Data Show RA Antibodies Increase Mortality Rate

Postmenopausal women with rheumatoid arthritis (RA) and highly RA-specific antibodies had twice the mortality rate of healthy women, an analysis of data from the Women’s Health Initiative found.

All-cause 10-year mortality among women who tested positive for anti-cyclic citrullinated peptide (CCP) antibodies at baseline was 20.2 per 1,000 person-years (95 percent CI 15.6-26.1), compared with 11.4 per 1,000 (95 percent CI 10.3-12.5) for unaffected women, according to Lewis H. Kuller, M.D., D.P.H., of the University of Pittsburgh, and colleagues.

In addition, in a multivariable analysis, having probable RA — as defined by CCP positivity and use of disease-modifying anti-rheumatic drugs (DMARDs) at baseline — significantly predicted 10-year mortality, with a hazard ratio of 2.8 (95 percent CI 2.2-3.5), the researchers reported online in Arthritis & Rheumatism.

It is well recognized that RA patients have an elevated mortality risk, particularly from cardiovascular causes, but the precise pathophysiology remains uncertain, with potential contributors including inflammation, immune abnormalities involving T cells and cytokines, and disease severity as evidenced by levels of antibodies including anti-CCP and rheumatoid factor.

To explore potential explanatory factors, Kuller and colleagues identified a sample of 9,988 participants enrolled in the Women’s Health Initiative between 1993 and 1997 who reported having RA either at baseline or during a follow-up visit. Their mean age at baseline was 62.8 years, and two-thirds were white. The cutoff for anti-CCP positivity was 5 U/mL or higher, which was considered more than 98 percent specific for RA.

In a previous study, the researchers found that the positive predictive value of anti-CCP positivity plus DMARD use was 100 percent.

A total of 8.1 percent of women with self-reported RA were anti-CCP positive, and of this group, 57.5 percent received treatment with DMARDs such as methotrexate, hydroxychloroquine, sulfasalazine, or the anti-rheumatic biologic agents at some point.

During the 10 years of the study, 13 percent of the women died, with a median time until death of eight years for those with RA at baseline. The main causes of death in the cohort were cardiovascular diseases, including coronary heart disease and stroke, and all cancers.

Unlike for anti-CCP antibodies, death rates weren’t affected by whether or not patients were positive for rheumatoid factor, which is common in RA but less specific.

When the researchers looked at mortality risk factors among women who were anti-CCP antibody positive, they identified increased rates of death per 1,000 person-years for:

• Current smoking, 27.8 (95 percent CI 15.4-50.5)
• Coronary heart disease at baseline, 33.3 (95 percent CI 18-63.2)
• Diabetes, 32.3 (95 percent CI 16.1-66.7)
• Lower physical activity, 22.9 (95 percent CI 15.7-33.4)
• Physical function, 20.2 (95 percent CI 15.6-26.2)

General health also was “a very powerful predictor,” with death rates being quadrupled among women with anti-CCP antibodies who reported poor health compared with healthy women without RA.

Another factor associated with higher mortality among anti-CCP positive women was severe joint pain. Those women had mortality rates of 35.5 per 1,000 person-years, compared with 11.4 per 1,000 person-years for women without arthritis.

Additional work will be needed to more fully examine the effects of treatment on mortality risk in RA, and particularly the use of the highly effective biologic agents, and to consider the potential importance of other inflammation-related factors.

“Further longitudinal RA studies and clinical trials should focus on identifying the specific determinants of excess mortality, especially among the anti-CCP positive RA population and whether further modification of systemic inflammation and/or reduction in fibrosis and thrombogenesis will decrease mortality,” Kuller and colleagues concluded.

Limitations of the study were that the Women’s Health Initiative wasn’t population-based, and there were relatively small numbers of nonwhite, anti-CCP positive patients.