American College of Physicians: Internal Medicine — Doctors for Adults ®

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Options, challenges in treating RA

Drugs give better control of a once-crippling disease—but need close monitoring

From the October ACP Observer, copyright 2004 by the American College of Physicians.

By Margie Patlak

Talk to rheumatologists, and you can hear their excitement when the topic turns to rheumatoid arthritis. Over the past decade, treatment options for rheumatoid arthritis have grown with new therapeutics and an aggressive focus on early treatment and combined therapies. As a result, rheumatologists say they can now offer patients better control of a disease that was once crippling.

"There's never been a better time to treat rheumatoid arthritis because there are so many more options available to us," said Joel M. Kremer, FACP, a rheumatologist at The Center for Rheumatology in Albany, N.Y., and professor of medicine at Albany Medical College. "The old days when we just gave aspirin are long gone. We can now prevent bone destruction and disability."

More and more rheumatoid arthritis patients are being successfully treated with combination therapies. For patients who don't respond, new "biologic" medications are key additions to physicians' therapeutic arsenal, with the ability to control symptoms and help prevent the disease from progressing.

But physicians' enthusiasm about treatment options, while genuine, is tempered. The biologic drugs available to treat rheumatoid arthritis can cause immune suppression problems—and can cost more than $1,000 a month.

And patients on first-line therapies, which typically include methotrexate alone or in combination, need to be carefully monitored to guard against potential liver and kidney damage. Given the list of concerns, physicians say they have to weigh many factors when it comes to tailoring treatments to individual patients.

Biologics: pros and cons

Methotrexate, with its solid 20-year track record, is typically physicians' first treatment choice. Experts say it is now considered the "gold standard" of rheumatoid arthritis treatment and is the most widely used among a group of drugs known as disease-modifying antirheumatic drugs (DMARDs). Other DMARDs include leflunomide, hydroxychloroquine and sulfasalazine.

However, even methotrexate has its limitations. It doesn't work for everyone or particularly quickly, and it requires frequent monitoring to head off serious side effects.

That's why rheumatologists were delighted to see the first of the biologic rheumatoid arthritis drugs released in 1998. The new medicines—etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira) and anakinra (Kineret)—fight different mechanisms of the disease.

While traditional drugs like methotrexate target broad aspects of the immune response, such as T- and B-cell proliferation, biologics have narrow targets: the cytokines thought to play key roles in rheumatoid arthritis. Three of the biologics—etanercept, infliximab and adalimumab—target tumor necrosis factor alpha, while anakinra targets interleukin-1.

"The degree of improvement that you get with them is really dramatic in many cases," Dr. Kremer noted. "Not only do patients feel better, but they feel better immediately."

But although biologics can shrink swollen joints fast, some experts claim that overall response rates are roughly the same as for methotrexate. The drugs must also be administered by intravenous infusion or self-injection, so they aren't the drugs of choice for patients who balk at needles.

Far more troublesome are the increased risks linked to short-term biologic use. Complications include serious infections, as well as a possibly higher risk of developing lymphoma or a multiple sclerosis-like syndrome, or dying from congestive heart failure. And no one knows what the long-term complications might be. It's a particularly troubling thought, physicians say, given that patients may take biologics for decades.

And because the cytokines that biologics target help the body fight off bacterial and

opportunistic infections, the drugs have been associated with deaths from infections like tuberculosis and sepsis in a small number of patients who were among the first to receive them. As a result, physicians don't prescribe the drugs to patients with latent tuberculosis, as revealed by a purified protein derivative (PPD) test and chest X-ray, nor to patients prone to serious recurrent infections like pneumonia.

Physicians also advise patients to discontinue biologics if they have a fever, open skin wounds, a phlegm-producing cough or other signs of infection, and to avoid the medications until the infection clears.

"It's not that these people get a lot of infections," said Anne Winkler, FACP, PhD, a rheumatologist in Springfield, Mo., and Governor for the Missouri Chapter. "It's just that if they have an infection, they can't handle it as well. The rule is if you're thinking antibiotics, don't give them biologics."

What's less resolved is what to do about the threat of lymphoma. Dr. Kremer said he informs patients of a possible risk of lymphoma that must be weighed against the known risk of rheumatoid arthritis disease activity. Dr. Winkler pointed out that she doesn't prescribe biologics to patients who have had lymphoma, nor to patients with multiple sclerosis or severe congestive heart failure.

