing is therapeutic in so many ways.

For me, writing has played an important part in my life. From the age of 12 I started to keep a diary. It was at a time when I had just entered my first county tennis tournament. My diaries were full of excited scribbles about how much I wanted to be the next Chris Evert and win Wimbledon.

I was diagnosed with rheumatoid arthritis (RA) when I was 18 and on the verge of signing a tennis scholarship to America. I was one of the top ten national junior players in the UK, and overnight my dreams were torn apart. From that day forward, I stopped writing a diary. My world had shattered; I felt I had nothing left to say.

Ironically, this was probably the time when I needed to write more than ever.

However, six years after the diagnosis, I started to write again. My very first book, A Will to Win, was published nearly ten years ago, and it tells the story of my tennis-mad childhood and my battle to beat RA. The reason I started to write my story began back in the summer of 1997, when I was sitting in the garden with old family friends.

 ‘How are you feeling?’ Robert asked me, looking down at my white-plastered boots. I had just had an operation on the metatarsal joints in both feet.

Instead of saying, ‘Fine, thank you’, I started to tell Robert how much I still missed my tennis and that I dreaded the summer because Wimbledon was on the television. I told him how difficult it was to be at home and described the agony of the recent operation. I told him I felt lost and scared of the future.

Robert listened patiently. ‘Have you ever thought about putting this down on paper?’ he asked, finally.

‘No,’ I replied. ‘Why?’

‘Well, it might help you to make some sort of sense of what has happened. And …’ He paused and examined my face carefully. ‘You do have a story to tell.’

After Robert had left I wiped off the dust that had settled between the keys of my old word processor and I started to write about my tennis. Soon I was writing chapter after chapter. Something came alive within me.

Putting down in words my anger, pain and grief gave me a huge sense of freedom and relief. To begin with it all came pouring out in a great jumble of thoughts, but the more I wrote, the more I was able to look at events objectively. It was as if I were standing outside the picture, looking in.

When I was diagnosed with RA it seemed like the worst imaginable thing. I wished I’d never played tennis because then I would not have felt such a sense of loss. However, remembering the competitions made me think not only of the fun I’d had on court, but also of my dogged determination. It made me realise that my tennis experiences have been invaluable because I have been able to channel that determination I had on court into beating the RA. To this day I will never give up because my training has instilled in me the spirit to fight. I have come to see it as my saviour.

With renewed inspiration I dug out all my old tennis tournament drawers, the photographs, my old diaries that I had promised never to read again, but yet couldn’t quite throw away. I loved the whole creative process. However, there were many times when I found writing my story difficult too. The sadness of never lifting a racquet again and the agony I had gone through with my parents was still raw. But, at last I was confronting what had happened to me and to my family.

When I came to the end of my story, I had a choice to make. Had I written it as a cathartic exercise or did I want to try and get it published?

I wanted to see it in print, because the more I wrote, the more I realised how life-changing arthritis can be. Having been so ashamed of my RA in the past and doing my utmost to cover it up, I now wanted to raise awareness of this misunderstood condition.

Family and friends celebrated the launch of A Will to Win in 2001. My parents organised an event, together with Arthritis Research UK. Two hundred and fifty people attended and it was a chance for me to say thank you to everyone, especially to my family, for all their support.

Since writing A Will to Win, I have had two novels published. I think it’s inevitable that I am now drawn to writing about characters with some sort of disability. My character, Bells, who is the disabled sister in my first novel, Look the world in the eye,’ is loveable, frustrating, funny, rude and charming. She is a real character and I enjoy writing about these personalities in fiction.

After A Will to Win was published, I received many letters and emails from fellow sufferers telling me how much they could relate to my story, that they too had experienced pain, a deep sense of loss and a fear of the future. They described how reading my book had given them hope at the darkest of times because finally I’d found a drug that worked. But most importantly, the strongest message that came through was that the book had made readers feel less alone. To realise that there are others in similar situations, that we are all fighting RA together, is a huge reassurance. I too, drew great comfort in reading their responses. The messages made me realise how I was far from alone and that I was by no means the only young person to be diagnosed with RA. I received emails from teenagers, many of whom had had promising sporting careers or a hobby that they were passionate about and which they’d had to abandon. One girl told me that she had read my book twice to see how she could manage her condition when she went to university.

