Osteoarthritis: could stem cell therapies be the answer?

An exciting new trial to test the effectiveness of stem cells in early knee osteoarthritis is now under way. Jane Tadman reports.

Stem cells have long been heralded as the possible answer to a number of medical conditions, including osteoarthritis. And now a clinical trial testing the effectiveness of stem cells compared with cartilage cells in treating early osteoarthritis of the knee could point the way forward.

Funded by Arthritis Research UK, it is the first clinical trial in the UK to compare different cell types in the treatment of osteoarthritis, with the aim of repairing damage to the joint, stopping the condition getting worse and delaying, or even avoiding, the need for knee replacement surgery. 

The painful joint condition affects more than eight million people and there is currently no effective drug therapy or treatment to prevent it or slow down its progression.

Around 100 people with early osteoarthritis in their knees are taking part in the three-arm, randomised controlled trial run by orthopaedic specialists at the Robert Jones and Agnes Hunt Orthopaedic Hospital Foundation Trust (RJAH) in Oswestry, Shropshire. The hospital is part of the £6m Arthritis Research UK Tissue Engineering Centre launched in 2011.

Stem cells versus cartilage cells

The ASCOT (Autologous Stem Cells, Chondrocytes or the Two?) trial is testing stem cells derived from bone marrow (also known as mesenchymal stem cells) versus cartilage cells called chondrocytes. A combination of both types of cells will also be trialled. Chondrocytes alone have traditionally been used to repair small areas of cartilage damage.

The chondrocytes and bone marrow cells will be extracted from patients via keyhole surgery, grown in the lab and re-implanted back into the patient as part of the five-year £500,000 research programme.

Patients are only being recruited if their local orthopaedic surgeon or GP refers them to the RJAH, and strict eligibility criteria are in place. It can only be offered to people who have previously undergone another surgical treatment, such as microfracture, which has failed to help their symptoms.

Participation in the trial involves two operations and a period of six months’ convalescence and rehabilitation. The Oswestry team will follow up the patients for 15 months and will measure success by looking at the quality of the cartilage and the patient’s ability to perform everyday activities. Some additional follow-up work will also be funded by a recently awarded grant from the Medical Research Council.

The research team, led by scientist Professor Sally Roberts and Professor James Richardson, professor of orthopaedic surgery, are keen to stress that this treatment may be more suited to some people than others. 

Stem cells could reduce the need for knee replacement

“Hopefully the trial will help identify patients in the future who are likely to get most benefit,” said Professor Roberts. “There remain many unanswered questions about cell therapy in general, for example, it is not known if stem cells may actually cure osteoarthritis (particularly at an early stage), or simply delay the need for a knee replacement.”

Professor Richardson said: “This trial has been a long time in the planning, partly due to changes in the regulatory environment, but this research remains exciting and novel. We are grateful to the Arthritis Research UK for their continued support and are very excited to be starting to recruit patients.”

RJAH director of research, Andrew Roberts, said: “I am delighted to support Professors James Richardson and Sally Roberts in the arthritis research work they are undertaking. The trial to improve on existing cell therapies, comparing the patient’s own chondrocytes and bone marrow stromal cells for the treatment of chondral defects, will depend on the continued collaboration of scientists and surgeons at the hospital. This is a traditional way of working at Oswestry, of which we are justifiably proud.”

For many years the RJAH has been at the forefront of using a surgical technique, originally pioneered in Sweden, called autologous chondrocyte implantation (ACI) which uses engineered cartilage cells taken from patients with cartilage problems – often caused by sports injuries.

Professor Richardson established special facilities for culture-expansion of autologous chondrocytes and marrow-derived mesenchymal stem cells for cartilage and bone repair around 15 years ago. 

Professor Richardson and Professor Roberts, whose academic base is at Keele University, have been instrumental in monitoring progress in the clinic, developing outcome measures for objective assessment of the procedures used and studying the biology of repair. Their colleague Professor Alicia El Haj at Keele University is examining ways of controlling production of, scaling-up production and targeting of cells for tissue-engineered cell therapy.

