New Drugs Attack Pain of Arthritis

Allene Goodman can remember the precise day her arthritis began taking control of her life.

On Aug. 3, 1987, Goodman, a medical transcriptionist, began to shiver uncontrollably, unable to warm her hands and feet. Then her feet began to swell. A trip to the nearest rheumatologist, 158 miles from her home in Caledonia, Miss., confirmed that she suffered from rheumatoid arthritis, and that day marked the beginning of a steady acceleration of her disease.

The worst part, she recalls, was the pain. “No one but God can understand the horror of what I experienced for several years,” she said. “My nightmares were present awake and asleep. I dreamed that my joints were being pulled apart by torturers and screamed aloud, awakening to find my joints . . . locked.”

But Goodman, 68, has found relief during clinical trials of a new drug called Enbrel, approved by the U.S. Food and Drug Administration last month.

It is one of four new types of drugs that are changing the face of arthritis research. Each of the four attacks the disease at a different stage of its progression, and most do not produce the side effects associated with conventional therapy.

None of the new approaches represents a cure, and most are substantially more expensive than existing treatments. But they offer relief for people in desperate need of it.

“This is about as exciting a time as we have ever had in rheumatology,” said Dr. Michael Weinblatt of Brigham and Womens Hospital in Boston.

“This is a tremendous time,” added Dr. Brian Butcher of the Arthritis Foundation. “We have gone from where we could not offer much hope to people to where we can diagnose, provide early treatment, and stop the progression of the disease.”

The new drugs primarily will benefit the 2.1 million Americans who suffer from rheumatoid arthritis, but also may help some of the 37 million who have osteoarthritis.

Osteoarthritis is caused by the general wear and tear of aging. In rheumatoid arthritis--a more serious form of the disease--the patient’s immune system goes awry, attacking the joints and causing inflammation and stiffness. Cartilage is destroyed, and joints often freeze, preventing patients from carrying out such routine tasks as getting out of bed or washing their hair. An estimated 40% of rheumatoid arthritis patients are unable to hold a job six years after diagnosis.

Existing drugs can be effective against arthritis but carry bothersome side effects. Most arthritis patients take so-called non-steroidal anti-inflammatory drugs, or NSAIDs, such as aspirin, acetaminophen and ibuprofen. NSAIDs reduce pain, fever and inflammation by blocking the production of prostaglandins, chemicals that mediate pain. But they can cause stomach irritation, bleeding ulcers and decreased kidney function.

About 13 million Americans take these NSAIDs regularly, but an estimated 76,000 of them are hospitalized every year for ulcers produced by the drugs and 7,600 die from them.

Patients with more severe forms of arthritis take steroids, which are better at reducing inflammation but cause more severe side effects, such as high blood pressure, weight gain, diabetes, bone loss, mood changes and susceptibility to infection.

The third class of drugs are the so-called disease modifying anti-rheumatic drugs, which interfere with the proliferation of white blood cells that mediate the immune attack. These drugs, such as methotrexate, gold salts and imuran, typically lessen symptoms rather than eliminate them.

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Perhaps the most promising of the new drugs are the so-called COX-2 inhibitors, which are expected to treat a variety of diseases beyond arthritis, such as angina pectoris and Alzheimer’s disease. Like NSAIDs, these so-called super-aspirins ease pain and inflammation by blocking the release of prostaglandins, but they are more selective in their action.

Dr. Harvey R. Herschman of UCLA and researchers at Brigham Young University and the University of Rochester discovered that aspirin and other NSAIDs block the action of two enzymes, cyclooxygenase-1 and cyclooxygenase-2. Blocking COX-2 inhibits the production of prostaglandins, but blocking COX-1 inhibits an enzyme that protects the kidneys and the lining of the stomach.

Drug companies seized on this discovery, designing drugs that inhibit COX-2 but leave COX-1 largely untouched. Clinical trials showed that these drugs--Celebrex, developed by Searle, and Vioxx, developed by Merck & Co.--are as effective as NSAIDs at relieving pain, but have far fewer side effects.

“It’s an advance in safety, not an advance in effectiveness,” said Dr. David Fox of the University of Michigan.

An FDA advisory committee recommended this month that Celebrex be approved, and Vioxx is expected to be submitted to the panel in the next six months. Celebrex is taken orally twice a day, Vioxx once, and they are expected to cost $2 to $4 per day.

The Enbrel that patient Goodman takes binds to a naturally occurring chemical called tumor necrosis factor. The factor is released by white blood cells as they multiply to attack joints, and it stimulates the production of more white cells, escalating the arthritic process.

Trials in more than 1,000 patients showed that Enbrel reduced pain and swelling in 62% of patients, usually within the first two weeks of treatment. Side effects were rare, primarily mild reactions at the injection site.

Enbrel, marketed by Wyeth-Ayerst, is taken by injection twice weekly and is expected to cost as much as $10,000 per year. Centocor has a similar drug, called Remicade, that is already approved for treating Crohn’s disease and may soon be approved for arthritis. Other drugs are in earlier stages of development.

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The third new drug is Arava, which blocks the proliferation of immune cells that attack the joints. Clinical trials showed that Arava, manufactured by Hoechst Marion Roussel, is as effective as methotrexate at reducing pain and inflammation and slowing the progression of the disease, but has fewer side effects such as diarrhea and rashes.

Arava has been approved by the FDA and is taken orally once a day. It costs about $240 per month.

The final new treatment is expected to be reserved for the most severe 10% of rheumatoid arthritis patients. The Prosorba column, a device manufactured by Cypress Bioscience Inc. of San Diego, is targeted at antibodies that attack the joints.

The device works something like a dialysis machine. Once a week, the patient comes in and blood is drawn out through one arm. Blood cells are separated out and the remaining plasma is circulated through a device that removes the antibodies. The plasma and blood cells are then reunited and infused back into the patient.

Clinical trials showed that 12 weeks of such treatments allowed patients--all of whom were severely ill at the beginning--to go without drugs for as long as 75 weeks, according to Dr. Jay Kranzler, Cypress president. The clinical trial was halted a year early because the results were so good, he said.

Prosorba was approved by an FDA advisory committee in October. Final approval is expected soon.

As for Allene Goodman, she is feeling much better these days. She still has pain, but has been able to resume many daily activities, such as brushing her teeth and ironing her husband’s clothes. She is even able to begin writing stories about her early life for her grandchildren so that they will know what the Depression was like.

“What I want so badly,” she added, “is future research. They need to develop a sequel to Engrel or modify it so the next generation has a cure.”

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New Weapons to Fight Arthritis Pain

Rheumatoid arthritis strikes joints, causing pain, swelling and deformity. Four new treatment attack the problem in different ways.

The normal course of arthritis

1. Inappropriate signal triggers immune cells to multiply.

2. The multiplying cells produce tumor necrosis fac-tor (TNF), which signals for more.

3. The cells also produce prosta-glandins, which cause pain and swelling in the affected tissues.

4. Antibodies attack tissue at the joint.

New treatments

A) Arava and methotrexate inhibit multiplication of immune cells.

B) Enbrel binds to and removes TNF.

C) COX-2 inhibitors block binding of prostaglandins.

D) Prosorba removes antibodies from blood.

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Sources: Arthritis Foundation