She studied her degree at Leeds and kept in touch with me throughout this time, telling me that the book had given her the courage to be honest about her arthritis, not to hide it as I had done.

So this is why I am so excited to have the opportunity to see A Will to Win republished, under the new title, Another Alice. It is a lovely new edition with updated chapters and important additions and I hope it will continue to help those who suffer from this condition, as well as their families. 

• Another Alice’, published by ICON books, in paperback £7.99, January 2009. To find out more about Alice, visit her website: http://www.alicepeterson.co.uk/

Rheumatoid arthritis and cancer: a shared approach

It may be surprising to learn that, even though the two diseases are quite different, there are striking similarities between the underlying processes that contribute to the development of rheumatoid arthritis (RA) and cancer. Both involve the migration of cells to an area of the body remote from where they are formed, and the development of abnormal cell metabolism that results in the destruction of healthy tissue.

Finding out how to stop this migration and abnormal cell function is the focus of one research project underway at the Kennedy. Dr Yoshifumi (Yoshi) Itoh, principal investigator of this Arthritis Research UK-funded research initiative, previously worked in cancer research programmes at the University of Tokyo where he extensively studied many common factors between cancer and arthritis development. He is optimistic that applying knowledge gleaned from cancer studies can fast-forward RA research.

Most people think of RA as a disease that locates in certain areas of the body. So how do migrating cells fit into the RA story?

Dr Itoh explains: “In the arthritic joint, the synovial lining becomes inflamed, eventually forming thickened and overgrown tissue known as synovial pannus tissue. This synovial tissue is essentially an invasive cellular tissue that extends over the cartilage. It is very destructive because, like cancer cells, the synovial cells produce enzymes that destroy the tissue they are penetrating, in this case cartilage, and eventually bone. We think that if we can stop this enzyme activity, we may be able to halt joint invasion and destruction.”

The invasive nature of the synovial tissue is really striking. The front line of the invading synovium is known as the ‘invasion front’ and the cells localised on this line are responsible for breaking down the key structural component of the cartilage matrix, which is a protein substance called collagen. Cartilage and bone are actually difficult structures to invade, but the invasive synovial cells secrete enzymes that literally dissolve their way through them.

“We have discovered that one of the enzymes produced by the invasive synovial cells, called MMP-14, is the key enzyme responsible for collagen degradation during invasion,” explains Dr Itoh. “When we analyse localisation of this enzyme in tissue sections, we can see that it is always highly expressed at the invasion front.”

He has tested out the destructive action of invasive synovial cells freshly isolated from synovial tissue by incubating them on thin collagen layers. Within just a few days of incubation, the synovial cells have melted down the collagen layers.  He also embedded fresh synovial tissues within a collagen gel, and in three days, numerous synovial cells started to invade into collagen gel. He explains: “The invasive activity of synovial cells is MMP-14-dependent, and specific inhibition of MMP-14 completely halted the invasion process.”

The enzyme MMP-14 is a good target

MMP-14 is also produced by invasive cancer cells, and a US cancer research programme has recently developed an MMP-14 inhibitor. Collaborative work between the Kennedy and the US team will support the development of an inhibitory antibody for potential use in RA.

“We now know that this enzyme is a good target for therapy development,” says Dr Itoh. “If the drug development programme continues to be successful, we may have a therapy that could halt synovial invasion. We need to inhibit just this specific function so that we don‘t interfere with any others that may be beneficial in the body. Further research will determine what other functions this enzyme is involved in and whether or not we need to preserve them.”

He adds: “Ideally, it would be particularly beneficial to use an inhibitory drug like this early on in disease development. But that would depend upon obtaining a good diagnostic system, and of course, upon costs.”

An immunological approach - exploiting natural inhibition

One of Yoshi’s close colleagues, senior lecturer Dr Richard Williams, is investigating two major research areas that are exploring how the body’s immune system might be exploited to control disease mechanisms.

He has established that a special receptor molecule on the surface of some cells, particularly those in the immune system, may function to dampen down inflammatory functions - in other words, act as a brake on inflammation. This may be a natural way for the body to keep inflammatory reactions in check. In experimental models, administration of the receptor molecule, called CD-200, halts the progress of arthritis and has been reported to block TNF (tumour necrosis factor) production in the joint with an efficacy similar to that of anti-TNF therapy. Since anti-TNF therapy is considered the new benchmark in inflammation control, this is an extremely encouraging finding.

