Photographs by S. Peter Lopez

Issue: Summer 2003

Getting a Grip on Arthritis

A boring disease of old age? Hardly. As an avalanche of new knowledge blankets the landscape of rheumatology and orthopedics, USC’s Keck School is emerging as a major center for arthritis research and treatment.

By Carl Marziali

If not for the fear of being treated like a victim, Mabel Leon might be tempted to wear T-shirts with messages like, “I’m young, I have arthritis, and it really hurts.” That might stop the nasty looks thrown her way when she parks in a handicap space and walks into a store.

The problem is, Leon likes to dress well and wear makeup and not act like a victim. This, she says, helps her to forget that she is “full of metal” from a hip and shoulder replacement, not to mention full of drugs that tame her symptoms enough to let her appear healthy. Aging celebrities may subject themselves to Botox injections to remove wrinkles; young rheumatoid arthritis patients are often subjected to biologic agent injections, steroids, anti-inflammatory pills and syrupy antacids to save their stomach linings.

Mabel Leon has been treated at USC for the past several years, and she reports incredible progress from the darkest days, when she had to use a wheelchair. Still, there is no cure on the horizon. She has had rheumatoid arthritis for 34 years, since her diagnosis at age two.

“I’m waiting for the day to have just one day without pain,” she says.

Despite the folklore surrounding it, arthritis cannot be cured with exotic herbs, or copper bracelets or penetrating ointments. It is hard to say exactly what arthritis is, since it includes more than 100 conditions. The word means “inflammation of the joints,” a symptom observed in everything from age-related osteoarthritis to early disablers like rheumatoid arthritis, Crohn’s disease and lupus. Even some heart problems can show symptoms of joint inflammation.

Contrary to stereotypes, the following are true: arthritis does not strike only old people, and its pain is not the niggling type of the blister, spasm and wart variety. Osteoarthritis and especially rheumatoid arthritis are proving to be diseases of amazing complexity and subtlety, making their study and treatment an exciting challenge for physicians.

What a change from 10 or 15 years ago, when the entire specialty of rheumatology was in danger of suffering the ultimate indignity: demotion to general medicine. Arthritis is a chronic untreatable nuisance, the thinking went, and ambitious young doctors should look for more interesting specialties. Since then, rheumatology has made amazing progress, and medical students are no longer embarrassed to profess an interest in arthritis.

It is hard to grasp the significance of this progress, though, without understanding the seriousness of the disease.


USC rheumatologist Rodanthi Kitridou is both rheumatoid arthritis researcher and rheumatoid arthritis patient.

Arthritis today is about where senility was before it got an intimidating name (Alzheimer’s disease) and a celebrity victim (President Reagan), and before the public realized that, yes, people can die from it. Maybe the debilitating nature of rheumatoid arthritis would be taken more seriously if it were called “inflamed body disease.” And as for celebrity victims, there is the late actor James Coburn, who reportedly died from a massive heart attack. What was not reported was that, as a rheumatoid arthritis sufferer, Coburn had a high risk of heart failure.

On the other hand, common arthritis, known clinically as osteoarthritis, has never killed anyone. But you might not think of it as a boring disease if you couldn’t walk to the kitchen. And with Americans getting older and fatter and more sedentary, more of us are likely to experience the “train to pain” of arthritis, in the words of one orthopedic surgeon.

If anyone could ignore the pain of arthritis, it should be Edward Powers. As a World War II prisoner of war in the Philippines, Powers earned a rifle butt to the face for an insulting remark about a Japanese officer. The blow caved in his cheekbone and eye socket.

The nurses in the POW camp persuaded the Japanese to let Powers be treated by an American doctor in Manila. The doctor agreed to fix the fractures, but he had no anesthetic. With his head strapped to the table, Powers remembers watching as the doctor reached in with a hook to pull out the cheekbone.

“I remember him snapping it back in place and then I passed out,” he says. “Your pain is such that your body cuts you off.”

Powers describes himself as someone with a high tolerance for pain. A star 800-meter runner on the USC track team in the late ’30s, he has run all his life, and has had both his knees replaced for osteoarthritis, one twice. After his latest operation, last January at USC, he went through therapy without painkillers.

So how does he handle what some call “the minor aches and pains” of arthritis?

“You want to go hide sometimes. You don’t want to be with people,” he says. “It’s a very powerful, immobilizing affliction. You wake up in the morning and instead of [thinking], ‘Gung ho, I feel rested,’ you don’t. You feel very fatigued from it. It affects your personality. You’re not yourself. You don’t tolerate things that go wrong.”

And, he adds, “my experience with arthritis isn’t as painful or as difficult as many others.” At least the pain in his hands responds to COX-2 inhibitors, a class of anti-inflammatories.

