Cancer drug shows promise against lupus

September 16, 2004

A drug now used to treat a type of cancer appears to be very effective at treating lupus, with just one injection easing symptoms in several patients for a year or more. The results of the clinical trial involving 17 patients are in the August issue of Arthritis and Rheumatism.

The finding has its roots in a hypothesis put forth by the team of physicians at the University of Rochester Medical Center who did the study. They suspected that because lupus involves the same immune cells as lymphoma, a drug successful at treating lymphoma might also help lupus patients. So doctors tested the medication rituximab, approved in 1997 to treat lymphoma, in patients with the chronic inflammatory disease where the immune system mistakenly attacks a person's own tissues.

The results bear out the hypothesis. Eleven of the 17 patients had a significant drop in immune cells known as B cells, and the health of those patients improved significantly, an improvement that was evident for the 12 months that the study lasted. Several were able to reduce or go off their traditional lupus medications.

"In most patients, their lupus improved significantly," says rheumatologist R. John Looney, M.D., who led the study. "Since lupus differs a great deal from person to person, the ways that patients improved varied. Some had less joint pain; some had fewer skin rashes. But everyone who had fewer B cells had significantly improved health.

"These patients were treated for a very brief period of time, and some of them are still doing just great, several years later."

The benefit wasn't as marked for everyone, including patients who did not receive the full dose of the medicine in the "dose-escalation" study, as well as African-American patients. Scientists are investigating the differences.

Unlike many autoimmune diseases that target a specific system or organ, lupus can affect a person's joints, skin, blood, kidneys, and even organs like the lungs and brain. Fatigue, arthritic joints, and infections are among the most common symptoms. Many patients live a normal life while taking medicine and working with a doctor to keep tabs on the disease, perhaps feeling some joint pain or having a rash occasionally, while others are debilitated by the illness and have severe infections or organ failure. Women are about 10 times as likely as men to be diagnosed with lupus. Doctors estimate that anywhere from about half a million to 1.5 million people in the United States have the disease.

"Some patients don't need much treatment, while others need all you can offer and more," says rheumatologist Ignacio Sanz, M.D., an author of the paper and a lupus expert.

Besides the drug's success in treating the disease, scientists noted the lack of significant side effects with rituximab. Some patients had a reaction to the infusion of the medicine, but in the study, it occurred far less often than it does with cancer patients taking the drug.

Current lupus treatments, in contrast, are laden with severe side effects. The anti-inflammatory drugs used to dampen the immune system leave patients vulnerable to infection, while steroids at high levels can cause an array of problems, everything from thinning bones, weight gain, weak muscles, and heart disease to glaucoma and depression.

The difference in side effects is a result of the precision, or lack thereof, of the medicines. Current lupus treatments affect nearly all the cells of the body, including healthy and vital cells. In contrast, rituximab targets only B cells and is aimed at lowering their numbers. That's why the drug is available to lymphoma patients: Most have too many B cells, which make antibodies that flag down and kill microbes and other invaders in the body.

Lupus is also a problem with B cells: They're found in the wrong proportion in the body's blood and tissue, and they're often misguided, making too many antibodies that mistakenly attack the body itself. The infighting clogs up the body with cellular debris, causing a variety of symptoms; then when the immune system detects the problem, it tries to ease up, leaving the patient open to infection.

"Lupus patients tend to have fewer B cells than normal, but their B cells are hyperactive and function in a very abnormal way," says Sanz. "The immune system is hyperactive but disorganized; it's over-reacting to some things but not enough to other things."

It was Looney's idea to target B cells to treat lupus. A great deal lot of traditional research had pointed to other immune cells known as T cells as the major culprit. But Looney and his team uncovered a more complicated process than had been imagined, where cooperation between B and T cells is at the core of the disease. The success with rituximab opens up a whole new vista - targeting B cells, reducing their numbers, and ridding the body of errant B cells - for treating the disease.

The Rochester team is now helping to design a much larger study of patients that may begin within the next year or so at multiple sites around the country, including Rochester.

"Our basic knowledge of lupus has been increasing exponentially during the past few years, but there have been few new treatments," says Sanz, who heads the University's NIH-funded Autoimmunity Center of Excellence, where lupus is one of three diseases studied by two dozen researchers. "Prognosis has improved because of better support therapies like blood pressure control, anti-cholesterol drugs, dialysis and antibiotics, but this is the first really new and targeted therapy to come along in a long time."
-end-
Looney, Sanz, and rheumatologist Jennifer Anolik, M.D., Ph.D., run the University's lupus clinic at Strong Memorial Hospital, where about 800 patients who have symptoms of lupus are seen regularly. The clinic is one of 26 centers in the nation that make up the Lupus Clinical Trials Consortium, where patients have access to the latest experimental treatments.

The medication for the study was supplied by Genentech, Biogen Idec, and Roche, which make and market Rituxan, the brand name for rituximab. The study was also funded in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the Lupus Foundation of America.

In addition to Looney, Sanz, and Anolik, other authors of the paper are nurse Debbie Campbell; Raymond Felgar, M.D., Ph.D.; Faith Young, M.D.; Lois Arend, M.D., Ph.D., and James Sloand, M.D., all of the University of Rochester; and Joseph Rosenblatt, M.D., of the University of Miami, formerly of Rochester.

University of Rochester Medical Center

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