Abstract: Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus

New England Journal of Medicine Volume 349:1526-1533 October 16, 2003 Number 16

Melissa R. Arbuckle, M.D., Ph.D., Micah T. McClain, Ph.D., Mark V. Rubertone, M.D., R. Hal Scofield, M.D., Gregory J. Dennis, M.D., Judith A. James, M.D., Ph.D., and John B. Harley, M.D., Ph.D.

ABSTRACT

Background: Although much is known about the natural history of systemic lupus erythematosus (SLE), the development of SLE autoantibodies before the diagnosis of the disease has not been extensively explored. We investigated the onset and progression of autoantibody development before the clinical diagnosis.

Methods: The Department of Defense Serum Repository contains approximately 30 million specimens prospectively collected from more than 5 million U.S. Armed Forces personnel. We evaluated serum samples obtained from 130 persons before they received a diagnosis of SLE, along with samples from matched controls.

Results: In 115 of the 130 patients with SLE (88 percent), at least one SLE autoantibody tested was present before the diagnosis (up to 9.4 years earlier; mean, 3.3 years). Antinuclear antibodies were present in 78 percent (at a dilution of 1:120 or more), anti–double-stranded DNA antibodies in 55 percent, anti-Ro antibodies in 47 percent, anti-La antibodies in 34 percent, anti-Sm antibodies in 32 percent, anti–nuclear ribonucleoprotein antibodies in 26 percent, and antiphospholipid antibodies in 18 percent. Antinuclear, antiphospholipid antibodies, anti-Ro, and anti-La antibodies were present earlier than anti-Sm and anti–nuclear ribonucleoprotein antibodies (a mean of 3.4 years before the diagnosis vs. 1.2 years, P=0.005). Anti–double-stranded DNA antibodies, with a mean onset 2.2 years before the diagnosis, were found later than antinuclear antibodies (P=0.06) and earlier than anti–nuclear ribonucleoprotein antibodies (P=0.005).

For many patients, the earliest available serum sample was positive; therefore, these measures of the average time from the first positive antibody test to the diagnosis are underestimates of the time from the development of antibodies to the diagnosis. Of the 130 initial matched controls, 3.8 percent were positive for one or more autoantibodies.

Conclusions: Autoantibodies are typically present many years before the diagnosis of SLE. Furthermore, the appearance of autoantibodies in patients with SLE tends to follow a predictable course, with a progressive accumulation of specific autoantibodies before the onset of SLE, while patients are still asymptomatic.

Source Information

From the Arthritis and Immunology Program, Oklahoma Medical Research Foundation (M.R.A., M.T.M., R.H.S., J.A.J., J.B.H.), the Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center (M.T.M., R.H.S., J.A.J., J.B.H.), and the Department of Veterans Affairs (R.H.S., J.B.H.) — all in Oklahoma City; the Department of Rheumatology, Walter Reed Army Medical Center (M.R.A., G.J.D.), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (G.J.D.) — both in Bethesda, Md.; and the U.S. Army Center for Health Promotion and Preventive Medicine, Washington, D.C. (M.V.R.).

Address reprint requests to Dr. James at the Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, or at jamesj@omrf.ouhsc.edu.

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