Combination Therapy Often Best for RA

Multiple medications are often effective in controlling rheumatoid arthritis.

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When it comes to treating aggressive rheumatoid arthritis (RA), two medications – or three – often work better than one.

Doctors have long used combinations of drugs when treating RA, recognizing the synergistic effect of multiple medications against the disease. Now research is helping them understand which combinations are most effective, and some of their findings, they say, are surprising.

When Methotrexate Alone Doesn’t Control RA

In a 2013 study led by James R. O'Dell, M.D., at the University of Nebraska Medical Center in Omaha and published in the New England Journal of Medicine, researchers followed 353 patients who had active RA despite taking methotexate. The patients continued taking methotrexate, but were randomly assigned to also receive either sulfasalazine plus hydroxychloroquine, or etanercept. Neither doctor nor patient knew which drug regimen a patient was getting. Patients were assessed every six weeks for 48 weeks.

After 24 weeks, the majorityof the patients were doing well and continued with their assigned regimen, but equal numbers – 27 percent – from each group were not doing well and were switched to the other treatment (still not knowing which treatment they were receiving). Twenty-four weeks after they switched treatments, all patients were equally improved as measured by DAS28 scores (a measure of disease activity that assesses 28 joints as well as inflammatory markers in the blood) and radiographic progression (joint damage as seen on an X-ray).

Medication Combinations for Early RA

Results were similar for a large study published a year earlier in Arthritis & Rheumatism. In the so-called TEAR – Treatment of Early Aggressive Rheumatoid Arthritis – study, researchers followed 755 patients at 44 different medical centers across the United States for two years. All patients had been recently diagnosed with RA at the time of enrollment and also had what is considered severe or aggressive RA.

The patients were randomly assigned into four groups. One group immediately started on the combination of methotrexate and etanercept. Another immediately started on triple therapy (methotrexate, sulfasalazine and hydroxychloroquine). A third and fourth group received methotrexate alone for 24 weeks. At that point, people in these two groups were stepped up to one of the combination therapies if their DAS28 score still indicated aggressive disease. Neither the patients nor doctors knew who received which treatment.

The researchers found that at week 24, disease activity was lower in the two groups that had started on immediate, combination-drug therapy than in the two step-up groups (those who started on methotrexate alone). However, 28 percent of people treated with methotrexate alone did achieve low disease activity at six months, which means they did not need to step to more intensive therapy.

When researchers looked at DAS28 scores for week 48 through 102, they found scores were essentially the same in all treatment groups. There were no significant differences in DAS28 scores in people who had immediately started on – rather than stepped up to – combination therapy.

Surprising Findings

Perhaps most surprising to researchers in both studies was that DMARD triple therapy works similarly to the methotrexate-etanercept combination.One would have expected that combining methotrexate with the newer, more expensive biologic agent would have been more effective. “Our assumption all along was that the biologic agents would be superior and they are not,” says Jonathan S. Coblyn, MD, director of the Center for Joint Diseases at Brigham and Women’s Hospital in Boston, who was not involved in the study.

“What we found is that triple therapy is just as good at slowing down disease activity as methotrexate and etanercept,” says Larry W. Moreland, MD, lead author of the TEAR study and division chief of rheumatology at the University of Pittsburgh.

Unanswered Questions

While the studies offer support for treating RA aggressively with combination therapy, they still leave some unanswered questions. For example, how can doctors determine which patients will respond to methotrexate alone, which would do best with a combination therapy from the start, and which combination will work better for which people?

“What we’re not able to predict is which patients can take methotrexate alone or be on combination therapy,” says Larry W. Moreland, MD, lead author of the TEAR study and division chief of rheumatology at the University of Pittsburgh. “A large percentage of patients respond to methotrexate alone. But the problem is that no test allows us to know which patients need more.”

Another question is whether triple therapy will be as effective at slowing joint damage as the methotrexate-etanercept combination. The TEAR researchers found that patients on triple therapy had slightly more joint damage – as evidenced on X-rays – than those on methotrexate and etanercept.

“The majority of patients had no new erosions regardless of the treatment used,” says Dr. Moreland. “The group that got the triple therapy had a slight increase in erosions, but we don’t know what the clinical significance of that is.” One reason is that even without RA, people can have radiographic changes that look like damage.

Further research is needed to help answer those questions. Regardless of the findings, treatment must be individualized for each patient – some things work better in some patients while other things work better in others.

“Every time you open the door to see a patient, you are going to see something different with this disease,” Abby Abelson, MD, chair of the department of rheumatic and immunologic diseases at Cleveland Clinic in Ohio, who was not involved in either study. But now, Dr. Abelson has an additional treatment to consider when she opens that door. “Now I can say, we do have data that in some patients triple therapy is a non-inferior alternative and offer them that,” she says. 

Updated May 2015

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