Results from a multi-center trial suggest that patients with rheumatoid arthritis (RA) who have had stable, low disease activity while on the biologic drug etanercept (Enbrel) may be able to cut their dose in half without relapsing. The results of the PRESERVE trial, published recently in The Lancet, are promising for patients.

“If you cut the dose of etanercept in half, the patients’ responses were about the same as on a full dose. That has incredible implications for cost savings and for taking less medication,” says Eric Ruderman, MD, professor of medicine in the division of rheumatology, Northwestern University Feinberg School of Medicine in Chicago. Dr. Ruderman was not involved in the study.

A 2012 study by Thomson Reuters Healthcare in Cambridge, Mass., found that the average annual payment for etanercept is $15,345. Etanercept is a tumor necrosis factor inhibitor (anti-TNF), meaning it blocks TNF, a protein involved in inflammation. Other anti-TNFs currently approved for RA include infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumbab (Simponi).

For the PRESERVE trial, a total of 834 patients who continued to have moderately active RA despite using methotrexate – a traditional disease-modifying antirheumatic drug (DMARD) – were enrolled at 80 centers in Europe, Latin America, Asia and Australia. Each week for 36 weeks, they received full doses of etanercept (50 mg) plus methotrexate. At the end of that time period, 604 had achieved low disease activity and sustained it until the end of the 36 weeks. Those patients were then divided into three groups: For the next 52 weeks, a third continued taking the full dose of etanercept, a third were given 25 mg of etanercept, and a third got placebo. All patients continued taking methotrexate. Neither doctor nor patient knew which patients were assigned to which group.  

Low disease activity was defined as having a disease activity score (DAS28) ≤ 3.2; remission was defined as having DAS28 < 2.6. The DAS28 is calculated using the scores of certain blood tests and counting tender and swollen joints in 28 places.

At the end of the 52 weeks, the researchers found that 82.6 percent of those who took the full dose of etanercept continued to have low disease activity, compared with 79.1 percent of the half-dose group, and 42.6 percent of the placebo group.

“It is good news that a huge proportion of patients with moderate disease activity can attain low disease activity or remission,” says lead study author Josef S. Smolen, MD, chair of the division of rheumatology at the Medical University of Vienna in Austria. “It is also good news that a good response can be maintained over a prolonged period in so many patients and that this maintenance can be achieved also with a reduced dose of etanercept in a vast majority of patients.”

The more difficult result of the study is that if patients stopped taking etanercept, most did not do well. “The study’s key message is that people who are on a biologic drug like etanercept need to stay on it,” says Nathan Wei, MD, director of the Arthritis Treatment Center in Frederick, Md. “One thing not mentioned in the study is that if a patient is taken off a biologic and then [relapses], it is much more difficult to get her back into remission, although we don’t know why.”

Also unclear from the study is who might do best on half a dose or even off the drug. “We are working on this aspect,” says Dr. Smolen. “Low disease activity may be a sufficiently good state for dose reduction. But the longer someone is in remission the better.” 

“That’s the next challenge,” says Dr. Ruderman. “Some people who stopped etanercept did OK. The big question in rheumatology is: Who are the right people to take off a biologic? Are there biologic markers for that?” He notes that if someone appears to be doing well but still shows signs of joint damage, he or she should not be taken off a biologic.

One observation researchers have made is that the longer the low disease activity or remission, the better a patient will do without biologics. “If someone is in remission for six months or more, they are stable, but [whether being stable] beyond six months makes a difference, we don’t know,” says Dr. Ruderman. And technically remission doesn’t mean someone has absolutely no disease. “You can meet the criteria for remission and still have one swollen joint,” he says.

Other lingering questions: Will patients on half a dose of etanercept still show joint changes on X-rays or have other RA complications? “We don’t have those answers,” says Dr. Ruderman. “And we don’t know if lowering the dose also lowers the risk” of infection that all biologics carry, he says.

Dr. Wei says patients have legitimate reasons to want to cut back on etanercept. “Some patients may have been on the medication for a long time and want to stop. And sometimes it’s an insurance issue: A patient may have switched companies, and the new insurance won’t pay for that biologic,” he says. 

Although the study suggests good news for those who do want to lower their doses of biologic medications, Dr. Ruderman warns that it’s premature to celebrate. “The study should not drive insurance policy yet. It is premature to think that cutting the dose of etanercept is for everyone until we can predict who will do well on half a dose only,” he says. “And we don’t know who will be doing just as well at five years as they were at one year. The study doesn’t give us that information.”