Like Mabel Leon, Edward Powers finds that his feelings are hard to share with healthy people.

“You say, ‘Boy, my arthritis is acting up,’ and they’ll say, ‘Oh, yeah.’ I think they have sympathy for it, but they don’t understand it.”

The public should know better. About 16 million people in the U.S. suffer from osteoarthritis. The number is expected to rise to between 40 and 75 million by 2020. As baby boomers age and put on weight, more will discover the throbbing, radiating pain of arthritic knees, hands and hips.

Rheumatoid arthritis is less common. On the other hand, rheumatoid patients are the youngest at the time of onset of all patients in internal medicine. So while rheumatoid arthritis affects less than 2 percent of the population, those who get it must live with it for a long time. Measured in person-years, rheumatoid arthritis is a plague.

The immediate cause of joint damage appears to be the same for osteoarthritis and rheumatoid arthritis. Special cartilage cells known as chondrocytes become diseased and react by releasing harmful chemicals called metalloproteinases. These eat away at the bone and cartilage, leading to painful bone-on-bone wear and other problems. For example, Mabel Leon’s wrists fused naturally – or unnaturally – as a result of rheumatoid arthritis, leaving her with little hand and finger dexterity.


Rheumatologist Daniel Arkfeld examines patient Mabel Leon’s wrists. Her joints spontaneously fused due to rheumatoid arthritis.

The difference between the two diseases becomes clear one step higher on the cause-and-effect ladder. In osteoarthritis, damage to the chondrocytes seems to happen as a result of wear and tear in the joints, possibly combined with some degree of genetic predisposition. For this reason, osteoarthritis is considered a non-inflammatory disease. Inflammation does not cause the joint wear, though joints may become inflamed at a later stage.

In rheumatoid arthritis, the immune system goes haywire. Immune cells called lymphocytes turn against the body for unknown reasons – stress, genes and infectious agents have all been suggested. The lymphocytes release cytokines, proteins that cause inflammation. The lymphocytes also induce other cells called macrophages to release their own cytokines. The inflammation can be sudden and massive or slow and subdued, depending on the virulence of the disease. The first symptom is a swelling of the joints, followed by bone and cartilage damage over two to three years as cytokines attack the chondrocytes. In time, joints can become deformed and useless.

Rheumatoid inflammation is not limited to the joints. Lymphocytes can also target the heart muscles, lung lining and blood vessels. Complications can be life-threatening and include heart failure, stroke and massive hemorrhage.

Because the immune system attacks its own host, rheumatoid arthritis is known as an autoimmune disorder. Other such diseases, including lupus and Crohn’s, also can cause rheumatoid arthritis.

Two other diseases – ankylosing spondylitis, a rare arthritis of the spine, and traumatic arthritis, a byproduct of injury – are also part of the arthritis universe.

At the Keck School of Medicine of USC, rheumatologists and orthopedic surgeons have created a major center for arthritis research and treatment. The Division of Rheumatology and Immunology ranks among the top 20 rheumatology programs in the country, according to U.S. News & World Report. Faculty, residents and fellows all benefit from the wide diversity of patients and conditions seen in the clinics of the Los Angeles County+USC Medical Center.

USC is known for its strength in “bench to bedside” medicine, and most of its arthritis specialists conduct research while maintaining a private practice and serving regularly in LAC+USC clinics.

Thomas Vangsness Jr., associate professor of orthopedic surgery and chief of sports medicine, is working on extracting the body’s natural inflammation-blocking protein for injection into problem joints.

Glenn Ehresmann, associate professor of medicine in rheumatology and immunology, has been involved in drug trials and has studied the relationship between arthritis and HIV/AIDS: a virus in goats that causes arthritis also gives the animals protection against HIV.

William Stohl, professor of medicine in rheumatology and immunology, was one of the first to study B-Lymphocyte Stimulator (BLyS), a cytokine that acts on immune cells to stimulate antibody production. When those cells begin to produce harmful autoantibodies, it may be possible to curtail their production by reducing BLyS counts. Stohl just completed a phase I clinical trial of a BLyS reduction agent, or BLyS antagonist. The results are promising enough to warrant further trials with lupus patients, he says, and possibly with rheumatoid arthritis patients as well.

Daniel Arkfeld, assistant professor of medicine in rheumatology and immunology, just finished a five-year trial of a powerful anti-rheumatoid “biologic agent.” In a collaboration with other researchers, Arkfeld also found unexpected variations in patients’ genes associated with rheumatoid arthritis.

Arkfeld remembers a time when it was hard to say “arthritis research” with a straight face. He recalls the gibes he endured after completing his rheumatology training in the late ’80s.

“Are you going to give aspirin this week or Motrin?” the other doctors would ask.

These days, USC gets 50 to 100 applications for two rheumatology fellowship slots.

