Combination Therapy for RA Control

Physicians typically do not use polypharmacy, or more than one medication, to treat their patients. However, for people with rheumatoid arthritis (RA), a long and scientifically well-supported tradition supports the combination of drugs to better treat the disease.

James O’Dell, MD, a physician in Omaha, Neb., first noted in the 1990s that using two or more traditional drugs—disease-modifying antirheumatic drugs (DMARDs) and newly developed biologics—worked better in controlling RA than using a single drug, according to Jerry Goldberg, MD, a staff rheumatologist at Marshfield Clinics in Marshfield, Wis. According to Goldberg, O’Dell pioneered the idea of combination therapy using three medications.

Two medication groups
DMARDs include methotrexate, a mainstay of RA treatment, and hydroxychloroquine. Newer biologics include etanercept, adalimumab, and abatacept. These laboratory-manufactured proteins intervene at various places in the body to aid in a patient’s response to RA.

“Using more than one drug for RA has been accepted for a very long time,” says Eric Matteson, MD, a rheumatologist with the Mayo Clinic in Rochester, Minn. “It was not unusual to use a nonsteroidal anti-inflammatory drug [NSAID], along with gold injections and corticosteroids, like prednisone, early in the history of successful treatment. This [practice] has continued through the advent of DMARDs and the beginning use of biologic medications in 1998.”

Long history of successful multiple medication use
Gold injections, hydroxychloroquine, and sulfasalazine were once the main drugs for treating arthritis and other rheumatic diseases. In the 1980s, methotrexate came into widespread usage.

“Methotrexate was becoming well-established, [but] many patients…simply needed something else,” says Matteson. “The idea of putting multiple drugs together became more popular.” In the early 1990s, the idea of combining DMARDs really began to take off as physicians began to combine methotrexate with drugs such as hydroxychloroquine. By this time, doctors were prescribing multiple medications, including combinations of DMARDs, to many patients with RA. They were also prescribing nonsteroidal drugs and corticosteroids, such as prednisone.

In 1998, when the first of the biologic medications came to market, the treatment of RA changed yet again. Since then, multiple studies have shown that combination of two or more DMARDs help lessen pain and joint erosion and that they improve patients’ ability to complete their daily activities. In many cases, these drug combinations accomplish these goals better than the use of one drug. These findings are consistent across regimens that use traditional DMARDs, biologics, or both.

Multiple pluses
Prescribing more than a single disease-modifying drug offers many benefits. Using additional medications allows physicians to take advantage of the many ways the drugs can help victims of this complex disease.

Physicians can, for example, prescribe lower dosages of these medications for most patients, and these lowered dosages yield fewer side effects from each drug. Using multiple medications does not increase the overall side-effect burden, however. Regardless of what measures researchers use to assess the severity of the arthritis, they find that the use of multiple-medication therapies improves control of the disease.

Easy individualized treatment
“Combination treatments are structured to address different parts of the rheumatic response; each medication has a different mechanism of action,” says Edwin Yelin, PhD, a professor of medicine and a health-policy and researcher at the University of California-San Francisco. “This [benefit] allows the physician to choose combinations that benefit the individual.” Current RA therapy enables physicians to easily individualize treatments based on the needs of each patient.

The experts stress that one of the strengths of current RA therapy is that it is very easy to individualize treatments based on the needs of the person in front of the doctor. Physicians consider many variables when deciding which drug or drugs a patient needs. For example, they may consider the degree of disease activity in each patient, factoring in the results of blood tests and the health of joints, using X-rays or magnetic-resonance imaging.

Interestingly, the strongest measure of disease severity is a standardized questionnaire that asks patients how well they can perform daily activities, such as combing their hair, walking, or buttoning their clothes. These tests of patients’ functioning provide a better view than most laboratory tests of how patients are faring. After evaluating a patient’s functional status and the activity of the disease, the physician consults with the patient to decide how aggressive the treatment should be.

