Cover Story
Joint Approach
Better drugs and early aggressive treatment are restraining rheumatoid arthritis.
By Kim Palmer
For years, Nicky N.* battled her rheumatoid arthritis (RA) with treatments that delivered more side effects than relief. First, she was prescribed steroids in high doses. Then she tried methotrexate, a widely prescribed anti-rheumatic drug. It helped, but she still suffered stiffness and fatigue, and her joints sometimes swelled so badly she couldn’t get shoes on her feet or walk downstairs in the morning. Then, several years ago, her physician prescribed etanercept (Enbrel), a newer drug that targets proteins involved in the inflammatory response.
“It was life-changing,” Nicky says. Within weeks, her inflammation subsided. She continues to take Enbrel, along with methotrexate. Although she still has some disease flare-ups, they’re shorter in duration and less severe than they had been, she says.
Etanercept, which in 1998 became the first biologic agent to be approved by the Food and Drug Administration for RA, is one of a new class of drugs that has helped transform treatment of the disease. “For decades there were only a few treatments—steroids typically,” says Mehrnaz Hojjati, M.D., an assistant professor in the division of rheumatic and autoimmune diseases at the University of Minnesota. “Now there are at least five or six new medications, especially for RA, with a new one coming every year.”
Hojjati says the availability of these new drugs has changed the way she and her colleagues manage the disease. Ten years ago, she says, it would take at least six months to get RA under relative control using drugs such as NSAIDS, corticosteroids, hydroxychloroquine, sulfasalazine, and methotrexate. Now, with biologics and other new therapies, most patients notice a significant improvement in joint pain, swelling, and other symptoms within a month or two. “It’s very promising.”
The new biologic drugs not only ease symptoms, they also offer an advantage over corticosteroids in that they suppress only targeted parts of the immune reaction. Etanercept, for example, targets TNF-alpha, a cytokine important in regulating immune response, inhibiting its activity and, thus, interfering with inflammation and lessening joint damage. “Medications like cortisone and prednisone suppress the immune system in a broad fashion,” says Gary Bryant, M.D., a rheumatologist with the University of Minnesota. As a result, they can cause severe side effects such as diabetes, osteoporosis, osteonecrosis cataracts, glaucoma, and cardiovascular risks.
A Complex Disease
Rheumatologists agree that the conditions they see are so complex and individual that no one drug or treatment is a silver bullet. “Immune system pathobiology is extremely complicated,” says Eric Matteson, M.D., chair of rheumatology at Mayo Clinic. “There is not a single defect or cell or protein responsible for rheumatoid arthritis [RA] and its activity. It’s polygenetic, and the disease course is highly variable, from mild to life-threatening. So far, we haven’t identified any particular drug that gets at the fundamental, underlying mechanisms of the disease. It’s not a single mechanism but many mechanisms.”
Because there are so many factors contributing to inflammation, rheumatologic conditions seem to morph, making their treatment even more challenging. “You stop one [factor], and another takes over and does an end-around,” says Hollis Krug, M.D., a rheumatologist with the Minneapolis Veterans Affairs Medical Center. “The disease can alter itself and rev up someplace else.” For example, patients with RA may do well for a couple of years on methotrexate or another disease-modifying drug, then their disease suddenly becomes much more active. This could be the result of that drug blocking one inflammatory pathway and the disease progressing in spite of it.
“The big challenge is that in general none of these medications is good enough to totally control the disease,” says Jerry Molitor, M.D., Ph.D., associate professor of medicine at the University of Minnesota. In fact, most of the RA patients he sees take three or four drugs to adequately manage their disease.—K.P.
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Biologics are generally more potent than methotrexate, an older drug often used as a first-line treatment for RA. They also may help alleviate the fatigue associated with RA, something older drugs do not always do. In addition to easing symptoms, these new medications, including methotrexate to some extent, also appear to prevent the skeletal destruction that has long been associated with severe disease in some patients. Less joint destruction means less surgical intervention down the road. “Joint surgery for people with rheumatoid arthritis is decreasing,” says Eric Matteson, M.D., chair of rheumatology at Mayo Clinic. “Biologics are part of that—so is more aggressive management.”
