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Targeted treatment is the future

Published on 13 April 2014

Stratified medicine aims to get the right treatment to the right patient at the right time. But could such a targeted approach to treating arthritis ever be a reality? Arthritis Today reports.

As we are all individuals, it makes sense to assume that that we experience arthritis in quite different ways. We are a complex mixture of our genes, environment and lifestyles, and that means that the same diseases will affect different people in different ways. This is often also true of how we will react to the medicines used to treat those conditions, and why one drug works well in one person and not at all in another.

Yet modern medicine has, until recently, treated people with arthritis and musculoskeletal conditions the same, irrespective of their particular characteristics.

This ‘one-size-fits-all’ approach to treatment is now slowly changing, and a new concept, known as stratified medicine, is slowly entering the clinic. Arthritis Research UK is currently concentrating a lot of its research in this area and investigating why people with the same condition respond differently to treatment.

So what exactly is stratified medicine? It means that instead of treating all patients with a particular type of arthritis in a uniform, standardised way, they are treated as part of a disease sub-group. It groups patients based on the way they experience their condition and how this affects their response to treatment.

Essentially, stratified medicine is all about ensuring that the patient gets the right treatment at the most appropriate dose at the right time. Patients are grouped using clinical biomarkers – which could be any test or clinical observation that indicates that one type of treatment will be better than another – for a particular group of patients. In addition to the testing of biological samples such as blood or tissue in the laboratory, this can also include imaging (such as ultrasound or MRI), clinical observations and self-reported patient surveys. This approach is already working well in cancer therapy and is now beginning to be applied to arthritis and musculoskeletal conditions. 

So what does this mean for arthritis patients? Instead of being given drugs that may or may not work for them, doctors will be able to prescribe treatments and therapies that they can be confident will be effective because they are specifically tailored to an individual’s genetic make-up. This would vastly improve their patients’ chances of getting better and reduce their risk of experiencing side-effects. 

Ultimately, the focus of treatment could shift to preventing people from experiencing symptoms and long-term damage, with treatments able to achieve remission instead of just controlling symptoms. If patients were able to receive the appropriate treatment early enough, it could stop arthritis in its tracks – preventing irreparable joint damage and pain in the future.

All of this is good news for patients and also for the NHS, as better targeting of resources to where they are needed may lead to a reduction in the costs of treatment, potentially saving millions of pounds per year. 

So what is Arthritis Research UK doing about developing stratified medicine from an interesting concept to its actually being applied in clinic? Although much of the work is in its early stages, the answer is a great deal, across a number of different conditions and medical specialties.

Stratified medicine in action

Regular readers of Arthritis Today will be familiar with the STarTBack screening tool for low back pain, developed at the Arthritis Research UK Primary Care Centre at Keele University. Some people with low back pain recover with advice and painkillers, whereas others need more intensive physiotherapy and sometimes psychological support. The difficulty has always been how to identify those people who need more intensive treatment. The screening tool, which is used to group people with low back pain according to their risk of long-term pain, does just that, and is an excellent example of stratification in action. 

The STarTBack tool is actually a short questionnaire given to patients with low back pain during their GP appointment and takes only a few minutes to fill in. Depending on their answers to a few basic questions about their pain, patients are then grouped according to whether they are at low, medium or high risk of their pain becoming long-term.

Those people who are at the highest risk are then offered a more intensive treatment approach, thus targeting the most appropriate care to those people who need it the most.

The STartBack tool is already in wide use by GPs across the country. As well as offering better targeted care, it was also found to be cheaper than ‘standard care’ and enabled more people with back pain to stay in work.

This work will be developed further to cover conditions treated in primary care, such as osteoarthritis and chronic musculoskeletal pain, polymyalgia rheumatica and gout, as part of the remit of the primary care centre’s new five-year programme.