The trial was originally due to start in 2010 but was delayed due to changes in the way that cell therapy products were regulated. Cell therapy products are now classified as drugs and so this trial is governed by the same regulatory processes as a drug trial. 

Arthritis Today will keep readers up to date with the trial’s progress.

Stem cell trial: questions and answers

With Tim Knight, one of the surgeons involved in the ASCOT trial at the Robert Jones and Agnes Hunt Orthopaedic Hospital in Oswestry.

Has this kind of trial ever been performed before in the UK or elsewhere?

This is the first randomised clinical trial in the UK comparing different cell types in the treatment of cartilage damage. Other trials have been performed comparing cell treatments to more traditional operations, but the current quest is to define which types of cell work best. 

Can you explain the differences between the three arms of the trial?

The three options are stem cells only (obtained from the patients’ own bone marrow),cartilage cells only (also called chondrocytes, these cells are obtained from the patients’ own knee) and a combination of stem cells and chondrocytes. Stem cells can be found in many places in the body. They are exciting as they have the potential to become any type of cell in your body, including cartilage, and they have even been used in some patients to treat early arthritis. Cartilage cells are found within the cartilage of normal knees and have been used, after being grown in the laboratory, to enable defects in cartilage to heal. 

What do you hope this trial will achieve?

Cartilage defects in the knee can be painful and may not heal on their own: they may then lead to osteoarthritis. We want to help the body repair the defect by implanting cells that can enable the healing. However, it is not known which type of cell works best, or even if the combination of the two types will be best. This trial is designed to determine this.

It is important that patients do not know what treatment they have received so that expectations of any one treatment do not influence the outcome. All three options are considered in their own right to be potential winners and we need to make sure we do not bias our results. 

Who is eligible to take part?

Patients with a symptomatic cartilage defect or early osteoarthritis, who are considered by their local surgeon to be suitable for cell therapy, are eligible. They must have tried simple keyhole treatments such as microfracture or debridement first and have an MRI scan to show where the cartilage and/or bone is damaged. (Microfracture is a surgical procedure in which small holes are punched into the bony surface of the joint, stimulating bone marrow cells from within the bone to form cartilage and cover the joint defect. Debridement involves the removal of loose debris around the joint). 

How are you recruiting people to take part?

We are excited about this work but must also limit the resource to those who will benefit from it most. Just over 100 patients will be recruited to the trial according to their clinical symptoms and the amount of degeneration in their joint. For some people, a joint replacement will be the best treatment option. People wishing to take part must fulfil the above criteria and be referred to us via either their GP or preferably their orthopaedic surgeon.

Can you explain the surgical procedures involved?

All three arms of the trial will involve two procedures and will be performed by a team of orthopaedic surgeons at the Robert Jones and Agnes Hunt Orthopaedic Hospital Foundation Trust (RJAH). The first procedure is an arthroscopy, in which cartilage cells are taken from the cartilage and a small cut is made to remove bone marrow from within the hip. 

An arthroscopy is a keyhole procedure where a camera is inserted into the knee joint through a few small incisions around the front and sides of the knee. Through these small incisions samples of cartilage can be taken, small defects in the cartilage can be trimmed and other problems such as ligament damage can be repaired prior to the cell therapy.

A few weeks later, following the growth of the cells in the laboratory, a second procedure called an arthrotomy is performed. This is an open procedure on the knee joint, with an incision over the front of the knee. This leaves a wound and scar similar to those after a total knee replacement.

Do trial participants have to take part in rehabilitation after surgery, and if so, is it provided?

After the second procedure patients will be enrolled into an intensive physiotherapy regime. This will be a progressively active 12-month programme, gradually increasing weight-bearing and range of movement. This will be carried out at the RJAH for patients local to Oswestry, but for those form further afield it will be undertaken via their local hospital. The regime will be very demanding and will require a high level of commitment. 

How long is the trial and when we will know the results?

The trial is designed to run for five years; we will be recruiting patents (approximately 35 each year) in the first three and a half years and each patient will be followed up for at least 15 months.  

Why is this type of surgery currently not available for people with advanced knee osteoarthritis?

