Killing immune cells thwarts arthritis

In a strategy compared to rebooting a frozen computer, researchers have successfully treated people with the debilitating disorder rheumatoid arthritis by wiping out most of their antibody-producing immune cells.

Those who responded to the therapy, some for as long as 18 months, have resumed activities such as gardening and exercising and no longer need arthritis medication, says Jonathan C. Edwards of the University College London. He described his group’s treatment of people with chronic rheumatoid arthritis at this week’s American College of Rheumatology meeting in Philadelphia.

“The magnitude of the response is far greater than one conventionally gets with the drugs and biological agents now used to treat the disease,” says John Klippel, medical director of the Arthritis Foundation in Washington, D.C.

In rheumatoid arthritis, which afflicts 2.5 million people in the United States, the immune system turns against its own body, damaging joints and producing pain and stiffness. Edwards’ work arose from his own hypothesis that the condition stems from, in essence, bad luck.

Every day, the human body generates many million so-called B cells, each making antibodies that bind to slightly different molecules, such as those on microbes. If by a stroke of bad luck, Edwards speculated, some B cells make antibodies to themselves and other normally beneficial antibodies, the resulting chaos causes rheumatoid arthritis.

Indeed, some 85 percent of people with the condition harbor so-called rheumatoid factors, which are antibodies that bind to antibodies. No one knows what role the factors play in the disease, but Edwards contends that they set off a “vicious cycle” of B-cell activity. He compares the situation to a computer running a program stuck in an endless loop.

As he worked on his theory, Edwards concluded that wiping out a person’s B cells—in effect, rebooting that part of the immune system—could stop rheumatoid arthritis. “At the time, that seemed like a crazy idea,” he recalls.

While eliminating a major class of immune cells sounds drastic, scientists have unexpectedly found that B-cell depletion doesn’t leave the human body vulnerable to infectious disease. Thousands of people with B-cell cancers have had the treatment with few problems. Other immune cells, as well as antibodies produced by plasma cells, a more mature form of B cells, can hold off germs for the months it takes for new B cells to repopulate the body.

Learning of this, Edwards forged ahead with testing B-cell depletion in 20 people who have had rheumatoid arthritis for an average of 22 years and have failed to respond to conventional drugs. Each patient received three drugs—a B-cell—killing antibody and two compounds that suppress new B-cell formation.

Of the 20 patients, all but two enjoyed an enduring and dramatic reduction in pain, swollen joints, and other symptoms of the disease, reports Edwards. In several cases, people relapsed after 6 to 9 months—when B-cells returned—but responded to another round of B-cell depletion. A new trial of the B-cell-depletion therapy, with 150 patients from Canada, Australia, and Europe, should start soon, says Edwards.

Klippel notes that B-cell depletion is the first rheumatoid arthritis treatment to have such long-lasting effects; current drugs must be taken constantly. He also notes that B cell depletion could treat additional illnesses in which the immune cells are hyperactive. “This therapy might have real potential in diseases other than rheumatoid arthritis, including ones like lupus,” says Klippel.

Other scientists in Philadelphia revealed a second potential advance in the fight against rheumatoid arthritis and lupus. Two research teams reported that people with these autoimmune disorders have elevated amounts of a specific protein in their blood. The protein, which goes by several names including B-lymphocyte stimulator (BlyS), boosts antibody production by triggering the growth and activity of B cells (SN: 8/21/99, p. 127).

The new findings suggest that inhibiting BlyS activity will help people with lupus or rheumatoid arthritis, says Robert P. Kimberly of the University of Alabama in Birmingham, who led one of the research teams. Human Genome Sciences of Rockville, Md., one of the companies that has laid claim to patent rights on BlyS, plans to test this possibility next year by treating lupus patients with an anti-BlyS antibody.

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