WASHINGTON, DC—In a "Frontiers in Translational Research" session at the American College of Rheumatology 2006 annual meeting, V. Michael Holers, MD, of the University of Colorado in Denver, suggested that rheumatologists may soon be able to use risk reduction strategies to prevent the development of rheumatoid arthritis (RA), much as controlling hypertension and reducing high cholesterol levels help reduce the risk of cardiovascular disease and stroke.

Autoantibodies precede onset of disease

The possibility that patients headed toward development of RA or other AI diseases might be identified at pre-symptomatic stages as candidates for therapeutic intervention rests on the recognition that development of measurable levels of autoantibodies typically precedes the appearance of clinical symptoms by several years. The risk factors (RFs) identified for development of RA in rheumatoid factor-positive (RF+) subjects include elevated anti-CCP antibodies, RF isotypes such as IgM-RF, and having two or more family members who have RA, as well as having the biomarkers' shared epitope (SE) and anti-CCP in combination.

Dr. Holers said that antibodies to citrullinated proteins develop in collagen-induced arthritis (CIA) in animals, precede the onset of disease and, if administered by passive transfer to another animal can contribute to RA-like changes. "This suggests that they have the potential for causing arthritis in humans," he said.

A number of large cohort studies have added to the understanding of asymptomatic subjects who are at high risk of RA. First-degree relatives of patients with RA are at 4–5-fold increased risk and are being studied in several trials. One includes the parents of 30,000 HLA-typed children with type I diabetes. Dr. Holers reported data for 425 parents, none of whom had RA at baseline. Further investigation showed that 38 (5%) were RF+, and five (1.2%) were anti-CCP-positive, rates considerably higher than those in the general population.

Cohort studies have also been used to study associations between RA and various environmental factors. Dr. Holers said that having ever used oral contraceptives decreased the risk of becoming RF+ (RR = 0.23), while a smoking history of 20 or more pack-years greatly increased the odds of being RF+ (RR = 4.40).

"Smoking increases, and oral contraceptive use decreases the risk of taking that first step from genetic risk to RA-related autoimmunity," Dr. Holers said. "This suggests that RA-related autoantibodies could be a modifiable risk factor."

Data from a military cohort study support this possibility. A study of blood samples from 83 military recruits who developed RA and 83 matched controls showed that 60% of those who subsequently developed RA were RF+ before diagnosis, 62% were anti-CCP, 72% were positive for either RF or anti-CCP, and 49% were positive for both markers. "Most became RF+ or anti-CCP-positive 4–5 years before diagnosis of RA," Dr. Holers said.

The lag time between anti-CCP positivity and RA diagnosis was age dependent. Subjects who became anti-CCP-positive before age 40 progressed to RA more quickly than those who became anti-CCP-positive after age 40. Dr. Holers said that this probably reflects the greater genetic risk of individuals who develop RA at younger ages.

However, Dr. Holers emphasized that the biomarkers so far identified as associated with high risk of subsequent RA apply only in subjects who are RF+.

"Seronegative RA is a very different disease and will require different preventive strategies," he said.

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