“It’s really changed from the fact that it’s this whole ‘just aging and degeneration [disease]’ to a very complex autoimmune, immunological process,” Arkfeld says. “It’s fascinating. The mechanisms – we’re just starting to understand them. It’s really become a very dynamic field.

“There was actually talk about eliminating rheumatology as a specialty in the early ’90s,” he adds, “because they figured a general doctor can handle it as well as us. We couldn’t really treat people very well. But now we can treat people, we can actually reverse their arthritis, we can prevent deformities. If we catch people early, we can prevent a lot of damage.”

It was biologic agents that saved rheumatology. The new drugs are the penicillin of arthritis. The best ones to date work by soaking up tumor necrosis factor-alpha, a key cytokine involved in inflammation. Other drugs in the pipeline target different cytokines contributing to inflammation and chondrocyte damage.

Until the mid-’90s, rheumatoid patients really did start with aspirin or Motrin, which relieve pain but do nothing to slow the course of the disease. An anti-malarial drug, hydroxychloroquine, achieved moderate relief in patients with mild symptoms, as did gold compounds.

Rheumatologists measure response rate on a scale developed by the American College of Rheumatology: ACR 20 means that the patient experienced a 20 percent reduction in symptoms; ACR 50 means a 50 percent reduction, and so forth. Before biologics, the most aggressive drug available achieved ACR 50 in some patients. Unfortunately that drug – methotrexate – worked by chemotherapy, killing large numbers of good cells along with the bad ones. Methotrexate is still prescribed, but the side effects are significant.

With biologic agents, 30 percent of rheumatoid patients achieve ACR 70 and remain at that level without major side effects, says Ehresmann. About 40 percent of patients reach at least ACR 50, and 70 percent get to at least ACR 20. In the imperfect world of medicine, this is a huge leap forward.

“They [biologics] are becoming just a remarkable therapy for rheumatoid patients to change the course of the disease,” says Ehresmann. “Most inflammatory arthritis happens to young people. Rheumatologists get their thrill out of seeing somebody who was very, very impaired be restored to an active life.”

Biologic agents work so well that Ehresmann has encountered a perverse consequence: patients who experience dramatic improvement are sometimes less enthusiastic than the doctors who treat them. He tells the story of a young baseball enthusiast who was on multiple drugs for rheumatoid arthritis, with severe side effects and highly impaired mobility. The patient was able to replace all the drugs with a single biologic agent, gaining dramatically in mobility and experiencing far fewer side effects.

Thrilled at this triumph, Ehresmann asked the patient one day how he was doing.

“I’m OK,” said the young man, “but I still can’t pitch.”

What about the patients who do not respond well to the new drugs? Since each biologic targets a different mechanism, success may be a matter of trial and error. For others, the only option is to wait for the next drug.

Rodanthi Kitridou, professor of medicine in rheumatology, is still waiting – both for her patients and herself. She is in the group of rheumatoid arthritis patients who reach less than ACR 50 when treated with biologics. Such patients, as she has discovered first-hand, often require more and more prescriptions just to keep the disease in check.

“Rheumatoid arthritis causes what I call dosage creep and number-of-medications creep,” she says.

Biologics were not around when Kitridou’s disease broke out on – she remembers the date – August 1, 1995. That was when “everything blew up.” Although she has sustained joint damage, especially in her feet and ankles, she believes that if biologic agents had not arrived a couple of years later, she would be in a wheelchair.

Nevertheless, Kitridou is not entirely satisfied with biologics – not only as a patient, but also as a scientist.

“We are aiming now at the mechanisms of the disease. We don’t know what the etiology, what the cause is. The immune system does attack the body, but why does it attack the body?

“We are shooting at mediators of inflammation. The biologic treatments we have target two particular mediators of inflammation: tumor necrosis-alpha and interleukin-1. Again, we are trying to attack mechanisms rather than etiology, and to me this is shooting in the dark. Well, in the twilight, not entirely in the dark.”

Kitridou stresses that drugs are not the only way of coping with rheumatoid arthritis. Regular activity is important, as are patient and family education. And never underestimate the importance of mind and spirit.

“Human beings are – what would we say – indomitable? Irrepressible?” she says. “My respect for people has increased manifold ever since I studied rheumatology and practiced rheumatology, because the coping mechanisms and the grandness of the human being are amazing. I’m not talking about myself, I’m talking about my patients. It’s amazing what they can do and turn around and support me.

“On an emotional basis, well, what can I say? Do I thank God for giving it to me, or whatever gave it to me? No. Am I angry to the point of hating people? No.

“It’s a very common illness. I try to have as healthy an attitude about it as possible. I don’t want it to totally ruin my life and take away the enjoyment of a concert or dinner with a friend.”

