By: Fintan Moore – Irish Medicine Weekly – Wednesday, November 16, 2005

The treatment of osteoarthritis can result in serious side effects that have encouraged the development of a therapy that mimics the unique properties of the joint¹s own synovial fluid. Dr Robert Petrella, Medical Director of the Canadian Centre for Activity and Ageing gives some insights into viscosupplementation

Introduction

Osteoarthritis (OA) is the fourth most common debilitating condition among women and the eighth most common among men in Western countries. At least 50 per cent of the population over 65 has radiographic evidence of osteoarthritis and more than 10 per cent have major disabilities as a result. Approximately 5 per cent of this population will require total hip replacement surgery. Non-medical management of the condition involves weight loss, exercise and physiotherapy.

Use Of NSAIDS

Palliative medical interventions use paracetamol as a first choice analgesic. An NSAID should only be used if paracetamol is ineffective or is there is significant inflammation involved. When given regularly in full doses, NSAIDs have an analgesic and anti-inflammatory effect, but they are generally more useful in rheumatoid arthritis than OA, although they can benefit patients with severe OA.
Of course, there are significant risks associated with long-term use of NSAIDs, particularly in the elderly. GI bleeding is the most serious side effect, but NSAIDs may also worsen cardiac disease and renal impairment in the elderly. However, NSAID tolerance varies widely. Cox-2 inhibitors are licensed for pain relief in OA. Where cox-2 therapy is used, they may be combined with H2-receptor antagonists or proton pump inhibitors to reduce GI effects. Finally, in the treatment progression of OA, is joint replacement therapy, although most patients with OA typically do not need it.
Corticosteroids are sometimes used intra- and peri-articularly in patients with localised inflammation, but they have only short-term benefits (typically three to six weeks) and are recommended for use infrequently or as an adjunctive therapy.
Viscosupplementation or synovial fluid replacement therapy using hyaluronan became available on the GMS in February. It has been licensed for clinical use in OA treatment in much of Europe since 1995 and in the US since 1997.

Benefits Of Viscosupplementation

The Director of the Canadian Centre for Activity and Ageing, Dr Robert Petrella, was in Dublin recently to talk about the benefits of viscosupplementation.
“The OA disease process is initiated through an inflammatory process in which joint cartilage is involved. Within the joint there is a milieu of material, of synovial fluid, which has a composition which allows patients to perform normal movements like walking, that create impacts on joints. But as the disease process continues, we know that the synovial fluid changes in its characteristics,” Dr Petrella explained.
“If you were to sample that fluid in someone who has no arthritis and someone with a very early onset of an arthritic condition, the composition of the fluid is really quite markedly changed. There is a change in its viscous property; it’s less able to withstand the stressors of activity,” he said. “Initially, patients may feel pain during particular activity such as going up and down stairs, but the rest of their activity may still be pretty good. As the disease process develops further they get further degradation of synovial fluid, typically with pain during very simple activities, such as getting out of a chair. So we think that the changes in synovial fluid are probably a marker or precursor of the changes that occur in the arthritis process.”
Eventually, he said, the patient will develop cartilage and bone changes which are irreversible.
“The opportunity that you have when the synovial fluid is being changed by arthritis is a fairly short window, an ongoing moving target. As in all the way through the condition’s progress, the material continues to change.”
Viscosupplementation is a process which tries to reintroduce a normal milieu within the synovial fluid in the joint space, altering its properties such that it can withstand different kind of stress.

