Adalimumab and methotrexate is about five times more effective than methotrexate alone for rheumatoid arthritis

Aug 15 2005

For people with long-standing rheumatoid arthritis, combined treatment with the new "biologic" drug adalimumab and methotrexate is about five times more effective than methotrexate alone, according to a new systematic review of studies.

In six randomized controlled trials, comprising 2381 people with at least 10 years of the disease, the authors report that adalimumab (Humira) plus methotrexate decreased pain and swelling in patients who fail to respond to standard treatment.

Adalimumab “is even more active when used combined with methotrexate,” according to lead reviewer Federico Navarro-Sarabia, M.D., chair of rheumatology at the Hospital Universitario Virgen Macarena in Seville, Spain, and colleagues. “More people had improved symptoms with adalimumab alone than with fake injections, but the improvement was not as much as when adalimumab was taken in combination with methotrexate.”

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

The reviewers found that after six months, 43 percent of all subjects on adalimumab plus methotrexate had achieved a 50-percent improvement in symptoms, compared with 9 percent of all subjects receiving placebo plus methotrexate.

In the longest-running study, X-rays showed that adalimumab injections slowed progression of joint damage more than placebo.

Adalimumab was given in injections of 40 milligrams every other week or 20 milligrams per week.

The reviewers determined clinical effectiveness of each drug by measuring patients’ improvement using a symptom scale devised by the American College of Rheumatology. They measured disease progression using European League Against Rheumatism radiologic criteria.

They found that the rate of side effects was not significantly different between the adalimumab and placebo groups, but noted that the long-term side effects of adalimumab treatment have not yet been determined.

Adalimumab works by preventing a protein called tumor necrosis factor (TNF) from signaling the release of joint-damaging substances. The other FDA-approved TNF blockers are etanercept (Enbrel) and infliximab (Remicade). Adalimumab is approved for the treatment of moderate to severe rheumatoid arthritis in adults who do not respond to other treatments.

Methotrexate is the most widely used of “disease modifying antirheumatic drugs” among rheumatoid arthritis patients. Although DMARDs play an important role in arthritis treatment, only one, leflunomide, was developed specifically for rheumatoid arthritis treatment. Methotrexate was developed as a cancer treatment.

“What we might be seeing here is a synergistic effect,” said Scott Zashin, M.D., coauthor of a book on TNF blockers for arthritis, and clinical assistant professor at the University of Texas-Southwestern Medical School in Dallas. “Doctors and patients need to know, and this review supports the claim, that combination therapy will generally have a more robust effect, though some patients will do well on either drug alone. For patients with long-standing disease, this review affirms combination therapy as the standard of care.”

Addressing future research priorities, the reviewers wrote, “The available clinical trials with adalimumab are short-term studies (six-months duration) and there is only one twelve-month study. Long-term efficacy and safety studies are needed.”

Rheumatoid arthritis is an autoimmune disease which develops when certain cells of the immune system malfunction and attack healthy joints. The cause of rheumatoid arthritis is unknown. The primary focus of the inflammation is in the synovium, the lining tissue of the joint. Inflammatory chemicals released by the immune cells cause swelling and damage to cartilage and bone.

More than 2 million Americans suffer from rheumatoid arthritis, according to the American College of Rheumatology. About 75 percent of those affected are women. While the disease appears most commonly between the ages of 40 and 60, it can develop at any age.

http://www.cochrane.org and http://www.hbns.org