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OneThousandOne represents the amount of time, verbally, that it takes to count to one second. In this one second of time, a great thing happened at Nebraska Medicine. In fact, several great things probably happened. A patient was cured, a researcher found the missing link, a nurse treated an injury, a doctor comforted a family or maybe a child just smiled.
MOMENTS IN MEDICINE
Fall | Winter 2010

Brighter Pathways

In his mid-50s, Jeff does everything and more than most men his age.

An avid bicyclist, he averages 100 miles of cycling a week in the summer. He’s completed the Bike Ride Across Nebraska (BRAN), a seven-day, 500-mile trek across Nebraska, five times in the last six years. And when he’s not bicycling or working, you will likely find him working on a new home remodeling project or gardening.

What makes Jeff’s case especially amazing is that he was diagnosed with rheumatoid arthritis nearly 10 years ago, a potentially crippling disease that attacks the small joints and eventually the entire body, causing bone erosion, joint deformity and chronic pain and fatigue.

Jeff is one of the fortunate ones as his disease could have taken him down a much different path. He got the right treatment at the right time to essentially halt the disease in its tracks. Thanks to the rheumatology specialists at The Nebraska Medical Center, the only evidence of his disease is the daily meds he must take to eliminate potential pain and swelling and keep the disease in remission.

“If I wasn’t taking drugs, I’d tell you that I don’t have the disease,” says Jeff. “I’d tell you that I am a normal 50-something guy, working hard to stay in shape and that I plan to live a long time.”

“Jeff is a perfect example of what we can do today to modify the disease process if the disease is diagnosed early and the patient is put on the proper therapies right away,” says James O’Dell, MD, a rheumatologist at The Nebraska Medical Center who has played a significant role in pioneering new and better treatment modalities for rheumatoid arthritis that have become the standard nationally and worldwide.

James O'Dell, MD (left) and
Lynell Klassen, MD

Dr. O’Dell is also division chief for the Division of Rheumatology and Immunology at the University of Nebraska Medical Center (UNMC) and a professor of Internal Medicine. He has authored many articles on treatment standards for rheumatoid arthritis in medical textbooks that are used by doctors nationally and worldwide. These include: the May 2004 issue of the New England Journal of Medicine; the two most recent editions of Cecil Medicine, a major textbook used by internists; the newest edition of Kelley’s Textbook of Rheumatology that will be published in 2012; the Annuals of Rheumatic Disease, one of the most widely used sources on rheumatoid arthritis in the world; and UpToDate, an online medical education program.

“Dr. O’Dell’s leadership in our rheumatoid arthritis program has elevated its status to an internationally-renown program that has been responsible for many of the standards that are used to treat the disease worldwide,” says Lynell Klassen, MD, a rheumatologist and chairman of the Department of Internal Medicine at UNMC. Dr. Klassen established the Division of Rheumatology and Immunology at UNMC in 1982 and was chief of the division until 1990 when Dr. O’Dell became chief.

While rheumatoid arthritis affects just 1 percent of the population, it is one of the most serious forms of arthritis. The disease usually starts in the hands and feet and progresses to the elbows, shoulders, neck, knees, hips and ankles. However, the disease affects not only the joints, but it can attack the entire body and become severely debilitating. It can cause fever, weight loss, anemia and deterioration of the muscles, joints, eyes and lungs. It is also recognized as a significant risk factor for coronary artery disease and stroke.

Rheumatoid arthritis is an autoimmune disease, which means the body mistakenly attacks the body’s own tissues. As the disease progresses, the immune system attacks the synovium, the lining of the membranes that surrounds the joints, causing the joints to become inflamed and fill with fluid. The resulting inflammation thickens the synovium, which eventually invades and destroys the cartilage and bone within the joint. The tendons and ligaments that hold the joints together also weaken and become stretched, causing abnormalities and deformities. Once joint damage has occurred, it is permanent.

Over the last 20 years, medical advances have dramatically changed the outcomes for many patients with rheumatoid arthritis. The Rheumatoid Arthritis Investigational Network, (RAIN), which was founded in 1989 by Dr. O’Dell to find new and better ways to treat the disease, has been a leading catalyst for these advances.

“By involving private practice doctors in the design of these studies, we are able to create studies that help answer questions that are clinically relevant to the patients they treat every day.”
James O'Dell, MD

Based at UNMC, the network includes approximately 50 rheumatologists and nurse-study coordinators located throughout Nebraska, North Dakota, South Dakota, Minnesota, Pennsylvania and California that collaborate on clinical research. The network has received national and international recognition for its clinical research and progress in advancing treatment of the disease. The group consists of eight faculty members from UNMC including Dr. O’Dell; Ted Mikuls, MD; Amy Cannella, MD; Alan Erickson, MD; Gerald Moore, MD; Dr. Klassen; Geoffrey Thiele, PhD; and Kaleb Michaud, PhD.