Once the knee is severely damaged and sometimes inflamed with advanced arthritis, we believe that the cell therapy will fail. It may become possible in time to offer cell-based treatments to people with severe arthritis once we know which factors are most likely to dictate the success of the procedure. 

Do you know how long the cartilage cells/stem cells implanted into the knee will last?

This is an interesting question but we do not know the answer. It is possible to label or ‘tag’ cells but so far these labelled cells have not been used for cell therapy. This may, however, become possible in the future as labelling and imaging techniques improve.

What if the surgery is not successful?

If surgery is not successful then more traditional treatment options will be available, for  example, further microfracture can be performed or osteotomy, or eventually a knee replacement. Indeed, as with all treatment, there is no guarantee of success. Currently one in five cell therapies have failed and we are trying to identify factors that are linked to this.

If I take part in the trial will I be able to run/play sport/ski etc once I’ve recovered?

It is likely that the cell treatment will allow you to regain normal activity levels, but this can take up to a year and varies between individuals, and depends on the type of activity. For example, patients can return to swimming or cycling (which are good non-weight-bearing activities for the knee) much more quickly than to contact sports.

How long will it be before this type of surgery is widely available on the NHS?

This is a trial being run by an NHS foundation trust hospital, but only for patients to be treated here. More widespread availability will depend on the success of this trial and the willingness of other hospitals and companies to take it up. We would be delighted to see more people receiving treatments that resolve their pain with predictable and reliable results. 

Case study

Robin Griffin is pinning his hopes on the ASCOT trial to restore him to a level of fitness he used to enjoy before a serious rugby injury robbed him of an active lifestyle.

Robin, aged 42, from Ruthin, in North Wales, is one of 100 people with early osteoarthritis of the knee who is taking part in the trial at the RJAH, and will receive one of three treatments – stem cells taken from his own bone marrow, cartilage cells taken from his knee or a combination of both types of cell.

Robin’s knee problem goes back to his 20s when he played rugby for the local first team in Ruthin. During a game in South Wales he fractured and dislocated his right kneecap and spent eight weeks in plaster.

He says: “I was working full-time as a lifeguard at that time, and for the rehabilitation they told me to swim a lot and do some weights to try build muscle up. But it didn’t work – the muscle in my right knee is much weaker compared with my left knee. After a few years I started playing rugby again, but I wasn’t 100%, and never got back to the standard I’d been playing at before.”

Robin has an extremely high pain threshold and over the years attempted a variety of sports and managed to ski regularly, although he relied heavily on massive amounts of NSAIDs. He took a more office-based job as a health and safety advisor, which meant he spent less time on his feet.

But about four years ago he had to give up playing rugby and skiing as the pain and swelling in and around his right knee increased. He now he swims and cycles to keep fit but is still in constant pain.

“The pain varies from day to day depending on what I do; whether it’s hot or cold,” he says. “Sometimes swimming makes it worse, and just going up and down the stairs is a struggle.”

Robin had keyhole surgery at his local hospital in Abergele to wash out the knee joint and trim bits of loose cartilage, but its effectiveness was short-lived. However, his surgeon referred him to see Professor James Richardson at RJAH, who was just starting to recruit patients for the ASCOT trial.

“I had a couple of MRI scans and they decided it was worth my trying this treatment and going on the trial. Professor Richardson told me my kneecap was half a centimetre out of line. There is also some arthritis, and I have some bone growth around the kneecap area and on the kneecap,” he explains.

“So they will take some bone marrow samples, grow my cells and re-inject them back into my knee. Professor Richardson will also remove and reshape my kneecap and put it back in the correct position.”

Robin is keeping his fingers crossed that whatever treatment he receives as part of the trial, it will take away the pain, and enable him to be more active. Weighing over 16 stone, he is currently trying to lose a stone before the first of his operations in August.

“I’d like to be as pain-free as possible and then I’d like to be able to rebuild the muscle around the knee area,” adds Robin. “I’d also like to be able to ski again after the treatment and operations.

“It sounds like fascinating research. You hear about stem cell therapies all the time, so to be involved in this trial is really exciting, and I hope this treatment will make a big difference to me and my quality of life. I’m happy to be a guinea pig!”

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