For years, millions of Americans with arthritis have been caught in a troublesome trap.
If they don’t take medication, they often suffer severe pain and life-wrecking disability. Yet if they do, they risk worrisome side effects. Some drugs, like methotrexate and high dose prednisone, can suppress the immune system. Others — notably painkillers like aspirin, Anacin, Advil, Motrin IB and others — can cause stomach ulcers and bleeding.
Every year, in fact, more than 60,000 Americans are hospitalized with complications from prescription and over-the-counter painkillers known as NSAIDS (pronounced EN-SAIDS), or non-steroidal anti-inflammatory drugs; thousands die.
But this grim picture could soon change dramatically, thanks to four drugs that are expected to be in drugstores soon: Arava, Enbrel, Celebra and Vioxx.
“In the last two decades, there hasn’t been any time like this, with four new drugs that appear to be very effective and very safe,” says Dr. Arthur Weaver, director of clinical research at the Arthritis Center of Nebraska and past president of the American College of Rheumatology.
These are “very exciting times,” adds Dr. Michael Schiff, medical director of clinical research at the Denver Arthritis Clinic, who calls two of the drugs “breakthrough medications.”
“Breakthrough” is a word researchers don’t use lightly, but it may be justified — though longterm side effects are still unknown.
Take Enbrel, the first arthritis drug in a relatively new class of compounds called biological response modifiers, which rev up or damp down specific components of the immune system.
Less than two weeks ago, an FDA advisory panel unanimously recommended approval of Enbrel for people with rheumatoid arthritis who have not improved on other treatments. The Food and Drug Administration usually follows the recommendations of its panels, and a decision is expected soon.
In rheumatoid arthritis, which affects 2 million Americans, an unknown factor — perhaps a virus — causes the immune system in genetically susceptible people to attack the synovium, a layer of cells that lines the joints. The result is chronic inflammation, pain, stiffness and joint destruction.
An additional 20 million Americans suffer from osteoarthritis, caused by wear and tear on joints.
A major culprit in many cases of arthritis is a natural substance called TNF-alpha, or tumor necrosis factor, that enters cells through a special receptor and helps promote inflammation. Enbrel, an injectable drug made by Immunex Corp. that has been studied in more than 1,000 patients, acts as a decoy receptor, mopping up TNF before it can enter cells, says Dr. Lee S. Simon, a rheumatologist at Beth Israel Deaconess Medical Center in Boston.
(Another drug that blocks TNF, Remicade, has already been approved by the FDA — for Crohn’s disease. But that means doctors can prescribe it for other problems, and evidence suggests it can help people with rheumatoid arthritis.)
Even more exciting, says Dr. Michael Weinblatt, director of clinical rheumatology at Brigham and Women’s Hospital, is Arava, made by Hoechst Marion Roussel. Following studies in 2,200 patients, it was approved by the FDA on Sept. 11.
Like the drug methotrexate, Arava actually modifies disease progression in rheumatoid arthritis. Taken orally, it inhibits pyrimidine, a building block of DNA. This affects immune cells called T cells, reducing inflammation in the synovium.
Promising though they are, nobody knows yet what the longterm side effects of Enbrel and Arava might be, warns Dr. Doyt Conn, medical director of the Atlanta-based Arthritis Foundation.
And then there are the new “super aspirin” drugs called Cox-2 inhibitors: Celebra, by Searle, and Vioxx, by Merck, as well as others in the pipeline. In late August, the FDA agreed to a fast-track review of Celebra, which means it could be approved in early 1999; Merck plans to file for approval late this year.
Unlike Enbrel and Arava, the Cox-2 inhibitors are aimed primarily at people with osteoarthritis, though they may be used, with other drugs, for rheumatoid arthritis, too.
In arthritis, it’s not just TNF that drives inflammation, but often other natural chemicals as well, notably the prostaglandins, which trigger those all-too-familiar symptoms: pain, swelling, redness and heat.