Before the formation of this group, there were few comprehensive networks to evaluate rheumatoid arthritis patients in clinical trials. The RAIN group allows academic centers to partner with private practice doctors who see the bulk of rheumatoid arthritis patients in their clinics. “By involving private practice doctors in the design of these studies, we are able to create studies that help answer questions that are clinically relevant to the patients they treat every day,” says Dr. O’Dell.

James O'Dell, MD

One of the group’s most important advancements, says Dr. O’Dell, director of RAIN, has been establishing the benefits of treating rheumatoid arthritis using a combination of three disease-modifying antirheumatic drugs (DMARDs), which is now the number one triple drug combination used in the United States and Europe. “While these drugs had been used for a long time, what was new was combining these drugs together to provide a safer, more effective and less costly treatment option for our patients,” says Dr. O’Dell.

The group’s research on triple therapy was first recognized in the New England Journal of Medicine in 1996, which validated it as an effective treatment therapy. The Yearbook of Rheumatology chose it as the most significant treatment breakthrough in 1997.

In another groundbreaking study, RAIN published the results of the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study in 2009 that compared triple therapy to TNF-alpha inhibitors, one of the mainstays of treatment before the introduction of triple therapy. The clinical trial, which involved 755 patients, is the largest investigator-initiated trial ever done on rheumatoid arthritis patients. While the results showed nearly identical outcomes in controlling the disease, the study helped spotlight the benefits of triple therapy compared to TNF inhibitors. TNF inhibitors can be very expensive, toxic and even life-threatening as opposed to triple therapy, which is associated with less dramatic side effects and is much more affordable, notes Dr. O’Dell.

Safe administration of DMARDs requires critical and careful monitoring, cautions Dr. O’Dell, which may include complete blood counts (CBCs), serum albumin and aminotransferase levels every four to eight weeks. “I’ve had patients on these combinations for 20 years or more,” says Dr. O’Dell. “As long as we stay on top of their labs, they do well indefinitely.”

“Our success in treatment over the last 30 years has been dramatic,” says Dr. Klassen. He remembers the days when the standard therapy for rheumatoid arthritis was high-dose aspirin — up to 30 tablets a day. Because of the side effects, most patients had to discontinue use within two years.

“We felt we were doing a good job if 15 percent of our patients said, ‘I think I’m doing better,’” says Dr. Klassen. “Most patients went on to develop significant pain and deformities in their hands, feet and knees and we could do nothing about it.”

Today, that is rarely the case. “Treatment advances have now made the possibility of putting rheumatoid arthritis in remission a realistic goal,” says Dr. Klassen. “Today, we don’t accept modest changes in clinical response. The key is early diagnosis and treatment. If this occurs, patients can do extraordinarily well. If we get to them early enough, we can stop the active component of the disease process in half of our patients. In another 30 percent, we are able to reduce its impact so that it has a minimal impact on their lives. Unfortunately, there are still 10 percent of patients who have a very progressive disease and continue to struggle.”

Preventing permanent damage to the joints is highly dependent on early diagnosis. “Treatment within three months of onset of the disease can have a significant impact in preventing damage and destruction to the joints,” notes Dr. O’Dell. “Joint damage occurs early in the course of rheumatoid arthritis, often before patients begin developing symptoms. Thirty percent of patients have evidence of bony erosions at the time of diagnosis, and this proportion increases to 60 percent by two years. Unfortunately, bony erosions and deformities are largely irreversible. Ideally, we’d like to diagnose the disease and begin treatment before patients even realize it’s there.”

Barbara Francis
Barbara Francis

Barbara Francis is one of the less fortunate ones. Diagnosed with the disease when aspirin and non-steroidal anti-inflammatories were the mainstay, the disease was able to take its course causing swollen and deformed joints in her hands and feet. By the time Francis found Dr. O’Dell, the damage had been done.

After seeing Dr. O’Dell back in the late 1980s, Francis agreed to enroll in a RAIN study where she was put on DMARD therapy. She began to see immediate improvement in her pain and stiffness. “My pain went away almost immediately,” says Francis. “Very rarely do I have a flare-up today, and when I do it doesn’t last long.”

She has continued to see Dr. O’Dell over the last 20 years and deals with her deformities like they barely exist. “Barbara is a trooper and a true inspiration,” says Dr. O’Dell. “She has continued to work and be active despite her deformities. A positive attitude can go a long way.”

“If you make yourself a cripple, you’ll be a cripple,” says Francis, who is now 66 and still full of energy and spunk. Francis worked as a waitress and cashier for most of her adult life, retiring just two years ago. “I was faster at the cash register than most people I worked with,” she says.

The mother of eight children, 17 grandchildren and 14 great-grandchildren, Francis says she is in perpetual motion, keeping up with her own household and helping out with the grandkids whenever possible.