New and current research in stratified medicine

Inflammatory arthritis

In inflammatory arthritis, research is aiming to identify whether a patient’s disease will be mild or severe. Such knowledge will enable doctors to target those likely to get severe disease with the strongest drugs, and to prevent people who will only develop a mild form of the condition being given strong medication unnecessarily.

Professor Costantino PitzalisThe MATURA consortium is part of the Medical Research Council’s (MRC) stratified medicine research plan and is co-funded by a £1m grant from Arthritis Research UK. The consortium is based at Queen Mary University, London and involves 12 university groups as well as a number of private companies working together. The teams, led by Professor Costantino Pitzalis, are looking for biological and genetic markers in the blood and joints of rheumatoid arthritis patients, which could be used as clues to predict response to different types of treatment. If this approach is successful, it could potentially save the NHS £13–18m per year. 

Dr Jane FreestonDr Jane Freeston, at the University of Leeds is working to develop a set of imaging biomarkers for predicting the course of early inflammatory arthritis. In these early stages it cannot be predicted whether joint pain will resolve or become severe, developing into rheumatoid arthritis. This sometimes results in patients being over-treated when their symptoms would otherwise resolve on their own, or delays in the diagnosis of patients who do need treatment. Dr Freeston and her team are investigating whether imaging methods, such as MRI,can be used to predict whether patients with early signs of joint inflammation will recover or go on to develop rheumatoid arthritis and how they will respond to treatment. The group’s eventual aim is to develop a test for routine clinical use. 

Dr Ian ScottDr Ian Scott at King’s College London, has found that patients whose blood contains a specific antibody calle anti-citrullinated protein antibody (ACPA) benefit from intensive drug combination therapy, compared with patients without the antibody, who don’t benefit. His findings could lead to future clinical guidelines being updated to take into account the impact of these ACPA antibodies on patients’ responses to treatment.

Dr Madeleine Rooney and Dr David Gibson are part of a team at Queen’s University, Belfast investigating whether the levels of specific proteins in the blood may be used as a tool to predict the severity of juvenile idiopathic arthritis. If this proves successful, it may allow doctors to make the best treatment choices early on, thereby reducing the risk of disability in the long term. 

The lack of biomarkers currently available makes stratification of osteoarthritis patients a real challenge, but one which our researchers are working hard to overcome. Osteoarthritis is a very complex condition in which a number of things occur at the same time in the joint – inflammation, extra bone growth and the wearing away of cartilage. There is now evidence that cartilage damage is driven by different mechanisms in different patients, and that gait and posture can also be important factors.

Professor David FelsonProfessor David Felson at the Universities of Manchester and Salford is aiming to develop new treatment approaches for osteoarthritis. As well as cartilage damage, patients may also suffer from loss or misalignment of the underlying bone and inflammation of the joint lining, resulting in chronic joint and muscle pain. However, the underlying cause of the pain may vary between patients. Readers of Arthritis Today will be familiar with the work of Prof Felson’s group, which is trialling different treatments for different subgroups of patients with osteoarthritis of the knee, such as knee braces and different types of insoles, targeted to their specific problem. 
In new research, a team led by Professor Ray Boot-Handford at the University of Manchester are attempting to stratify patients with osteoarthritis of the knee. The group’s initial work indicates that osteoarthritis patients can be divided into four categories, based on the genes that are present in their cartilage. By analysing the genes in cartilage from people with and without osteoarthritis, the team hope to be able to confirm their findings and find ways to identify and treat the disease in these different groups of patients. 

Dr Mohammed Sharif’s group at the University of Bristol have been recently awarded funding to investigate whether molecules in the blood of people with osteoarthritis can be used to diagnose the condition and identify whose condition will get worse over time, as well as who is likely to benefit from specific treatments. The group also hope to find out how each molecule is related to specific disease processes such as cartilage loss, bone changes and inflammation of the joint lining. 

Arthritis Research UK is funding two exciting new research projects which will help bring stratified medicine a step closer to the clinic.

