The first findings from a major study comparing options for treating severe rheumatoid arthritis, or RA, soon after diagnosis brings reassuring news to patients and doctors. The TEAR – Treatment of Early Aggressive Rheumatoid Arthritis – study found that good disease control appears to be possible whether a patient starts on one drug and has therapies added within the first six months as needed, or if a patient starts immediately on several therapies. It also found that older-drug combinations appear to be equally as effective as the newer biologic drugs.

Previous studies have shown that aggressive treatment of RA with disease-modifying antirheumatic drugs, or DMARDs, soon after diagnosis leads to better control of the disease – which results in less joint damage and better physical function – compared with less intensive treatment. Currently, doctors generally take a “step up” approach to therapy, starting with a DMARD like methotrexate, and adding more drugs as needed if disease activity remains high.

But questions remain: Is immediately starting treatment with more than one drug a better strategy than stepping up, so as not to miss the crucial window of opportunity to keep disease activity to a minimum? How large is the window of opportunity? And which drug combinations work best? The study, published recently online in Arthritis & Rheumatism, aimed to address some of these issues; it is the first set of findings released from the TEAR study.

The researchers looked at two questions. First, are results better if treatment starts with a combination of drugs, or is it just as good to start with methotrexate alone and add drugs only if needed to gain control? Second, which combination of drugs gets better results: methotrexate plus etanercept, or Enbrel – a biologic drug that blocks tumor necrosis factor-alpha, or TNF – or traditional “triple therapy” of methotrexate plus sulfasalazine and hydroxychloroquine? (Both drug combinations are commonly used by rheumatologists when RA disease activity remains high on methotrexate alone.)

To address these questions, the researchers studied 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. They also had what is considered severe or aggressive RA. Severity is determined by whether the patient tests positive for RA-related antibodies, has signs of joint damage on X-rays, and/or has a high disease activity score as measured by the DAS28, which reflects swollen and tender joints in 28 spots around the body. The average DAS28 score at the start of the study was 5.8.

The patients were randomized into four groups. One group immediately started on the combination of methotrexate and etanercept. Another immediately started on triple therapy. A third and fourth group received methotrexate alone for 24 weeks (six months). At that point, people in these two groups were stepped up to one of the combination therapies if their DAS28 score was 3.2 or greater. The study was double-blinded, meaning neither patient nor doctor knew who received which treatment.
 

A total of 596 patients completed the study. The main outcome, or measure, was how much the average DAS28 score went down for a particular treatment group during the second year of the study (week 48 through week 102).

The researchers found at six months (week 24), average DAS28 scores were lower in the two groups that had started on immediate, combination-drug therapy than they were 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 meant they did not need to step up to more intensive therapy.

“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.”

When the researchers looked at DAS28 scores for week 48 through week 102, they found the 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, or in people who received triple therapy versus methotrexate and etanercept.

“What we found is that triple therapy is just as good at slowing down disease activity as methotrexate and etanercept,” says Dr. Moreland.

Results from the TEAR study do not quite line up with the American College of Rheumatology’s new RA treatment guidelines, released in March of this year. They recommend that doctors closely monitor and adjust RA treatment at 3-month intervals in order to achieve remission or low disease activity. But in severe cases of RA – those with high disease activity scores and poor prognostic features – the guidelines recommend immediately starting off on either a biologic (with or without methotrexate) or triple (or double) therapy.

Rheumatologist Nathan Wei, MD, director of the Arthritis Treatment Center in Frederick, Md., calls the TEAR study a sound, well-designed one, noting that patients have a lot to consider when deciding whether to add one or more drugs to methotrexate including effectiveness, side effects and costs; newer biologics are much more expensive than the older triple therapy.

But Dr. Wei, who was not involved in the TEAR study, says when it comes to stepping up, he is more aggressive than the TEAR researchers. “There is such a narrow window in treating RA,” he says. “I make my decision [about methotrexate] after four to eight weeks, and if a patient is not responding, I’m fairly aggressive with using a biologic.”

The TEAR researchers, however, did find one difference in outcome between the treatment groups: 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.

Although Dr. Wei notes that rheumatologists rarely take radiographic images to find out whether there is RA damage except in study situations, it does concern him that people on methotrexate plus triple therapy had more radiographic damage than those on methotrexate and etanercept. “Even if you are in clinical remission, the disease may still be smoldering. That has been the argument for offering biologic medication earlier than later,” Dr. Wei says.