Therapies to block T-cell activity have been rather disappointing

Dr Williams comments: “There is no evidence that CD-200 is under-produced in arthritis but it would be useful if administering more of it would increase its inhibitory effects upon inflammation. It is an existing natural inhibitor and our aim is to see if boosting levels will improve its anti-inflammatory effect. Its function in humans has not yet been studied but it is hypothesised that it will have a similar role. Very little is known about CD-200 and our future research will concentrate on investigating the detail of this molecule and its functions.”

Dr Williams’ second research area focuses on T-cell activity. T-cells are a type of white blood cell (or lymphocyte) responsible for immune defence. There are different sorts of T-cell, all with different functions, and it is generally accepted that T-cell function, or rather malfunction, is a major cause of the excessive inflammation in RA. 

However, Dr Williams points out: “Unfortunately, therapies designed to block T-cell activity have been rather disappointing in clinical trials. We now know that there are two different kinds of T-cell influenced by such therapies: ‘bad’ T-cells, or effector cells, that increase inflammatory effects, and ‘good’ T-cells, or regulatory cells that increase anti-TNF cell activity. The overall effect in terms of inflammatory reactions will be affected by the balance of their actions. Earlier therapies inhibited both types of cell and so probably didn’t alter the overall effect significantly. What we need is a completely different approach that will activate the regulatory cells alone.”

Studies have shown that a cell receptor called CD3 may be the key to achieving this. Using an inhibitor to this receptor appears to increase ‘good’ T-cell activity and blocks ‘bad’ T-cell activity. If the T-cell ratio can be normalised, the ‘good’ regulatory T-cells might be able to emerge and take a prominent role. Already tried and tested in patients, anti-CD3 therapy has been used to counter inflammation in organ transplant programmes, and has shown encouraging results in treating Type 1 diabetes patients.

“Now it’s important to establish whether this approach will be effective in RA,” says Dr Williams. “Initial studies in animal models show that a single injection of very low-dose drug produced long-term suppression of arthritis. We need to analyse exactly how the drug is working and then test it in clinical trials, starting off with low doses and building up slowly.”

“As with CD-200, an attractive aspect of this therapy,” he adds, “is that it stimulates a natural inhibitory mechanism to re-establish the immune system balance. Diabetes studies have shown that just one treatment can achieve long-term effects. If this is successful in arthritis, it would offer an advantage over existing therapies, such as methotrexate and anti-TNF, where treatment has to be frequent and long-term.”

Dr Catherine Swales

About Catherine

I have two small boys (3½yrs and 18 months) who keep me extremely busy with their hobbies - football, swings and slides, jigsaws and general mischief!

What does your work involve?

I’m correlating what happens to patients with arthritis with what happens at a cellular and protein level in their blood, any fluid that builds up in their joints and in their joint linings. I have a special interest in the proteins that “switch on” osteoclasts - cells designed to break down bone which go into over-drive in a lot of the inflammatory types of arthritis.

How long has Arthritis Research UK been funding you?

My fellowship in Oxford started in September 2008 and will run for three years, so it’s very early days, but bringing a clinical, patient-centred dimension to the laboratory is already proving very fruitful.

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

Although TNF (tumour necrosis factor) is very concentrated in the fluid that builds up in inflamed joints, other inflammatory proteins build up to even higher levels. This is quite a surprising finding, since it’s generally felt that TNF is the “major player” in joint inflammation, hence the success of the anti-TNF (biologic) therapy. This result obviously opens up the possibility of blocking these other proteins alongside TNF to damp down joint disease even more successfully than is possible currently.

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

The overall aim is to clearly determine what role various inflammatory proteins play in inflammatory arthritis – both in terms of disease severity (such as fluid building up in joints or bone erosion and destruction) and in patients’ response to treatment. In addition I’m hoping to understand exactly what activates osteoclasts to erode bone so aggressively in patients with arthritis. The ultimate aim is to find new ways to stop arthritis – to identify proteins playing a major role in arthritis and to block their action. Although anti-TNF therapy has transformed rheumatoid arthritis treatment, up to one third of patients don’t respond to it; we’re looking to see if there’s a different protein we should be blocking in these patients.

