Arthritis : Biologics Block Cytokines, Joint Replacement

by Food and Drug Administration (FDA)

(Page 2 of 4)

Today, the first pharmaceutical line of defense against arthritis is the NSAIDs (nonsteroidal anti-inflammatory drugs), which include the salicylates, such as aspirin, prescribed at higher than usual doses. Coated and timed-release preparations can lessen the risk of gastrointestinal bleeding, the major side effect of these drugs.

The NSAIDs block release of prostaglandins, which trigger inflammation. Some more commonly used NSAIDs include ibuprofen, flurbiprofen, indomethacin, and naproxen. Currently, 15 NSAIDs are available.

Drugs called disease modifiers are used in rheumatoid arthritis patients who have had symptoms for at least six months and for whom NSAIDs no longer control swelling of joints. One such treatment is gold injected into a joint, which helps about 50 percent of patients, but unfortunately remains effective in only 5 to 15 percent of them after five years of use.

"No one knows how it works, but it is not an anti-inflammatory," says Pease. The physical presence of gold in the joint may reduce swelling, or the metal may chemically react with a biochemical in some as yet unknown way.

Another disease modifier is methotrexate, an anti-cancer drug that tempers the runaway cell division in the synovial joint. If these disease modifiers do not work, agents that suppress the immune response, such as cyclophosphamide, may be tried.

Biologics Block Cytokines

Unraveling the immune imbalances that underlie some forms of arthritis, and investigating how drugs alter immune function to quell inflammation are opening up an entirely new avenue to treating arthritis — the use of "biologics," or body chemicals. A prime target for new arthritis drugs is blocking cytokine production, a different approach to halting prostaglandin synthesis, which is the mechanism of most existing arthritis drugs.

Innovative approaches under way include work at Nova Pharmaceuticals in Baltimore with unusual amino acids that, in test animals, block the release of inflammation-provoking cytokines from activated T cells (a specialized type of white blood cell). Laboratory research at Immunex Corporation in Seattle, Synergen Corporation in Boulder, Colo., and Hoffmann-La Roche in Nutley, N.J., focuses on using interleukin-1 to prevent inflammation. Interleukin-1 is an immune system chemical that must bind to the lining inside joints to start the inflammatory process.

Joint Replacement

For advanced arthritis, joints can be replaced with synthetic materials, usually metals like cobalt-chrome and titanium alloys in the larger joints and polymers (long-chained molecules) such as silicone in the smaller joints, such as in the fingers. The devices must be durable and must not stimulate attack by the already overactive immune system, interfere with healing, or push surrounding structures out of their normal position.

Before the advent of implants, surgeons would remove joint surfaces, hoping that the scar tissue filling in the area would allow more mobility than the arthritic joint. This type of surgery often failed. Implants proved far more successful. They were pioneered by an army surgeon from Grand Rapids, Mich., Alfred Swanson, M.D. He fashioned the first such devices in the late 1950s out of silicone elastomers, polymers made from the element silicone, which is found in quartz.

Research to fine-tune the implants continued in the 1960s, and in 1969, the first silicone-based joint implants came on the market. These implants provided a flexible hinge for the joints of the fingers, wrists and toes. Since then, more than two dozen models have been developed, several by Swanson, who is now a professor of surgery at Michigan State University. More than a million people have received joint replacements — mostly in the hip — and they are still based on silicone.

During implant surgery, technically called "implant resection arthroplasty," the surgeon first removes the surface of the joint bones as well as excess cartilage. The centers of the tips of abutting bones are hollowed out, and the stems of the implant are inserted here. Between the bones lies the hinge part of the implant, which both aligns the bones and allows them to bend at the joint. The implant is "fixed," or held in place, with bone cement and, finally, the tendons, muscles and ligaments are repaired. As the site heals, the patient must exercise, but it can take a year of physical therapy to achieve maximum rehabilitation.

A new type of hand surgery replaces joints and realigns fingers at the same time. "All rheumatoid arthritis patients who have a severe deviation of their fingers away from the thumb are candidates for this procedure," says Robert Pearl, M.D., associate professor of plastic surgery at Stanford University Medical Center.

He recently introduced an operation that repositions the tendon at the base of the little finger. He finds that holding the pinky in place forces the other fingers to align properly. Pearl's patients start moving the hand the night after the operation, and wear a splint-like support device for the next three weeks. "By six weeks after the operation, patients are able to do most of their usual activities, especially the simple tasks that most of us take for granted, but were virtually impossible for these individuals," he says.

Newer joint replacements use materials that resemble body components. "Recent hip implants have been coated with calcium phosphate materials, like hydroxylapatite, which interact with bone. The aim is to enhance the attachment of the implant to the bone with a biologically active material," says Tom Callahan, Ph.D., of FDA's Center for Devices and Radiological Health. Rather than filling in the spaces with cement, investigators are testing a variety of porous coatings that allow "biological fixation," in which bone can grow into the implant area.

About the Author

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