Initially, biologics were only used for those patients who did not have success with methotrexate. However, rheumatologists have since discovered that they tend to be most effective when combined with methotrexate. “They work better and continue to work longer when used together,” says Hollis Krug, M.D., a rheumatologist at the Veterans Affairs Medical Center in Minneapolis and associate professor of medicine at the University of Minnesota.
Combination therapy increases the chance of the disease going into remission, a phenomenon that was once rare but is now a reality for many patients. But drugs aren’t the only factor in helping patients achieve remission. “It’s more new management strategies than new drugs,” says Tim Bongartz, M.D., a rheumatologist at Mayo Clinic. “We’re treating earlier and more aggressively. Primary care physicians are more willing to refer to rheumatologists, and our family medicine colleagues are more alert to recognizing these patients and sending them to us right away, instead of just treating their symptoms.” As Krug puts it: “Why wait until patients have severe joint destruction?”
Risks and Costs
Although they have transformed the lives of some patients, biologic drugs come with some heavy baggage. Because they suppress parts of the immune system, the drugs put patients at higher risk of infection. Nicki N. says she is more susceptible to colds, yeast infections, bronchitis, and pinkeye. There’s also a risk that they may cause a common illness to turn into a more serious one such as a cold turning into pneumonia. In addition, biologic agents may cause chronic diseases such as tuberculosis that have been dormant to flare up. Consequently, only about 30 percent of the 1.3 to 1.5 million people in the United States with RA are currently good candidates for biologics, Matteson estimates. They are not recommended for patients with multiple sclerosis, congestive heart failure, demyelinating diseases, or a previous malignancy.
Furthermore, there’s data, although somewhat controversial, linking long-term use of TNF inhibitors and other biologic drugs to lymphoma and other cancers. In 2006, Matteson and Bongartz published the results of a meta-analysis of several randomized trials in the Journal of the American Medical Association that suggested arthritis patients treated with anti-TNF antibody therapy had an increased risk of malignancies and serious infection. They also indicated that malignancies were significantly more common in patients who received higher doses of biologic agents than those who received lower doses. At the American College of Rheumatology meeting last fall, however, Spanish researchers who studied patients enrolled in a drug registry reported the incidence of developing cancer in those who received TNF blockers was very close to that of a control group. Despite the conflicting findings, in August, the Food and Drug Administration began requiring stronger warnings about the occurrence of lymphoma and other cancers in children and young adults using TNF blockers.
Another huge drawback to biologic agents: the cost. Treating a patient with biologic drugs typically costs more than $20,000 a year, many times that of older drugs such as methotrexate, which cost about $1,000 to $2,000 a year. Over the course of a disease, that can be astronomical. “All the biologic therapies are very important additions, but none of them have shown they can cure the disease, take the disease away, so there’s a lifelong expense of many thousands of dollars a year,” says Jerry Molitor, M.D., Ph.D., an associate professor of medicine at the University of Minnesota.
For those reasons, biologics are rarely the first drug prescribed for a newly diagnosed patient. “The likelihood of responding to first-line treatment is so high that we shouldn’t expose patients to those risks and costs,” Bongartz says. He says trials are underway in the Netherlands that suggest anti-TNF drugs have no advantage over aggressive use of methotrexate as a firstline treatment. “If a patient’s disease doesn’t respond to methotrexate,” he says, “then these drugs are really a blessing. But we cannot claim that anti-TNF drugs are better than methotrexate because the likelihood of not responding to Enbrel is just as high.”
Molitor says the patients for whom they typically prescribe TNF inhibitors are those who have tried several other drugs and whose inflammation markers can’t be brought down to normal levels, a risk factor associated with bone destruction. Those patients get moved onto biologic therapies, typically TNF inhibitors, a B-cell depleting drug (rituximab), a T-cell specific drug (abatacept), or anakinra, an interleukin-1 receptor antagonist that is extremely costly and effective for only a minority of patients. “That’s the drug of last resort,” he says.
Research in Minnesota
Currently, about 15 rheumatologic treatment studies are underway at Mayo Clinic, a national leader in rheumatology research. Conducting clinical trials for biologic drugs is a significant part of that research, Matteson says. Mayo is currently conducting a number of treatment studies including follow-up studies of two newly approved TNF inhibitors, golimumab (marketed as Simponi) and certolizumab pegol (Cimzia). These are self-administered injectable drugs that have a longer half-life than the self-injectable TNF-alpha blockers that are currently on the market. Their potential advantage is that patients would take them once every four weeks rather than once every one or two weeks. Researchers are also assessing the impact of biologic drugs on major organ health. “Rheumatologic patients are at higher risk of heart failure,” Matteson says. “We think the disease causes disruption in the lining of the blood vessels, but we don’t know if the drugs have a direct effect on some of those processes.”