What do you do in a typical day?

There’s no such thing as a typical day, which is very energising! My time is balanced between the clinical/patient time and laboratory work. I meet patients at various stages of their disease, including those having joint replacements, and perform a thorough assessment of disease activity and the disability it causes. If the patients are having blood tests or a joint aspirated I take a sample of the blood or fluid to the lab to study, and if they’re having a joint replaced I take a small amount of the joint lining that’s been removed. The laboratory side involves looking at expression of inflammatory proteins and cells in blood, joint fluid and lining. In addition I look at how these patient’s cells mature into osteoclasts and erode bone. The great thing is that although I am doing research it’s so heavily patient-focussed I don’t feel that I’ve abandoned the clinical world altogether.

What is your greatest research achievement?

Watch this space!

Why did you choose to do this work?

I wanted to do something exciting and relevant to the majority of patients that we meet in clinic or on the ward…and to try to explain why even our best treatment doesn’t work for everyone.

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

All the time - it’s the reason I’m doing it all and the project wouldn’t be possible without the kindness and support of our arthritis patients. It also makes the lab samples seem very precious: even though every sample is totally anonymous, I know that it came from one our patients who, even in the midst of clinic or the ward or even the operating theatre, still had the time, energy and generosity to help others by helping research. 

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

I never seriously considered doing anything else but if I could choose anything in the world I’d love to be on the stage.

Dr Catherine Swales is an Arthritis Research UK clinical research fellow at the Nuffield Orthopaedic Centre in Oxford.

Professor Anisur Rahman

About Anisur

I have two children called Lana and Asif and my wife is a GP in Tower Hamlets. When I am not at work I especially enjoy spending time with my children. I also enjoy playing the piano (badly), watching football and have been known to write and recite comic verse, some of which has been published in Rheumatology journals.

What does your work involve?

I have a very varied job. I am a clinician running three clinics per week covering autoimmune rheumatic diseases, chronic pain and general rheumatology. I spend a lot of time teaching medical students and running the rheumatology teaching course in my hospital. I have a number of research interests including the molecular biology of antibodies that cause diseases like lupus and the associated blood-clotting condition antiphospholipid syndrome, heart disease in patients with lupus and better ways to look after people with chronic pain. I am also one of the two editors of the Arthritis Research UK patient leaflets about different types of arthritis.

How long has Arthritis Research UK been funding you?

My first Arthritis Research UK grant was in 1997.

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

The antiphospholipid syndrome was originally described as a disease in which antibodies stuck to phospholipid molecules on the surface of cells and that led to clots, strokes or miscarriages. Over the years it became clear that the antibodies were actually sticking to proteins linked to the phospholipids and that the way in which they cause clots is probably different to the way in which they cause miscarriages. During the last year my group compared antiphospholipid antibodies from patients who had suffered clots but no miscarriages with antibodies derived from patients who had miscarriages but no clots. We found that these two types of antibody have measurably different effects on cells that we grow in culture in our laboratory. We also found that a fragment of one of the proteins that are recognised by antiphospholipid antibodies can be made artificially in bacteria and shows great promise in being able to block the ability of these antibodies to stop clot formation. Both these lines of research may help us to understand how antiphospholipid antibodies cause disease.

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

I hope that my Arthritis Research UK funding will help to enable us to manage the care of patients with rheumatic diseases better. This can be achieved in several different ways. In the antiphospholipid syndrome we are working towards developing new drugs which will hopefully prevent patients getting clots without causing the side-effects that warfarin causes. In the study of heart disease in lupus we are trying to work out which blood tests and scans will accurately identify patients with those heart problems at an early stage so that we can do something to stop the problems worsening. In looking at chronic pain, which is very common and often does not respond well to drugs, we are looking at ways in which people can be helped to live with their pain in such a way that they have a better quality of life.

What do you do in a typical day?

On a research day, I will meet my research team in the laboratory. We try to make our meetings lively, supportive and interactive and find that everyone can contribute ideas. I spend the rest of the day reading and writing papers and grant applications. On clinic days I see patients and also teach medical students. Teaching is one of the most enjoyable activities of my week.

