WASHINGTON—A recently begun Department of Veterans Affairs cooperative study is pitting different pharmaceutical treatments for rheumatoid arthritis (RA) against each other and promises to take a comprehensive look at what drugs work in what combination for which patients in the hope of improving RA therapy across the board. The study will also generate a dense database of patient information that will allow future researchers to examine links between a patient’s genetic blueprint and the success of different drugs.

Changing Outlook, Changing Therapies

The last two decades have seen drastic changes in the way that RA is thought of as a disease process. It has become recognized as not just a disease of the joints—something that causes mere discomfort for patients—but a systemic disease that can affect multiple organ systems as well as being a source of severe discomfort and morbidity for patients.

Dr. Jay Persselin, chief of rheumatology for the Greater VA Healthcare System—one of the VA physicians involved in the RA study—explained that, left untreated, RA can become a matter of life and death. “Early mortality has been known for years now to be linked to patients with RA,” Dr. Persselin said. “And it turns out that it’s really that group of folks who have the more severe disease. There are comorbidities that arise just from inflammation of RA, not just the disease process affecting organs and the joints, but just chronic inflammation.” Those cormobidities range from anemia and fatigue to an increased risk of cardiovascular disease. “So there’s been a realization that the approach to therapy is really based on making early diagnosis and initiating therapy very early in the course,” he said.

The biggest leap forward in RA treatment was the creation of methotrexate, an antifolate and antimetabolite, in the 1980s and used commonly in Europe in the 1990s before being adopted widely in America. “To this day, methotrexate is sort of the foundation of all therapy of rheumatoid arthritis, particularly for patients that we can see early,” Dr. Persselin said. “The problem is that, as good as methotrexate is, in many patients with time it will fail to continue to have a good response.”

In the mid 90s, a VA investigator, James O’Dell, M.D. working out of the Omaha VA, showed that methotrexate combined with either sulfasalazine or hydroxychloroquine, or with both drugs, worked better than methotrexate and a placebo in treating RA. Both sulfasalazine and hydroxychloroquine are used to reduce inflammation.

Since then other therapies have been developed using methotrexate combined with biologic agents that have been developed using DNA biotechnology that counteract the effects of cytokines, act as inflammatory mediators and affect activation of RA-relevant cells. But whether biologics or the older, nonbiologics work better has never been determined.

Comparing Therapies

“All the studies up to now have really compared a new drug—one of the biologic agents—to placebo when added to methotrexate in patients in which methotrexate has failed,” Dr. Persselin explained. “And until very recently, there has been no study that has directly compared any of the medical therapies added to methotrexate—none of the biologic agents or even comparing the biologic agents to the nonbiologic agents.”

And that is what VA Cooperative Study 551, Rheumatoid Arthritis Comparison of Active Therapies in Patients with Active Disease Despite Methotrexate Therapy—more commonly known as the RACAT study—is designed to determine.

“Patients who have signifi cantly active rheumatoid arthritis are entered in the study and they’re randomized either to receive hydroxychloroquine and sulfasalazine in addition to ongoing use of methotrexate [or] etanercept—one of the first biologic agents directed at tumor necrosis factor alpha,” Dr. Persselin explained. “The primary goal of this study is to compare the efficacy of these two strategies that have shown to be effective in the past. And the reason there’s so much interest in this, particularly at the VA is because of the fact of cost consideration. But it’s not just cost consideration. The newer drugs do have significant toxicity. We’ve seen significant infections with these [biologics].”

The study will involve 600 patients from 15 VA sites for whom methotrexate alone has failed, as well as at community providers in the Rheumatoid Arthritis Investigator Network (RAIN) and 10 sites in Canada that will be coordinated through the Canadian Institute of Health. All patients will be tracked for 48 weeks.

Erosion Progression

A secondary goal of the study is to carefully track bone damage in patients to determine whether some therapies are successful in halting progression of bone erosion.