In addition, they are hoping to solve the mystery of why some patients respond differently than others to particular drugs. The goal is to identify those who would have the best response to a certain drug earlier. “The best drug doesn’t work if you give it to the wrong individual,” Bongartz says. Researchers at Mayo are trying to find the proteogenomic signatures for rheumatoid arthritis. “We’re trying to discover how serious the disease will be and how rapidly it will progress,” Matteson says. “If I as a physician knew the genes and proteins related to severe disease course, my therapeutic recommendations might be more aggressive.” They also are studying patient response to initial drug therapy at the cellular and molecular level. “We’re looking at the pattern of gene expression profiles and cytokine activity, comparing people who respond poorly and people who respond well,” says John Davis, M.D., a Mayo consulting rheumatologist. “Sometimes it’s hard to know how well a person is doing on treatment,” he says. “You might think a person is doing well, and damage is still occurring.”
The goal is to help determine who is likely to respond well to a particular drug and at what dosage, Davis says.
Alternative Approach
Not all the research into how to best treat patients with rheumatoid arthritis is focused on drugs. Nisha Manek, M.D., a consulting rheumatologist at Mayo Clinic, is interested in the effects of augmenting conventional drug therapies with alternative therapies such as qi gong, a low-impact, meditative form of T’ai chi. She’s seeking funding for a long-term study that would assess whether patients who practice qi gong in conjunction with conventional treatment are better able to manage their disease and experience less of the anxiety and depression that may go along with it. She would also like to learn what types of patients are most likely to benefit from qi gong as an adjunct to their conventional treatment.
Manek says she recommends qi gong to her patients, and many tell her it’s been beneficial. “There’s lots of anecdotal evidence that it helps, but it needs formal study.” —K.P.
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“Right now, we overtreat some patients and undertreat others. Delays in effective therapy can translate into higher rates of damage. If you could find those people and treat them more aggressively up front, you could prevent that.”
Not all research is focusing on developing costly new drugs. Both the VA Medical Center in Minneapolis and Mayo Clinic are participating in a multi-center study comparing the effectiveness of a combination of three older, less-expensive drugs—sulfasalazine, hydroxychloroquine, and methotrexate—with that of methotrexate and etanercept given together. “Combination therapy showed promise, but it fell by the wayside when new drugs came out, and it was assumed that biologics were better,” Krug says. In addition, a number of small companies are looking at ways to make a safer steroid, Molitor says. “Prednisone is highly effective at cutting through the inflammation. The problem is that the side effects make it a horrible long-term solution.” He says there’s hope that changing the release formulation and creating chemically modified forms will result in fewer side effects.
On the Horizon
Within a year or so, physicians anticipate FDA approval of tocilizumab (Actemra), a new drug already approved in Europe and Japan, which inhibits activity of the interleukin-6 receptor. Interleukin-6 is a pleiotropic cytokine that participates in a variety of physiological processes and is one of the inflammatory cytokines present in the synovium in RA. “It’s a very promising new therapy that hopefully will open the door to other treatments,” Krug says of tocilizumab. Last year, researchers at the University of Leeds in the United Kingdom found that when combined with methotrexate, the drug was effective for RA patients who did not respond to anti-TNF therapy.
More targeted drugs will continue to be developed, Matteson predicts. “Small molecules may come into play, combined with biologics, which we can’t combine right now because the side effects are too great.” He believes the future is individualized care and knowing in advance what a patient’s outcome and response will be.
Because RA represents a huge market, the bulk of research to date has targeted that disease. But physicians are optimistic that new treatments for other, less-common autoimmune diseases such as systemic lupus erythematosus and scleroderma also will emerge.
Says Molitor: “The development of more options for rheumatoid arthritis has led the way into looking at a variety of therapies across the rheumatologic spectrum.” And that’s good news for patients who have struggled for years to find relief from the pain and disability associated with rheumatologic diseases. MM
Kim Palmer is a freelance writer in Eden Prairie.