Rheumatoid arthritis can be especially hard on younger people, she says, many of whom are not about to accept the concept of a chronic disease. These patients, she warns, are particularly susceptible to “alternative” remedies which are often useless and sometimes dangerous.

Mabel Leon learned that lesson the hard way. Desperate to overcome the disease, she visited a clinic in Mexico as a teenager. She was among hundreds of rheumatoid patients lured by reports of miraculous improvement from treatment with exotic Swedish herbs. Leon discovered that the reports were right on. She did improve, dramatically.

“I felt so great I thought, ‘Gosh, why doesn’t the FDA approve this?’”

The reason soon became clear. She gained 50 pounds, developed severe thyroid problems, and broke her leg in a trivial fall. The herbs turned out to contain enormous doses of steroids, and the clinic eventually was exposed by investigative reporters.

Now Leon really does feel better, thanks to a more realistic course of treatment. Hip and shoulder replacements at USC have relieved many of her symptoms. The pain in her right knee is now bad enough that she is ready for another replacement, even knowing the weeks of agonizing recovery that lie ahead.

The closest thing to a miracle herb for Leon has been a new biologic agent. As Arkfeld’s patient, Leon had access to a biologic so hard to obtain that some physicians call it a “lottery drug.”

“It’s wonderful. It’s incredible,” she says. “It has brought my inflammation quite a bit down. It’s at levels I haven’t seen since my early 20s. I am so much better. I am independent.”

Physicians who treat osteoarthritis are taking notice. Vangsness and Ehresmann call biologic agents the next frontier in the treatment of osteoarthritis. The cytokines involved in osteoarthritis differ slightly from those targeted by rheumatoid arthritis biologic agents, but the principle is the same.

“I feel real encouraged” about biologics’ potential, says Ehresmann.

In the meantime, osteoarthritis patients have a growing range of options beyond routine anti-inflammatories. For mild cases, the over-the-counter supplements glucosamine and chondroitin have been shown to work, says Vangsness. Hyaluronic acid injections provide relief lasting several months after a course of three to five injections. Knee replacements are becoming more durable and sophisticated: surgeons now can replace only one part of the knee, with less trauma to the joint. Another option is a synthetic spacer to replace torn meniscus, the spongy disc of cartilage that cushions impact inside the knee.

Some patients are even getting cartilage transplants, either from cadavers or, incredibly, from cells harvested from the patient’s own body and grown into replacement cartilage by a specialized biotech company.

Andrea Long ’00 is one of them. She graduated from USC with a bachelor’s in communication and two cartilage transplants, one synthetic and one from a cadaver. An arthritis sufferer, Long injured her right knee repeatedly playing sports (“It was definitely odd to be diagnosed with arthritis at the age of 21,” she says).

Since her cartilage transplants four years ago, Long has had no pain in her knee save for occasional stiffness. She walks, runs and works out. “I would say it’s at 90 percent,” she says. She is planning a skiing trip.

Edward Powers, the ’30s track star with two knee replacements, is planning a trip of his own. He placed fourth in the 800 meters at the National Senior Olympics in Orlando, Florida, in 1999. This year, the Nationals will be held in Virginia at the end of May, and Powers intends to be there.

Seeing as he already knows how to run with knee replacements – it’s no different, he says – Powers wants to try a new move in Virginia: stepping onto the podium.


The ABCs of Arthritis
A decoder to the doctor’s jargon

Arthritis: a Greek word meaning “inflammation of the joints.”

Autoantibodies: immune cells that, instead of defending against viruses and other intruders, attack the body itself.

Autoimmune disorder: a disease in which the immune system attacks its host body. It includes rheumatoid arthritis, lupus, Crohn’s disease and others.

Biologic agents: a new class of drugs for rheumatoid arthritis that act by blocking the proteins that lead to joint inflammation.

Chondrocytes: specialized cartilage cells that release harmful chemicals when attacked. They are involved in joint damage for both rheumatoid arthritis and osteoarthritis.

COX-2 inhibitors: a class of nonsteroidal anti-inflammatories that block the enzyme cyclooxygenase, which can trigger the release of inflammation-causing prostaglandins.

Cytokines: a class of proteins that, in the case of arthritis, cause joints to become inflamed.

Macrophages: a white blood cell that normally attacks bacteria. In rheumatoid arthritis, autoimmune cells cause macrophages to release harmful cytokines that cause joint inflammation.

Metalloproteinases: chemicals that eat away at the bone and cartilage. Released by damaged chondrocytes in the cartilage.

Lymphocytes: a class of immune cells.

Osteoarthritis: non-inflammatory arthritis caused by wear and tear in the joint and progressive damage to cartilage and bone.

Rheumatoid arthritis: inflammatory arthritis caused by the body’s own immune system.

Rheumatology: the study of diseases that affect the joints.