Professor Ray Boot Handford“Not everyone with osteoarthritis has exactly the same pattern of disease, and because not all people’s disease is the same it makes sense that not everyone would respond to the same treatment”

– Professor Ray Boot-Handford

Researchers in Manchester are embarking on ‘a completely fresh approach’ to new research that could one day lead to more effective treatment for osteoarthritis.

A team led by Professor Ray Boot-Handford at the University of Manchester has been given funding of almost £260,000 from Arthritis Research UK over three years to identify groups of patients that may respond well to different, more targeted treatments, rather than the current ‘one-size-fits-all’ approach. 

They aim to ‘stratify’ or segregate patients into different disease groups by identifying the pattern of genes that are active in their joints. Osteoarthritis is a complex condition and the biological cause of cartilage breakdown is thought to vary between individuals.

“Osteoarthritis is incredibly complicated, and rather than one condition it is often regarded as an umbrella term for a disease that affects cartilage in many different ways,” explained Professor Boot-Handford, from the Faculty of Life Sciences. “Not everyone with osteoarthritis has exactly the same pattern of disease, and because not all people’s disease is the same it makes sense that not everyone would respond to the same treatment. 

“Most research in recent times has approached osteoarthritis as one disease that will respond to one treatment, and as a result there has been little progress in developing new treatments. We’re proposing a new approach to tackle its complexity by identifying different patient groups that will provide targets for developing new treatments.”

Professor Boot-Handford and his team are now planning to apply a powerful, newly developed gene-sequencing technique called RNAseq to analyse the gene activity and cell functions in the cartilage of people with osteoarthritis, comparing them to normal cartilage.

There are currently no diagnostic tests that have been shown to identify subsets of osteoarthritis that help to guide treatment, but the Manchester team are hopeful that this new technique will enable them to understand, for the first time, the distinctive processes driving cartilage damage in different groups of patients, which will also guide the development of new, specific treatments in the future. 

Dr Mohammed ShariThere’s an urgent need to find new and better biomarkers, and we’ve now identified two that are likely to prove useful for diagnosis and monitoring of osteoarthritis” 

– Dr Mohammed Sharif

Researchers at the University of Bristol are hoping to develop new blood tests that would help to diagnose and monitor osteoarthritis.

A team led by Dr Mohammed Sharif have been awarded of almost £300,000 by Arthritis Research UK to find out if two new biomarkers found in the blood of patients with osteoarthritis can be used not only to diagnose the condition but also inform doctors which patients are likely to get worse over time, and who is likely to benefit from specific treatments. (Biomarkers are biological markers found in blood or in tissue that indicate an abnormal process).

At present there are no simple tests for the early diagnosis of osteoarthritis, and usually by the time a definitive diagnosis is made using x-rays, the disease is in its advanced stages. Nor are there any means of predicting how it will develop or respond to therapy. Biomarkers could be used to identify patients in the early stages of osteoarthritis or those who will worsen over time, but current biomarkers are not good enough to perform these tasks reliably.

“There’s an urgent need to find new and better biomarkers, and we’ve now identified two that are likely to prove useful for diagnosis and monitoring of osteoarthritis,” explained Dr Sharif.

“However, we need to be sure they will be good enough for use in an individual patient. Therefore in this research project we hope to find out whether they can reliably distinguish between a healthy person and a person with osteoarthritis, identify which patients’ condition will get worse, and whether a particular drug is working or not.”

Osteoarthritis-specific biomarkers will enable doctors to direct specific treatment options such as physiotherapy towards those patients most likely to benefit, and may also help to identify early who will require a joint replacement.

The Bristol team have been working on biomarkers for osteoarthritis for many years, but say that new state-of-the-art technology now available has greatly increased their chances of developing novel biomarkers specific for osteoarthritis.

“Overall our study should have a major long-term impact on how the NHS manage and treat patients with osteoarthritis,” added Dr Sharif.

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