What is your greatest research achievement?

Continuing to contribute to a range of very different fields of research whilst also maintaining my commitment to teaching.

Why did you choose to do this work?

I owe it all to my PhD supervisors David Isenberg and David Latchman who introduced me to academic research and to the field of autoimmune rheumatic diseases in particular. By the time I finished my PhD I was hooked.

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

Yes, and that’s why I enjoy my work editing the Arthritis Research UK patient leaflets – this is the most direct way in which what I do impacts on patients.

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

In my dreams, centre forward for Bristol Rovers! More realistically, I would have been a teacher.

Anisur Rahman is Professor of Rheumatology at University College London

“Feet are the window to your health,” says Jim Woodburn, and if anyone is qualified to make this pronouncement, it’s the Professor of Rehabilitation at Glasgow Caledonian University (GCU).

 “If you have problems with your feet you probably have other health problems too,” he adds. “And a very high proportion of people with rheumatoid arthritis have painful feet problems; probably about 90 per cent of patients. Feet are a critical site for involvement in early disease.”

Jim Woodburn has spent a large part of his distinguished professional career as an academic podiatrist trying to get the medical and health professions to treat feet as seriously as they deserve to be.

Many people with rheumatoid arthritis (RA) describe how it feels like walking on broken glass, and looking at the pressure scans of their feet in Professor Woodburn’s office makes it clear why this is so. In RA the foot becomes deformed, and the toes rise off the floor so that the patient walks on the balls of their feet. Bursae, small fluid-filled sacs or calluses then form. Because there is no fatty padding beneath the foot to act as a cushion, the pressure on the ball of the foot increases, causing extreme pain and altering the walking pattern.

People with these sorts of foot deformities tend to compensate by walking more slowly and shuffling, which then causes problems elsewhere, such as weakness in the calf muscles. “A minor foot problem can cause major problems, and people often tell us that it really limits their activities,” says Jim Woodburn.

Despite the high prevalence of painful foot symptoms in RA, treatment around the UK remains fairly woeful. “It might be the patient’s chief concern but most rheumatologists often don’t routinely examine the feet as they would the hands, for example,” explains Dr Debbie Turner, the recently appointed arc senior lecturer at GCU. “Even if you are treated at a good rheumatology department, the feet are not included in many of the standard outcome measures of disease activity (the score used to assess how active RA is) unlike the hand, shoulder and knee, although the feet are commonly involved and the rate of joint destruction is very high.”

Podiatry services are very patchy

Podiatry services for patients with arthritis and musculoskeletal conditions are very patchy throughout the UK, from centres of excellence providing a first-rate podiatry service for patients, to absolutely no foot care provision whatsoever.

Amid this background, Jim Woodburn was appointed at GCU three years ago, after being funded by Arthritis Research UK and the Medical Research Council over a long period while at the University of Leeds.

He has since been gathering together a pool of expertise, including Dr Turner, whose Arthritis Research UK lectureship will run for five years, lecturer Ruth Semple, who has an Arthritis Research UK allied health professionals training fellowship, and PhD students Gordon Hendry, Elaine Hyslop and Lisa Newcombe. In total Arthritis Research UK is pumping more than £650,000 into the Foot and Ankle Research Group in a bid to build up academic podiatry.

There are no standard treatments for foot problems in RA

The team are also building up a Glasgow-wide approach to podiatry by establishing close links with rheumatologists involved in related musculoskeletal research: Arthritis Research UK Professor (and former chairman of trustees) Roger Sturrock and Professor Iain McInnes at Glasgow Royal Infirmary and Arthritis Research UK Clinical Senior Lecturer in paediatric rheumatology Dr Janet Gardner Medwin at the Royal Hospital for Sick Children at Yorkhill. Jim and Debbie are also supervising NHS physiotherapist Mhairi Brandon’s academic research as she works towards a consultant grade.

Jim Woodburn is aware that there are no standard treatments for foot problems in RA and only a very small established evidence base, although custom-made orthoses (insoles), steroid injections and ultimately surgery appear to work best.

High resolution pressure images of the ball of the foot showing (left) a normal foot and (right) the foot of an RA patient showing high spikes of pressure overlying damaged and deformed joints.