“[We’ll] see whether or not there’s progression of erosions or if there’s any radiographic progression at the end of 48 weeks,” Dr. Persselin explained. “One of the issues—and arguably one of the gold standards for treatment of RA—is to prevent structural damage. This is a chronic inflammatory disease that if not controlled early can result in damage of cartilage, bony damage, and even damage of ligaments. And once there’s significant damage, it’s irreparable. And even if we control the inflammation later in the course, there’s enough structural damage that there’s even progression of the arthritis and developing of secondary degenerative changes. So the development of erosions has been one of the measures of efficacy for these drugs.”

What is also at stake is whether or not some drugs can prevent erosions even if they do not help inflammation.

“The alpha inhibitors have been shown in studies to prevent or slow down the progression of erosions. Even on people who have been on alpha inhibitors, who have had really poor control of their inflammation of their joints, there is still have an improvement of slowing of progression of erosions,” Dr. Persselin said. “There’s this disconnect between inflammation [and the] actually possible structural damage to the bone.”

It is currently not clear whether the other therapy, the one using the older nonbiologics, will be as effective—a question VA researchers hope to answer with this study.

Standardization of Function

An added benefit of the study will be the further dissemination of standardized measurements for the pain and lack of function caused by RA. “If you look at our charts, probably 10 or 15 years ago, on how people are doing in RA, you’ll see clinical providers mentioning patients are ‘much improved’ or ‘50 percent improvement.’ It’s always subjective. And we now realize that we need to use standardized tools to measure efficacy, not only in terms of improvement in inflammation, but also improvement in function,” Dr. Persselin declared. “Ultimately it’s not just what the X-rays look like; it’s not just what the labs look like. We want to maintain function. And traditionally most VA sites have [been] regularly measuring, using standardized tools, the activity of the disease [and] the patients’ assessment of how they’re doing overall.”

Functionality—whether an improvement or degradation of how easily a patient is able to go about the everyday movements of life—may be the best predictor of long-term outcomes, he noted.

The RATAC study will be using the Disease Activity Score (DAS-28), which is based on an assessment of 28 joints. “To be included in this study you need fairly moderate disease activity to even enroll. And there’s a complicated formula to input the number of joints that are tender, the number of target joints that are swollen, the CED rate, the visual analog scale, or how the patients think they’re doing on a scale of 1 to 10, where 0 is in the best shape they can be in. And it spits out a number,” Dr. Persselin said. “A score of 3.2 or less is considered good control, and actually a persistent score of 2.6 is associated with remission. Anything between 3.2 and 5.1 is considered active, moderate disease. To enroll in the study, patients need to have a score of at least 4.4.”

At midpoint—24 weeks into the study—researchers will reassess the patients, and if they haven’t had an improvement of 1.2 units or more, they will get switched over to the other strategy, ensuring that VA will do its best to improve the health of their patients.

“If they don’t respond to the first randomization, they’re going to be switched over. If they’re doing fine at midpoint, they’ll continue on the initial strategy,” Dr. Persselin explained. “And absolutely no patient in this study will be administered a placebo.”

At the end of the 48 weeks, researchers will be able to see if the functional status of the patient is equivalent in the two groups.

DNA Database

What Dr. Persselin considers to be one of the most powerful and potentially useful aspects of the study is the sheer amount of data that will be collected on patients being treated for RA. The data will give future researchers the ability to further explore the link between genes and RA therapy.

“One of the most important factors of this study is that when it’s completed, we’ll have a very large database of clinical data of these patients who have been on two different strategies,” Dr. Persselin explained. “The study will collect DNA samples and plasma, so at the end of the study investigators will be invited to actually propose studies to look at biomarkers and look at genetic factors that may predict which strategy may be most efficacious in certain patients. We may be able to predict using biomarkers or genetic factors which patients are more likely to have some of the poor prognostic factors, such as bony erosions.”

For example, some patients may have genetic polymorphisms of enzymes that metabolize drugs. By knowing whether they have a variance of enzymes that degrade drugs, researchers may be better able to assess who’s going to have more toxicity to those drugs, or how to adjust dosages.

“That’s sort of the future of the treatment of rheumatology and a lot of our diseases,” Dr. Persselin said. “Molecular medicine will be utilized to try and predict those factors early in the course of disease that may help guide therapy.”

The study is set to be completed in February 2010, at which time the double-blind on the trial will be broken. However, patients doing well will be asked to stay on.