“There are limits to the things I can do, but I try my best to do most everything,” she says. This includes mowing her lawn, painting the house, gardening for herself and her children and acting as the surrogate mother to her 10-year-old granddaughter. “My feet hurt badly,” says Francis, “but I just deal with it. I don’t want to just exist, I want to live.”

Jeff knows his life might be much different today had he not fallen under the skilled care of Dr. O’Dell. “I often wonder how my life might be different if I had lived in a different city, if I’d not had a primary care doctor who took my symptoms seriously and if I had not found a doctor like Dr. O’Dell who is really on top of it. I really feel fortunate. I’ve seen pictures of people with deformities and here I am today with no pain or stiffness. I wake up each morning ready to go.”

For most people, the outward symptoms of rheumatoid arthritis begin to develop over a year or less. Within a year, the pain and swelling usually has become painful enough that most will seek medical advice.
For Jeff, the symptoms emerged quickly and furiously in just a few months time. “I remember feeling very fatigued,” he explains. “After awhile, it was painful to stand for more than a couple of hours.” Eventually, the pain in his hands made it difficult to use his hand tools for any length of time. It even became painful to shake hands. “I thought it was just the stress from my job,” says Jeff. “I thought it would go away.”

“My pain went away almost immediately. Very rarely do I have a flare-up today and when I do, it doesn’t last long.”
Barbara Francis

Instead it got worse. When the pain and swelling became overwhelming, Jeff decided it was time to get it checked out. His primary care doctor suggested that it might be arthritis and recommended Jeff see Dr. O’Dell. “I didn’t even know what rheumatoid arthritis was,” he says. “Dr. O’Dell started me on triple therapy right away and I immediately noticed a dramatic improvement. The pain, the swelling and the fatigue all went away.”

Jeff sees Dr. O’Dell every three months to get his blood drawn to monitor his body’s response to the medications. He has nothing but praise for Dr. O’Dell. “He really wrestles with my treatment plan to make sure the numbers are just right,” says Jeff. “We talk very openly about the numbers and what they mean. This is important to me because I have a very detailed and analytical mind. He is progressive in his treatment, he communicates well with me and he is attentive. What more can I ask?”

“I expect Jeff to live a totally normal life if he stays on his medications and maintains good control of his disease,” says Dr. O’Dell. “Both Barbara and Larry have a tremendously positive attitude about their disease. They cope well and stay active. How patients handle things and deal with their disease and how they work with their doctor has a tremendous impact on outcomes.”

What causes rheumatoid arthritis is still uncertain. It is known that the disease is three times more common in women than men and that men are more likely to develop the disease in their 60s and 70s, while women are more likely to develop it in their 40s and 50s. It is also known that 70 to 80 percent of patients who have rheumatoid arthritis carry a gene that is associated with the disease. The problem is that approximately one-quarter of the population carries this gene, but only one of 25 of these individuals will eventually develop the disease. It is thought that some sort of environmental factors such as infection with certain viruses and bacteria may be responsible for triggering the disease. Other environmental factors such as smoking or periodontal disease may increase the risk of developing rheumatoid arthritis.

The future for rheumatoid arthritis treatment holds promise, says O’Dell. “Our hope is that we will some day be able to predict which patients are going to respond best to which therapies so we can get them on the right therapy more quickly,” he says.

Barbara Francis
Barbara Francis

The RAIN group is currently involved in a trial that is looking at peoples’ antibodies, inflammation levels, genetics and other factors to determine commonalities that correlate to how they respond to various medications. Dr. O’Dell says they are also looking at indicators that would allow doctors to diagnose the disease even before the patient knows he or she has the disease. For many patients, it can take up to five years from the time the disease begins to break down the immune system to when they actually begin to experience physical symptoms of the disease.

“As we understand more about the biology of rheumatoid arthritis and the pathways the disease takes to cause the inflammatory process, we hope to make progress in developing drugs that target and interrupt these pathways,” says Dr. O’Dell.

Shutting down these pathways could essentially eradicate rheumatoid arthritis altogether. It may be too late for Jeff and Francis, but both have participated in research studies that will help the next generation of patients. And they both are quick to say they are thankful for the pathway given to them by Dr. O’Dell and his staff at The Nebraska Medical Center — a pathway that has given them quality of life and a much brighter future than they could have ever imagined.

For this article, Jeff asked that his real identity not be revealed. Jeff is a very private person and, even after 10 years, the only people who know about his disease besides his doctor are close family members. “I don’t want to be known as the guy with crippling arthritis,” says Jeff. “I want to be known for who I am.” And if Jeff’s treatment continues on the same positive course, no one else will ever know — and that’s just the way Jeff wants it.

Next article in the Fall | Winter 2010 issue of One Thousand And One:
Staying on Course