National Institute of Arthritis and Musculoskeletal and Skin Diseases

January 14, 1995

Contact: Elia Ben-Arii 
Office of Scientific and 
Health Communications 
(301) 496-8188

Results of a 48-week multicenter clinical study of 219 adults with rheumatoid arthritis show that the drug minocycline reduces joint pain and swelling and is safe in patients with mild to moderate disease. Findings of the Minocycline in Rheumatoid Arthritis (MIRA) Trial are reported in the January 15 issue of Annals in Internal Medicine. Lead author Barbara C. Tilley, Ph.D., is from the Henry Ford Health Sciences Center in Detroit, Michigan, which served as coordinating center for the study. Graciela S. Alarcón, M.D., from the University of Alabama at Birmingham, chaired the MIRA steering committee.

"Minocycline is another drug to add to the armamentarium of treatments for rheumatoid arthritis," said Michael D. Lockshin, M.D., acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The MIRA Trial was conducted at six clinical centers across the United States and supported by research contracts from the NIAMS, a component of the National Institutes of Health (NIH). Stephen P. Heyse, M.D., M.P.H., of the NIAMS, managed the trial, with the assistance of Stanley R. Pillemer, M.D., and Marilyn Tuttleman, M.S.

In an editorial accompanying this paper, Harold E. Paulus, M.D., a rheumatologist at the University of California, Los Angeles, calls the MIRA Trial "well designed and [well] executed." Paulus says that the modest-but significant-clinical benefit of minocycline combined with minimal toxicity "compares favorably with currently used disease-modifying antirheumatic drugs."

Rheumatoid arthritis is a chronic, potentially crippling inflammatory disease in which joint linings become inflamed and cause damage to nearby bone and cartilage. This causes pain, stiffness and loss of movement, and can eventually lead to destruction of the joints. At least two million people in the United States, the majority of them women, have rheumatoid arthritis. Just what causes rheumatoid arthritis is unclear, and is the subject of much research.

Previous reports on whether tetracycline drugs such as minocycline are effective for rheumatoid arthritis have been contradictory. Minocycline and other tetracyclines are known and used in medicine primarily for their antibiotic (anti-infection) properties. However, recent research indicates that these drugs have various anti-inflammatory actions that may make them useful for treating rheumatoid arthritis.

The study was a randomized, double-blind, placebo-controlled trial. "The MIRA Trial is an example of the way a clinical study should be done," said Lockshin. At the beginning of the study, patients were split ("randomized") into two groups with very similar characteristics. One group, consisting of 109 patients, received 100 milligrams (mg) of minocycline twice a day by mouth; the other 110 patients received a matching placebo (inactive capsules) twice daily. In a double-blind placebo-controlled trial, neither physicians nor patients know who is receiving the test drug and who is receiving the placebo.

To participate in the trial, patients had to meet established criteria for rheumatoid arthritis and have six or more swollen joints and nine or more tender or painful joints. All study participants taking nonsteroidal anti-inflammatory drugs and/or low doses of oral steroids such as prednisone prior to the study could continue taking these drugs. If patients were taking any of the so-called disease-modifying antirheumatic drugs (such as gold, hydroxychloroquine, methotrexate, or sulfasalazine) or intravenous steroids, they were taken off these drugs for at least 4 weeks before starting to take minocycline.

The two main objectives of the MIRA Trial were to find out whether minocycline produces improvement in joint swelling and in joint tenderness in patients with rheumatoid arthritis. Another objective was to determine whether minocycline is safe over a 48-week treatment period in these patients. At the end of the 48 weeks, 54 percent of patients taking minocycline and 39 percent of patients taking the placebo had at least a 50 percent improvement in the number of swollen joints. In terms of joint tenderness, 56 percent of the minocycline group and 41 percent of the placebo group had at least a 50 percent improvement.

There is often a "placebo effect" in clinical trials of potential treatments for rheumatoid arthritis. Other factors may have contributed to the unexpectedly large improvement in the placebo group, including the fact that study participants were encouraged to continue taking stable doses of nonsteroidal anti-inflammatory drugs. Although improvement began by week 12 of the study in both groups, improvement in joint swelling and tenderness continued through week 48 for patients receiving minocycline but reached a plateau at week 24 for those receiving placebo.

Patients taking minocycline also showed significant improvement in several laboratory measures of disease activity, including such blood tests as erythrocyte sedimentation rate, hematocrit, platelet count and rheumatoid factor levels. Both physicians and the patients themselves made subjective assessments of how the patients were faring. These subjective measures were not significantly different between the minocycline and placebo groups.

Adverse reactions that were clearly due to minocycline were infrequent and mild. Only seven patients stopped taking minocycline because of side effects. The most common of these was dizziness, a known side effect of minocycline.

Minocycline has several actions that may explain its usefulness in rheumatoid arthritis. Recent research shows that, besides their antibiotic effects, some tetracyclines, including minocycline, can block the actions of enzymes called metalloproteinases that play a role in the destruction of bone and cartilage in the joints in rheumatoid arthritis. There is also evidence that these drugs can dampen or modify some of the body's inflammatory responses. However the MIRA Trial was not designed to provide information on how minocycline works.

The results of the MIRA Trial show that minocycline has some benefit for treating rheumatoid arthritis; how effective minocycline is compared to other treatments for the disease remains to be determined. The results also show that minocycline has relatively low toxicity over a year's time.

The six clinical centers that participated in the MIRA Trial were: The Beth Israel Hospital, Boston, Massachusetts; State University of New York Health Sciences Center at Brooklyn; The University of Alabama at Birmingham; The University of Utah, Salt Lake City; Henry Ford Hospital, Detroit, Michigan; and The University of Vermont College of Medicine, Burlington. Minocycline and placebo capsules were provided by Lederle Laboratories. The Centers for Disease Control and Prevention assisted by performing blood tests to help rule out Lyme arthritis.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health, leads and coordinates the Federal research effort in all forms of arthritis by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and by disseminating information on research results.

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