Dynamic Molecules

Synovial fluid is made up of various chains of hyaluronan. It is responsible for the viscous properties observed in the fluid. Hyaluranon is a dynamic molecule. It changes in its configuration and its physicochemical properties, depending on what types of stressors are being placed on the joint.
“If you were to sample a joint after a high level of bouncing activity, for example, in a basketball or volleyball player, you’ll see that there is a shift in the molecules’ composition to a more dynamic form, with a more viscous property, as opposed to what you would find in someone who has just been sitting around or gently walking,” Dr Petrella explained.
“There are a number of products that try to mimic what should be in the joint. They vary in their molecular weight and in their concentration. The idea behind all of them is that, if you can mimic what the joint needs, you would be able to forestall the progression of arthritis to the irreversible bone and cartilage changes, but also you could enable patients to function in a more normal way,” according to the doctor.
All of the products are introduced as a liquid gel, intra-articularly injected into the joint space, he commented, but stressed that there is a dosing aspect involved.
“In order to get the material up to a level that’s actually bio-useful in the joint requires a certain volume at a certain dosing frequency. For instance, in the knee at any one time you can introduce between 2-3.5ml of any fluid, including hyaluranon, before you would begin to cause pain due to stretching of the joint capsule. So you would introduce maybe 2ml of viscosupplementation to the joint, then allow it to equilibrate and dose again a week later. The typical treatment tends to be 2ml once a week for three weeks to reach a critical concentration/volume to allow the surrounding tissue to withstand physical force.”
“The material introduced to the joint is gradually cleared through the lymphatic system surrounding the joint, and probably has a half-life of four weeks or so. However, the relief from symptoms tend to last up to six months and even up to one year. Patients at my own practice who have had the series of three injections and have had good resolution of their symptoms, maybe not 100 per cent, but very close, have typically had this relief for eight to 12 months.”
“The beauty of this material is that because it is natural, it can be introduced at any time and has no accumulative effects. So patients come back in, have another series of three injections, and get a repeat of symptom relief for a similar period,” Dr Petrella said.
“I think that another advantage of the product being natural is that it has no interaction with other drugs. It’s not excreted through the liver or kidney, so there’s no problem with co-morbidity, so it really has no contra-indication for any patient with arthritis. The only thing of course, as with any injection, is that it must be introduced using sterile technique, to protect from infection. The incidence of adverse events is very very low; between 1-2 per cent per injection. And those side effects tend to be in the range of what the patients are already experiencing – pain within the joints, some swelling. These also tend to be very transient side effects.”

Active Investigation

“An area of very active investigation is the change in synovial fluid composition or its characteristics as the condition progresses. What we would like, but don’t have now, is a way or a marker to determine at what stage a patient may be in the disease progress” he commented.
“We do know from clinical history that certain occupations, activities or being overweight may predispose people to the development of OA, as does having arthritis in other joints. We just don’t have a good marker of the development of arthritis in a joint we are studying that would allow us to say that this is the point when we should start using viscosupplementation. Obviously that would be very useful, allowing us to predict the optimal time to start therapy.”
“More importantly right now, we know that this is a process that starts very early and continues to develop until the end of the joint’s life. We can introduce this product at any time in the disease process. Even patients who are waiting for a total knee joint replacement can still have about a 60 per cent improvement in their symptoms if they have viscosupplementation injections, even if they have very late stage arthritis. We really don’t have any other options in that case. Patients are typically waiting considerable periods before they will have the replacement surgery. I know in Ireland the wait can be two years or more but in the interim patients actually do very well with this therapy,” he said.
“It’s safe to use viscosupplementation if a patient has a co-morbidity such as cardiovascular problems or GI disease, or are taking NSAIDS for arthritis. The big issue about viscosupplementation is awareness,” according to Dr Petrella. “I think there is a lack of awareness of the therapy as an option, particularly in Ireland, where it has just been introduced.

Lifestyle Modification

Dr Petrella’s role as Director at the Canadian Centre for Activity and Ageing at the University of Western Ontario is to oversee its activities as a clearing house for community-based programmes and laboratory-based research into activity-related disease.
³Specifically, the work that I’m doing is related to musculoskeletal changes with ageing. We’re also very much into lifestyle modification, so we investigate exercise and dietary changes within the older population to enhance activity and to lower cardiovascular risks.”

Dr.Robert Petrella was in Ireland to address a meeting to discuss the treatment of OA, chaired by Dr. Doug Veale, consultant rheumatologist,St Vincent’s University Hospital.

Irish Medicine Weekly

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