Researchers have begun to use newly available natural chemicals, normally found in the body, to regulate the immune system in an attempt to limit the damage and pain of rheumatoid arthritis.
Although interferons, interleukins and monoclonal antibodies, all substances derived from the body's immune system, have been tested as treatments for cancer, recent research indicates they may also help control rheumatoid arthritis and other autoimmune diseases.
An autoimmune disease occurs when the body's immunologic defenses begin attacking normal tissue. Besides arthritis, examples include multiple sclerosis, systemic lupus erythematosus, some forms of kidney disease and intestinal disorders such as Crohn's disease.
A small number of arthritis patients in Kansas underwent brief but successful treatment with gamma interferon last summer, and a group of multiple sclerosis patients in Boston receive antibody therapy to temper their disease-producing immune system. By the end of this year a few patients with rheumatoid arthritis will start treatment with another experimental drug, interleukin-2, the compound that grabbed attention late last year as a promising cancer therapy.
"We are entering an era when immunomodulatory agents will be readily available, providing us with the potential to exert major effects on human immunology and human disease," said Dr. Alfred D. Steinberg, a rheumatologist with the National Institutes of Health.
"The traditional approach for treating rheumatoid arthritis and other autoimmune diseases is to knock the hell out of the patient's immune response," said San Antonio investigator Dr. Norman Talal. "But this may not be the best approach. We are now taking our first baby steps using immunopharmacology."
Doctors realized years ago that the human immune system, a complex arsenal of numerous types of cells and cellular secretions, is by far the best defense against disease and cancer. The challenge to researchers was to marshal and direct a patient's immune response when it was not adequately fighting disease on its own.
Genetic engineering produces the natural chemicals that clinicians need to manipulate a patient's immune system. These immunologic controls were developed primarily with cancer and acquired immune deficiency syndrome (AIDS) in mind, but they can also be used to manipulate the immune system when immunity itself is causing disease.
Rheumatoid arthritis, for example, which afflicts more than 2 million Americans, is an immune response running amok inside a bone joint. This festering inflammation unleashes cells and enzymes that eat away at the joint from within, destroying the tissue and causing great pain.
Rheumatologists administer a series of drugs to arthritic individuals in an effort to find a regimen that controls the patient's autoimmune disease. Treatments that are effective for some do not work in others.
The typical list of treatments begins with aspirin and related drugs that can tone down immunity while also relieving pain. If these drugs prove inadequate, the physician goes on to other agents that dampen immunity, such as corticosteroids, gold compounds and methotrexate, a drug used to treat cancer. But more than half a million people in the United States have a form of rheumatoid arthritis that does not respond to any of these drugs.
"Rheumatoid arthritis is a disease of immune disregulation, and [restoring normal immune function] may be a potential treatment," said Talal, head of clinical immunology at the University of Texas Health Science Center in San Antonio. He plans to administer interleukin-2 to patients who have failed standard therapies in an effort to offset their immunologic imbalance.
At a December meeting of rheumatologists and immunologists in Salt Lake City, Talal reviewed the evidence that suggests patients with rheumatoid arthritis, "are impaired in their production of, and responsiveness to, interleukin-2," particularly within their affected joints. This deficiency appears to lessen the activity of "natural killer" immune cells in joints, which in turn leads to enhanced activity by antibody-releasing cells. The antibodies that these cells make play a major role in destroying the joints.
"If the interleukin-2 levels [in the joint] were increased, would it turn off the antibodies and restore an immunologic balance?" Talal asked. He hopes to soon find out, but he is proceeding cautiously because interleukin-2 has already earned a reputation as a drug with many toxic side effects.
Clinical studies using interleukin-2 to treat cancer showed that it can produce severe fever, chills and drastic drops in blood pressure, said Dr. Richard M. Pope, a rheumatologist from Northwestern University in Chicago. Pope also hopes to use interleukin-2 soon as an arthritis therapy.
