This new optimism reflects better understanding of arthritis biochemistry, said Peter Lipsky, MD, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas. "What we're seeing is the tip of the iceberg of basic arthritis research," Lipsky explained.

Medications that stifle proinflammatory cytokines are the first arthritis drugs to go beyond symptom relief by attempting to slow the disease's chronic, joint-damaging inflammatory process. Biologic TNF inhibitors are in the late phases of clinical testing. Early in the immune attack on the joint, macrophages secrete TNF, which triggers a series of events that leads to inflammation.

Many pharmaceutical companies are developing their own versions of TNF inhibitors. At Immunex Corporation in Seattle, researchers have engineered a recombinant soluble receptor for TNF, TNFR:Fc, that binds to excess TNF and blocks it from its normal cell surface receptors (N Engl J Med. 1997; 337:141-7). During phase II clinical trials, patients with rheumatoid arthritis receiving TNFR:Fc injections twice a week for 3 months reported less joint swelling, tenderness, and morning stiffness. Laboratory tests confirmed a reduction in joint inflammation. Now that TNFR:Fc is in phase III trials, Immunex plans to submit it for approval by the U.S. Food and Drug Administration in 1998. Roche Holding Ltd. in Switzerland is in the early phases of testing a similar drug. A third TNF inhibitor, infliximab, is being developed by Centocor, Inc., in Malvern, Pennsylvania. Scheduled for phase III clinical trials in the fall of 1997, infliximab is a monoclonal antibody that blocks TNF when given intravenously. The drug is being tested in combination with methotrexate, a widely used second-line antirheumatic drug.

TNF is not the only cytokine target. Interleukin proteins, including IL-1, IL-4, IL-6, and IL-10, all play a role in either stimulating or blocking arthritis inflammation. Some animal studies suggest that IL-1, for example, causes much of the early cartilage damage of rheumatoid arthritis. Amgen, Inc., in Thousand Oaks, California, is conducting a pilot study of a potential drug, IL-1ra, to block IL-1. Researchers in Japan are studying an IL-6 antagonist.

The long-term effects of anticytokines are not well known. What is clear is that when therapy stops, patients have a relapse. "Mostly what we have are 6-month studies: short, placebo-controlled trials," said Michael Weinblatt, MD, a rheumatologist at Harvard University in Boston. "What we need to know is the long-term clinical effect. How do the drugs compare to methotrexate? What effect do they have on progression of the disease?" Researchers are still learning how anticytokine agents interact with existing drugs and how they benefit patients with different stages of arthritis.

Safer Pain Relief

Meanwhile, others are working to make pain relief safer for both rheumatoid arthritis and osteoarthritis patients. Their target: nonsteroidal anti-inflammatory drugs (NSAIDs). In 1989, researchers discovered that the cyclooxygenase enzyme, which produces prostaglandins, is in fact two enzymes: COX-1 and COX-2. The prostaglandins produced by the COX-1 isoform protect the gastrointestinal tract; COX-2 is induced during tissue injury and leads to the inflamed joints of arthritis. By inhibiting COX-1, aspirin, ibuprofen, and other NSAIDs can cause ulcers in about 2% of patients who take the drugs to fight chronic inflammation.

Selective COX-2 inhibitors are a new class of drugs that primarily inhibit the COX-2 enzyme, leaving the population of COX-1 prostaglandins intact. G.D. Searle & Co. in Skokie, Illinois, is conducting phase III clinical trials of its COX-2 inhibitor, celecoxib. A similar drug, designated MK-966, is also in phase III clinical trials at Merck & Co., Inc., in Whitehouse Station, New Jersey. The challenge for COX-2 inhibitors is to be both specific and potent. To work safely, the drugs must be highly selective for COX-2 and avoid COX-1 even when administered in doses large enough to ease inflammation.

Reaching beyond immediate clinical therapies, researchers hope within 5 years to begin identifying arthritis susceptibility genes, according to Betty Tsao, PhD, a geneticist at the University of California in Los Angeles. Discovery of such genes could lead to promising drug targets and disease risk studies, she added. In September, a national consortium of 12 research centers was formed with support from the National Institutes of Health to coordinate the search for genes that determine susceptibility to rheumatoid arthritis. *

Rethinking Assumptions

Already, osteoarthritis risk studies are prompting some researchers to question their understanding of the disease. For years, it has been thought that painful osteoarthritis of the knee causes patients to stop exercising, which leads to muscle atrophy and weakness. That is probably true much of the time, but rheumatologist Kenneth Brandt, MD, of Indiana University in Indianapolis suggests that abnormal muscle weakness may sometimes be a risk factor for osteoarthritis from the outset and actually lead to-rather than result from-the disease. In community studies, Brandt and colleagues found substantial numbers of osteoarthritis sufferers who displayed muscle weakness but had no pain or signs of atrophy (Ann Intern Med. 1997; 127:97-104). "Clinically, this implies that it might be a useful public health measure to intervene, taking people before they become symptomatic and teaching them to do simple strength training," said Brandt, who is about to begin a controlled clinical trial to test this hypothesis.

Piece by piece, clinical and basic researchers are building better ways to understand and fight arthritis, Lipsky said. But the ultimate goal, a cure, remains out of reach. "This is our big challenge. All of the data available say that when you stop therapy, the arthritis comes back. We're still far away from being able to cure it."

-Kathryn S. Brown

*Families with two or more siblings with rheumatoid arthritis can enroll in the genetics study through the coordinating center at North Shore University Hospital at 800-382-4827. The consortium also has a site on the World Wide Web (http://www.medicine.ucsf.edu/narac/narac.html).