Treatment of mild disease
For those who have mild disease, methotrexate may be the only medication prescribed, and it’s also used to anchor treatment with any of the other options. Unless other illnesses such as heart or lung problems are present, methotrexate is given to almost all people with RA.

“Methotrexate is the go-to drug for RA treatment,” says Matteson. “It has a very good track record, is tolerated well, and is easy to take. Another big plus is that it’s very inexpensive compared to some of the other medications available.”

Depending on individualized needs, methotrexate alone may be the first medication given, especially if the RA is very mild. A rheumatologist may follow the patient closely for 12 to 16 weeks while the medication begins to work; if the patient is getting better, he or she may need no other therapy. However, don’t be surprised or concerned if a rheumatologist begins treatment by prescribing more than one medication even for mild cases of RA. Multidrug therapy has been shown to be more effective than monotherapy for a large number of patients.

“In the 1960s and 1970s, RA was mostly treated in a pyramid fashion,” says Goldberg. “You started with one and then added another as needed. What has been shown to be more effective, especially if you have had RA for less than three years, is to start with multidrug therapy until the arthritis is controlled and then remove drugs until there is only one left.”

The more aggressive medication plans result in better outcomes, higher functioning, and better control of joint erosion over the long term. Patients also have less pain and are more likely to be able to work and remain independent.

Moderate disease interventions
For some patients with mild disease and for most of those with moderate to severe RA, physicians use combination therapy from the start. This therapy usually includes the use of two traditional DMARDs. Studies have shown that combinations of the older medications generally work as well as those that include the newer biologics.

“The reason we don’t start out with biologics is both the cost and added risks for little or no additional improvement from what we see with the traditional DMARDs,” says Goldberg. “The costs can be…$2,000 or more per month. There’s also an increased risk of infection, including tuberculosis, and cancers that needs to weighed against the benefits of using biologics.”

Many people hear the words “cancer” and “tuberculosis,” and learn about the adverse effects of the medications, and immediately become concerned about taking them. However, deciding to forgo medication altogether also involves risks.

“Although patients are concerned about the side effects of the medications, they don’t often know about or consider the side effects of untreated RA,” Goldberg says. “RA has been shown to reduce your life span by as much as 15 years. It’s also associated with non-joint diseases, including heart and lung inflammation, and can affect the eyes and skin. You have to balance the adverse effects of not treating the disease with those associated with the treatments.”

Severe RA hard to treat
People with severe RA may have difficulty finding an effective mix of medications. Some patients could be prescribed a combination of three or even four medications—including DMARDs and nonsteroidal drugs, such as ibuprofen or naproxen—at the beginning of treatment. In addition, they be put on a short course of corticosteroids to “tamp down the fire”; for example, prednisone begins to work within hours or days, whereas traditional DMARDs can take as long as 12 weeks to begin lowering pain and swelling.

“[For patients with] intense pain and bad joint swelling who are really disabled from arthritis, steroids work faster than the other medications,” notes Matteson. “For these patients, prednisone treats the symptoms while the other medications ramp up to effective levels.”

Other options
The large number of different medications with different actions is also important from the perspective of the patient: If a particular regimen doesn’t work, others are readily available.

“If one drug or combination doesn’t work, the patient needs to know that that there are other options,” says Dr. Yelin. “This isn’t the best you are going to feel for the rest of your life—switching or adding another agent can often make dramatic improvements in your symptoms. The literature and clinical experience are strong indicators that you shouldn’t give up, that there are still a lot of opportunities available.”

The results can be nothing short of amazing. Goldberg refers to a 15-year-old girl who came to him with RA so severe that her father had to carry her into his office. After aggressive initial treatment with five medications, her disease regressed to the point at which she takes only one drug and can play basketball on her college team.

Despite these results, however, some people still find the need for combination therapy difficult to accept.

“When we tell people that we want to place them on three or even more drugs, the first reaction is usually, ‘That is way too much medicine,’” says Goldberg. “It is important that both patients and family understand that each of these medications do their work at different points in the biologic system that is resulting in RA.”

Kurt Ullman has been a medical writer for 30 years. He is based in Indiana.

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