And the price of biologics can be daunting—as much as $1,000 a month, compared to methotrexate for $5 to $20 a month. That price tag puts biologics out of reach of patients with large copays or no prescription coverage.

Even with coverage, some insurance companies require patients to fail three other drug therapies before they will cover a biologic for rheumatoid arthritis. Medicare currently will pay only for infliximab because it is infused in a doctor's office, as opposed to the other biologics, which are self-injected. Likely changes in Medicare coverage policy, however, may put other biologics on an equal footing in the future.

Treatment strategies

Because of biologics' costs and possible complications, they are rarely indicated as first-line therapy.

Dr. Kremer said he first uses a tried-and-true drug like methotrexate. Although the response rate to methotrexate equals or surpasses that of other rheumatoid arthritis drugs, about half of patients with the condition do not respond sufficiently. For nonresponders, Dr. Kremer will use a biologic or leflunomide in addition to, or instead of, methotrexate.

A study that appeared in the May 16, 1996, New England Journal of Medicine found that nearly three-quarters of patients responded to conventional therapies such as hydroxychloroquine and sulfasalazine combined with methotrexate. Other researchers have seen similar response rates when a biologic is combined with methotrexate.

In fact, the success of combination therapy and the new emphasis on early diagnosis and treatment (see "Detecting early RA symptoms is key, but tricky") have sparked a debate over whether to take a step-up or step-down therapeutic approach.

In the step-up approach, physicians prescribe a single drug like methotrexate, then add other DMARDs to the mix only if the first treatment doesn't provide adequate control. Most rheumatologists favor this approach, and it is the one health plans are most likely to cover.

An alternative that may be more effective at staving off joint destruction is to immediately initiate several different drugs. Physicians then subtract agents—stepping down the therapy—until they achieve the minimal amount of treatment needed to keep the disease in check.

This was the approach taken in what's known as the COBRA trial, which compared sulfasalazine alone to sulfasalazine combined with low-dose methotrexate and prednisolone; the findings were published in the Feb. 5, 2002, issue of Arthritis & Rheumatism. European researchers tapered patients off prednisolone after 28 weeks and stopped methotrexate at 40 weeks.

Patients in the combination group responded more rapidly to treatment and had fewer side effects. These patients also showed less radiographic evidence of disease progression after five years.

Other studies have shown that for patients with early disease, similar step-down approaches can be more effective than a single agent alone. But no study has directly compared step-up and step-down approaches head-to-head, although such studies are in the works.

For now, rheumatologists say they immediately use aggressive combination therapy only in patients who present with severe disease. Whether patients' insurers will reimburse those combinations is another story, particularly if the combination includes an expensive biologic.

Rheumatologists do offer tips to improve a patient's chances of getting some treatments covered. Kaiser Permanente, for example, requires patients to fail three synthetic rheumatoid arthritis drugs, such as methotrexate, hydroxychloroquine and sulfasalazine, before they can receive a biologic. For patients whom she thinks need biologics, Dr. Winkler said she may give them all three synthetic drugs simultaneously. The faster they fail, she figured, the sooner the insurer will cover other therapies.

But if you want to start patients off with more than methotrexate, Dr. Kremer said, you should plan to be aggressive with payers. "You need to get beyond the clerk level and talk to the medical manager of the insurance plan," he said. "Once you speak to a physician and explain that the patient has severe disease, you can usually get another drug approved."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute of clinical judgment and does not represent an official position of ACP.

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Detecting early RA symptoms is key, but tricky

Physicians' ability to take advantage of therapies for rheumatoid arthritis hinges largely on early diagnosis. This puts more pressure on primary care physicians to recognize the disease's nascent symptoms and to take them seriously.

Joel M. Kremer, FACP, a rheumatologist at The Center for Rheumatology in Albany, N.Y., and professor of medicine at Albany Medical College, compared seeing a patient with potential early rheumatoid arthritis to seeing one with chest pain. Just as a physician should send a patient with a potential myocardial infarction to the emergency room immediately, Dr. Kremer said that a patient with several inflamed joints should be referred right away to a rheumatologist.

The analogy may be extreme, but recent studies suggest that physicians may have a relatively small window of opportunity to prevent joint destruction in rheumatoid arthritis patients. Several studies have found, for example, that delaying treatment for only three months leads to more bone damage in five years.

But early rheumatoid arthritis can be hard to spot because it can resemble several other conditions, including psoriatic arthritis and lupus. Viral infections, such as those caused by the Epstein-Barr virus, influenza virus or hepatitis C virus, can cause syndromes that present exactly like rheumatoid arthritis but last only a few weeks.