Prostaglandins are made in cells under the direction of an enzyme called Cox, or cyclooxygenase, and many painkillers work by blocking this enzyme. But it turns out that there is not just one Cox enzyme, as scientists used to think, but at least two. Cox-1 releases “good” prostaglandins that protect the stomach and kidneys. Cox-2, made primarily by cells at the site of an inflammation, releases “bad” prostaglandins that further drive inflammation.
The reason NSAIDs are a mixed blessing is that they work against both Cox enzymes, blocking both the bad and the good prostaglandins.
The new Cox-2 drugs block only the bad prostaglandins, which means they “hold the promise of being as effective as the old NSAIDs in managing pain and inflammation without the same side effects,” says Conn of the Arthritis Foundation.
So far, Celebra has been studied in trials of nearly 13,000 people. One of them was Rich Dillon, a 53-year old firefighter from Lincoln, Neb. who gave up long games of raquetball because of osteoarthritis in his knees. Celebra, he says, “makes a great difference,” and he can play short games again.
It appears to be living up to its billing as a stomach-friendly painkiller. In one study, notes Simon of Beth Israel, no one taking Celebra (a twice-a-day pill) developed an ulcer, but 19 percent of those taking a prescription form of naproxen, an NSAID, did.
Vioxx, a once-a-day pill tested so far in studies involving 9,000 people worldwide, appears to be even more potent than Celebra at blocking Cox-2, though it may also increase edema, or swelling.
In addition to these drugs, the FDA next month is expected to consider expanded use of a blood-filtering device called Prosorba that removes antibodies that contribute to inflammation.
Financially, the combined impact of the new arthritis drugs is expected to be “huge,” says Maryann Quinn, an industry analyst at BT Alex. Brown, Inc. in New York. Celebra alone could do $500 million in sales in 1999, she says.
The drugs will be expensive — an estimated $3,000 to $4,000 a year for Arava, $6,000 to $8,000 a year for Enbrel, for instance.
And the Cox-2 drugs in particular will help treat symptoms, but probably won’t alter the underlying course of disease.
Still, this slew of new drugs could finally bring safe relief to millions. It’s been years, says Weinblatt of the Brigham, “since we’ve had such promising therapies.”
SIDEBAR:
Help for Alzheimer’s?
It’s not just arthritis sufferers who may benefit from the new Cox-2 inhibitor drugs, but people with cancer and Alzheimer’s disease as well.
In recent years, 14 studies have shown that NSAIDs — drugs like Anacin, Advil, Nuprin, and others — can slow progression of Alzheimer’s disease by 30 to 50 percent, says Dr. Clifford Saper, chief of neurology at Beth Israel Deaconess Medical Center in Boston.
That’s probably because inflammation, well-known as a culprit in arthritis, plays a role in Alzheimer’s, too. As parts of the brain become clogged with deposits of a protein called beta-amyloid, inflammation often develops around these sites.
The NSAIDs probably slow progression of Alzheimer’s by blocking so-called Cox enzymes, which promote inflammation. But the NSAIDs have a major drawback: They often cause ulcers by causing changes in the stomach lining. By contrast, the new Cox-2 drugs block inflammation just as well as the old NSAIDs, but are far gentler on the stomach.
With colleagues at other centers, Saper is testing several hundred people with mild Alzheimer’s, giving some Celebra, a new Cox-2 inhibitor, and others a dummy pill. After six months, researchers will re-test all participants to see whether Celebra slows progression of the dementia.
The Cox-2 inhibitors may also lower the incidence of colon cancer, says Dr. Jerome Groopman, chief of experimental medicine at Beth Israel. Several studies in the last decade have shown that NSAIDs can reduce the risk of colon cancer by 50 percent.
Colon cancer often arises after a two-step process. In the first step, a gene mutation leads to high levels of the Cox-2 enxyme, which results in growths called polyps. Another mutation then causes the polyps to become cancerous.
In mice, Celebra seems to block formation of polyps, thus stopping cancer before it starts. Studies are underway to see if the drug can prevent colon cancer in people at high risk. Someday, “we may be able to exploit this for people with already-established tumors,” Groopman says.
For more information, you may call the Arthritis Foundation at 1-800-283-7800, or contact them on the Net at www.arthritis.org.