"We must be very careful using interleukin-2 on rheumatoid arthritis," he said, "since we would be treating a patient who is not terminally ill with a drug that can kill." One advantage of arthritis therapy is that the interleukin-2 can be injected in small amounts directly into the diseased joint, Pope said. Such doses may avoid the side effects seen during cancer therapy, when high doses of the interleukin-2 were injected into the bloodstream. Another potential danger of interleukin-2 is that it may cause unexpected immunologic changes that only make the disorder worse. "Because rheumatoid arthritis is so complex a disease, it is unclear what the bottom-line effect of interleukin-2 will be," Pope said.
Gamma interferon presented investigators with less of a dilemma, since its side effects are much less severe than those of interleukin-2. But until last summer there was scant reason to think of using gamma interferon to treat rheumatoid arthritis.
"If you had polled 100 rheumatologists, they all would have predicted that gamma interferon would make their patients worse," says Dr. Seth Pinchus, a pediatric rheumatologist at the University of Utah.
But some patients with both arthritis and cancer received gamma interferon during a study of the compound's anticancer potential, and their arthritis improved, said Dr. John Schindler, director of clinical research for Biogen Research Corporation in Cambridge, Mass. This chance observation lured Biogen to sponsor a preliminary test of gamma interferon's potential for treating arthritis.
Last summer a clinician in Wichita, Kan., administered gamma interferon to 33 arthritis patients who had failed their previous therapies, Schindler told the Salt Lake City meeting. Each patient received a single injection of a small amount of interferon five days a week for four weeks.
Of the 30 patients who completed their regimen, 17 had a "significant improvement" in their disease, a reduction of at least 50 percent in the number of swollen or tender joints. Another eight patients had a 25 percent to 50 percent reduction in affected joints, Schindler reported. The side effects of interferon therapy -- fever, nausea and headache -- were well tolerated by the patients, he said. Three participants withdrew from the study for reasons unrelated to their therapy.
Meeting participants who heard this report cautioned that the study was flawed by the absence of a control group of similar patients who received no interferon. Biogen plans to repeat its study using control patients early this year. Nonetheless, many at the meeting were buoyed by the unexpected success of gamma interferon.
"The lesson from this study is that there is still much to learn about lymphokines compounds that regulate the immune system and rheumatoid arthritis," Pinchus said.
Another strategy for controlling rheumatoid arthritis involves using monoclonal antibodies that selectively inhibit a key component of the autoimmune disease process.
Monoclonal antibodies are laboratory-produced versions of natural antibodies used by the body to fend off infection. Certain kinds that appear capable of exerting just the necessary effect for arthritis control were described by many investigators in Salt Lake City, but scientists are still wary of using these antibodies on people. Like interleukin-2, monoclonal antibodies offer a therapy that is sound in theory, but researchers are reluctant to risk unexpected adverse reactions by using the treatment on people with a nonfatal disease.
This reluctance abates when researchers turn "We must be very careful using interleukin-2 on rheumatoid arthritis, since we would be treating a patient who is not terminally ill with a drug that can kill." -- Dr. Richard M. Pope, Northwestern University their attention to a disease like multiple sclerosis, an autoimmune disorder that causes a progressive deterioration of the nervous system leading to tremors, paralysis, mania and death. There are no effective treatments for MS.
Spurred by this bleak scenario for MS patients, physicians at Brigham and Women's Hospital in Boston began to treat MS with monoclonal antibodies last year. The antibodies are designed to attach to and inactivate certain types of immune cells -- T lymphocytes -- and thereby slow the patient's immune system and curtail the autoimmune disease. A total of 20 patients have received daily injections of the antibody for five to 10 days.
Although it is too early to judge if this therapy has halted the progression of MS, it is apparently causing no ill effects, said Dr. Howard Weiner, codirector of the hospital's neurologic disease center.
During the next few years clinicians developing immunotherapies will stumble and grope as they try to learn how these new treatments are best used on a variety of diseases. "Since we don't have a good idea of what the effects of immunomodulators will be in people, empiricism will have to guide us," Pinchus said. But investigators are confident that these powerful drugs will somehow be harnessed into better therapies.
Said NIH's Steinberg: "We are in the infancy of an era of treatment that is comparable to where antibiotics were during the 1940s."