He and his team’s research programme is therefore a combination of academic research to find out more about the structure and biomechanics of the foot in inflammatory arthritis, and to improve the care and treatment of painful foot problems for patients. To do this the team aim to develop and test new treatments such as customised orthoses and specially designed footwear, and targeting stubborn or persistent inflamed areas, even when patients are doing well on medication.

Debbie Turner is enthusiastic about the use of ultrasound in the diagnosis, prognosis and treatment of inflammatory arthritis in the feet and is currently developing important skills in this still fairly new field. “With ultrasound you can look much more accurately to quantify disease activity and to find out about the relationship between inflammation and mechanical abnormality,” says Dr Turner. In another example of its versatility, using ultrasound can improve the accuracy of giving a steroid injection in the back of the foot from 60 per cent to more than 80 per cent leading to better results.

Arthritis Research UK recently awarded the team a new piece of equipment called a high resolution pressure measurement analysis system, which, when used in conjunction with diagnostic ultrasound, can provide a better understanding of the effects of inflammation on the structure and function of the foot.

The team employs 3-D motion tracking which uses special cameras to detect the movement of reflective markers on the patient’s foot and leg and a force-plate to build anatomical and functional models. This enables them to study in detail the complex movement, forces and pressures experienced by joints and muscles which are damaged in inflammatory joint disease.

The use of diagnostic ultrasound and the foot pressure measurement analysis system is popular with patients. “It’s an invaluable tool from an educational point of view, as patients can see what is going on with their joints from looking at the images on the screen. Explaining what’s going on is always a crucial part of patient management,” says Debbie Turner. “If they can see from the ultrasound images that joints have been extensively damaged by their disease and that foot pressures overlying these joints are so extreme that they can’t be relieved effectively by any other means but surgery, then they are often far more willing to consider having foot surgery. So the equipment will help them make critical decisions based on evidence.”

Patients also benefit from attending the specialist monthly clinic at the gait lab at GCU and talking to the podiatry team, as it’s often the first time they have had an opportunity to speak about something that has been troubling them and disabling them for a long period of time. Debbie Turner is only too well aware of the hit and miss nature of podiatry provision in the UK and particularly in Scotland and is working with NHS colleagues to gather evidence and create a business case for more posts, following examples of best practice in NHS areas such as Fife, and Ayrshire and Arran.

A direct, practical effect on patient care

The team are already running two patient-oriented trials which could have a direct, practical effect on patient care. The first is a small scale preliminary trial, run by Ruth Semple, using ultrasound imaging to diagnose inflammation around the tendon at the back of the foot, and comparing the effectiveness of a custom-made insole which acts as a splint to stabilise the foot joints, compared to an ultrasound-guided injection of steroid. Treatment will be provided for three months. “This double-headed approach tackles both the mechanical and inflammatory factors that may be at the root of this problem,” explains Ruth.

Testing the effect of a new footcare package

The second, being run by Jim Woodburn with PhD student Gordon Hendry, involves up to 60 children and teenagers with painful feet as a result of their arthritis, and is being co-run with medics at Yorkhill and Glasgow Royal Infirmary. Of the 250 youngsters being treated at Yorkhill, only 18 have attended any podiatry services.

They are testing the effectiveness of a new foot-care package which ensures that patients receive treatment quickly, and uses various techniques to diagnose foot problems, including, inevitably, ultrasound. Some of the youngsters will also be offered steroid injections, personalised orthoses, exercises and physiotherapy. The team are hopeful that these measures will make their foot problems more treatable and less painful.

 “The joints that are affected are still growing, and inflammation in growing joints can cause quite significant deformity,” explains Gordon Hendry. “Some kids with arthritis have really severe, rigid feet and may require multiple surgery before the age of 20. We’re trying to raise awareness of this problem as well as trying to improve treatment for these youngsters.”

Professor Woodburn is well aware that academic podiatry is still a new medical specialty and may take some time to take its place among more established areas like rheumatology.  He knows there’s so much to be done, and is aware that his team simply can’t do everything that’s needed. Nevertheless he is rightly proud of his young team and what they are achieving.  “We’re one of the most productive groups in the university,” he says, and you get the feeling there’s a lot more to come.