For that reason, patients aren't given a rheumatoid arthritis diagnosis unless they have four out of seven American Rheumatism Association diagnostic criteria for more than six weeks. The criteria are online.

Physicians have traditionally relied on a positive test for rheumatoid factor. Studies show that 80% of patients with early rheumatoid arthritis will test positive for this factor, although 20% of those with the disease won't test positive at all.

A new, more specific test for rheumatoid arthritis looks for antibodies to cyclic citrullinated peptides (CCPs). More than 90% of patients who test positive for CCP have rheumatoid arthritis.

"This is a good test for internists to know about," said rheumatologist Anne Winkler, FACP, PhD, a rheumatologist in Springfield, Mo., and Governor for the Missouri Chapter. "It is one of those things that, when elevated, clinches the diagnosis, and is readily available."

But there's a catch. Because CCP testing isn't very sensitive, it misses about half of all rheumatoid arthritis cases. Other useful lab tests include the erythrocyte sedimentation rate and C-reactive protein. Elevated levels suggest inflammation consistent with a rheumatoid arthritis diagnosis, Dr. Winkler said.

An MRI can also be helpful for early diagnosis because it can detect telltale signs of bone edema and early bone erosion before these conditions show up on an X-ray. But it is hard to justify an MRI's expense and inconvenience to patients. "It's much cheaper to get a rheumatology consult than an MRI, and with the consult, you can probably be more sure about the diagnosis," Dr. Winkler noted.

Getting a consult as soon as possible is critical for patients with suspected disease. Physicians should push to get these patients seen, especially when many patients face a three- to six-month wait for an appointment.

The good news is that rheumatologists are eager to see patients with early rheumatoid arthritis because they know the benefits of early treatment. "If a doctor calls me about a patient with possible rheumatoid arthritis," said Dr. Kremer, "I get the patient in within a week."

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Tips for managing the 'whole' rheumatoid arthritis patient

Even if your rheumatoid arthritis patients are being treated by rheumatologists, there is still plenty that primary care physicians need to do to keep these patients safe.

That's because many of the therapies prescribed for rheumatoid arthritis require heavy-duty monitoring. And patients taking biologics face a higher risk of contracting other diseases.

Most rheumatoid arthritis patients, for example, need monthly blood monitoring for complete blood cell counts, along with liver and renal function. If consulting with rheumatologists, physicians need to make clear whose office will do the monitoring, and see that the information is shared.

"We don't want to keep giving patients these medicines if their white blood cell counts drop off," noted Anne Winkler, FACP, PhD, a rheumatologist in Springfield, Mo., who said physician communication and coordination are key. "When the internist orders lab work, we try to get ours done at the same time so the patient doesn't get stuck twice or get repeat labs."

For patients not under the care of a rheumatologist, internists must be vigilant about getting and reviewing blood work. This can be especially tough for physicians in small towns who have large practices and no electronic record systems to help them track patients, said Ted L. Sussman, FACP, a general internist in Houlton, Maine, who is Governor for the Maine Chapter. For that reason, "methotrexate is easier for price, ease of administration and present comfort levels," he said.

There are also subtle disease effects. Rheumatoid arthritis patients are twice as likely to suffer from infections, especially in the lung. To help counter that heightened risk, all patients with rheumatoid arthritis should have yearly flu shots and be up-to-date on pneuomococcal vaccines.

And while joint inflammation is obvious, the effects of inflammation on the blood vessels and bones are much more hidden, and can double patients' risk of developing both cardiovascular disease and osteoporosis.

Soon after diagnosing patients with the disease, for example, Dr. Winkler orders a baseline DEXA scan for them. For many patients, she wants repeat annual scans.

"We assume most rheumatoid arthritis patients have osteoporosis," she said. "It's just a question of do they have it at two years or at 10 years after being diagnosed."

Internists also need to "make sure to control these patients' blood pressure and lipids." Dr. Winkler said. "Just the fact that they have an inflammatory disease means you should pay more attention to symptoms like subtle chest pain or shortness of breath."

Too, experts say that physicians might consider prescribing statins to rheumatoid arthritis patients who have other risk factors for cardiovascular disease, because statins are thought to decrease the risk of both atherosclerosis and inflammation.

And according to Joel M. Kremer, FACP, a rheumatologist at The Center for Rheumatology in Albany, N.Y., and professor of medicine at Albany Medical College, fish oil supplements are also therapeutic for both heart disease and rheumatoid arthritis.

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