Course Authors
Peter Barland, M.D.
Dr. Barland reports no commercial conflict of interest.
This activity is made possible by an unrestricted educational grant from the Novartis Foundation for Gerontology.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the role that hyaluronan plays in the function of the normal joint
Discuss the treatments now available for osteoarthritis
Discuss the guidelines for the use of intraarticular hyaluronan in osteoarthritis of the knee.
Introduction
The FDA has recently approved the use of hyaluronan for the treatment of osteoarthritis of the knee for patients who have failed treatment with acetaminophen, nonsteroidal anti-inflammatory agents and physical therapy. Hyaluronan is given as a series of weekly intra-articular injections (viscosupplementation) over three to five weeks and the beneficial results -- relief of pain, improved joint mobility and improved ambulation -- appear to last for several months to one year. This Cyberounds® will be devoted to review of this form of therapy.
Role of Hyaluronan in Normal and Osteoarthritic Joints
Hyaluronan (hyaluronic acid, hylan) is a high molecular polysaccharide consisting of repeating units of the disaccharide glucuronic acid and glucosamine. It is produced by the type B lining cells of the synovial membrane. There is a constant turnover of hyaluronan in the joint -- the half-life of hyaluronan injected into the joint is in the order of 24 to 48 hours. In normal synovial fluid, hyaluronan, because of its high molecular weight and negative charge, occupies a very large volume, with the molecules of hyaluronan overlapping to form a continuous mesh. It is this property of hyaluronan that gives normal synovial fluid its high viscosity at low shear forces which contributes to joint stability.(1),(2)
Hyaluronan can also dampen the response of the pain fibers in the synovial membrane by coating the nociceptors.(3) In osteoarthritis, the hyaluronan concentration in the synovial fluid is decreased, as is the molecular weight of the hyaluronan molecules. It is believed that these changes contribute to the decrease in joint function, as well as the pain, which are characteristic features of the disease. Hyaluronan is also synthesized by the articular choncrocytes where it forms the backbone of the macromolecular aggregates of proteoglycans that make up the matrix of all but the superficial layer of articular cartilage.(4) These aggregates are largely responsible for the elasticity and compressibility of articular cartilage. Chondrocytes appear to have a receptor for hyaluronan on their surface membranes (CD44) which, when linked to hyaluronan, inhibits the synthesis and secretion of an enzyme aggrecanase that leads to the dissolution of the articular matrix.(5)
Osteoarthritis is characterized by the degeneration of the articular cartilage leading to fissuring and eventual loss of the articular cartilage, followed by sclerosis of the subchondral bone, osteophyte formation and a mild synovitis.(6) The causes of the cartilage degeneration appear to include physical stresses, such as repeated trauma to the joint or sclerosis of the underlying bone, and biochemical changes, such as calcium pyrophosphate deposition in the articular cartilage. It appears that both decreased synthesis, as well as increased degradation, contribute to the changes in hyaluronan seen in osteoarthritis.
History of Hyaluronan for the Treatment of Osteoarthritis
A highly purified, noninflammatory form of hyaluronan can be purified from rooster combs. In 1970, Rydell and coworkers reported that, when this material was injected into arthritic equine knee joints, there was a clinical improvement.(7) In the early 1980s there were several uncontrolled studies of the benefit of intra-articular hyaluronan in the knees and hips of patients with osteoarthritis which reported beneficial effects in the majority of the patients often lasting six to twelve months. Very few or no adverse side effects were reported. With the advent and availability of total joint replacement, interest in intra articular hyaluronan waned for several years.
More recently, there has been renewed interest in hyaluronan as a result of controlled trials reported from Europe(8) and Canada.(9) In some of these studies, the group receiving hyaluronan was statistically improved for up to twelve months after the intra-articular injections. The most consistent clinical parameter to show improvement has been the patient's pain scores. As in the earlier studies, there were very few adverse reactions and no deaths have ever been reported after hyaluronan therapy. While some authors have referred to this form of therapy as chondroprotective, they have not presented evidence to support this claim. However, a recent study of intra-articular hyaluronan in a rabbit model of osteoarthritis reported that there was less macroscopic and less microscopic damage to the articular cartilage in the treated animals.(10)
Mechanism of Action
It is not at all clear how hyaluronan relieves the symptoms of osteoarthritis for such a long period of time since it is cleared from the joints within a few days after intra-articular injection. It has been proposed that the hyaluronan promotes long lasting changes in the homeostasis of the joint by stimulating the synovial lining cells to synthesize more hyaluronan, while, at the same time, inhibiting the production of aggrecanase by chondrocytes, thereby establishing a new homeostasis in the joint more closely resembling the condition in the normal joint.
Practical Considerations
Hyaluronan treatment is indicated in patients with osteoarthritis of the knee that is symptomatic despite treatment with conservative measures which include acetaminophen, physical therapy and nonsteroidal antiinflammatory drugs. Flares of synovitis (swelling and tenderness) probably will do better with intra-articular steroids than with hyaluronan. Hyaluronan, like most therapies, is more effective in patients who have some remaining range of motion and some remaining articular cartilage, as judged by X-ray or MRI imaging. While total joint replacement is probably the treatment of choice for patients with advanced disease, intra-articular hyaluronan may provide symptomatic relief in patients who are not surgical candidates or refuse surgery.
There are currently two hyaluronan preparations approved for use in osteoarthritis of the knee. One is Synvisc® (hylan G-F 20, distributed by Wyeth Laboratories), manufactured by the crosslinking of hyaluronan purified from rooster combs to a higher molecular weight form, known as hylan, which has a viscosity similar to the hyaluronan found in the joint. Synvisc® is retained in the joint for seven to fourteen days after intra-articular injection. Clinical trials have shown that three weekly injections of 16 mg. of this product into the knee results in an optimal response. The other preparation, Hyalgan® (sodium hyaluronate, distributed by Sanofi Pharmaceuticals), is a non-crosslinked hyaluronan purified from rooster combs. It has a viscosity considerably less than normal hyaluronan and has a biological half-life in the joint considerably shorter than hylan but may have wider distribution after intra-articular injection. The optimal dosing for Hyalgan® appears to be five weekly injections of 20 mg. each.
There are no comparative studies of the two agents in humans and the very low adverse reaction rates and costs appear to be comparable. Neither agent should be mixed with quaternary ammonium anesthetics either in the syringe or in the joint coprecipitation. Care should be taken not to inject the hyaluronan subcutaneously or intravenously. Patients who are allergic to chicken products should not receive these agents. The safety of the agents in pregnancy or for nursing mothers has not been established, though animal studies have not shown teratogenecity. Patients on anticoagulant therapy should be treated with caution, if at all. Repeat courses of hyaluronan have not been studied or approved by the FDA although, theoretically, they should be equally efficacious.
Other Forms of Therapy for Osteoarthritis
Recently, there have been additional treatments advocated for osteoarthritis in addition to those listed above. These include the use of oral glucosamine with and without chondroitin sulfate.(11) While the mechanism of action of these agents is unknown and the original enthusiasm was based mainly on testimonials and anecdotal experience, there is now at least one prospective controlled trial indicating some mild clinical benefit for the combination form of therapy. Experimentally, the use of autologous cartilage implants(12) and orthopedic procedures to stimulate new cartilage growth and to change the weight bearing surfaces of joints are attracting increasing interest. It appears that osteoarthritis is no longer considered an inevitable accompaniment of aging but rather a dynamic and largely treatable disease.