Rheumatoid arthritis and the impact of genetic factors on mortality

April 27, 2007

A chronic autoimmune disease, rheumatoid arthritis (RA) is marked by inflammation that takes a progressive toll on not only the joints, but also various organs and the whole body. RA sufferers, as many studies have shown, tend to face a high risk for early death, increasing with the severity of their symptoms. The most prevalent cause of death among RA patients is cardiovascular disease. As in the general population, classic factors such as age, hypertension, diabetes, and smoking have been implicated in the RA death rate. Little is known, however, about the specific influence of genetic factors on mortality.

To investigate the genetic risk for early death in RA, researchers in the United Kingdom targeted a likely suspect, already associated with disease susceptibility and severity: the HLA-DRB1 alleles encoding the shared epitope (SE), a region involved in antigen recognition. Their findings, featured in the May issue of 2007 issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis), suggest an increased risk of death for RA patients with HLA-DRB1 SE genotypes. In particular, the presence of 2 SE alleles was strongly linked to a high risk of early death from heart disease or cancer.

The study focused on a subgroup of patients recruited between 1986 and 1997 for the Early RA study (ERAS), a UK-based long-term, multicenter study of disease outcomes and predictive features. HLA-DRB1 genotyping was carried out on blood samples from 767 patients with follow-up over 18 years. Of the total subjects, 186 (24 percent) had died, of whom 80 were men and 106 were women. Dates and causes of death were obtained for all. The 2 major causes of death were cardiovascular disease (28.2 percent) and malignancy (24.7 percent). The most common primary cause of death was ischemic heart disease (23 percent). The most common malignancy-related cause of death was lung cancer, which accounted for 14 of the 46 cancer deaths (30.4 percent).

Using Cox proportional hazards regression analyses, researchers gauged the association of HLA-DRB1 alleles with risk of mortality. They also used multivariate stepwise models to assess the predictive value of HLA-DRB1 genotypes compared with other potential risk factors.

Of the patients who died from heart disease or cancer, 29 (32.6 percent) carried 2 HLA-DRB1 SE alleles. What's more, patients who had 2 SE alleles generally died younger than all other patients. This was especially striking in patients who died of ischemic heart disease; those carrying 2 SE alleles died at a mean age of 67.8 years. Another surprising discovery was that patients with the 2 alleles had no clinical evidence of heart disease up to 1 year before dying of a heart attack.

"Our data raise the possibility that a higher risk of sudden cardiac death is associated with particular HLA-DRB1 genotypes that are more frequent in patients with RA," note the study's lead authors, Dr. D Mattey and Dr. A. Young, affiliates of the National Health Service Trust. "Further studies are needed to determine whether clinically silent ischemic heart disease in RA is associated with certain HLA-DRB1 genotypes, and whether this can explain in part the higher risk of sudden death in these patients."

As Dr. Mattey and Dr. Young admit, their team cannot offer an explanation for the association of these 2 SE alleles with increased risk of death from heart disease or cancer in RA patients. They also acknowledge the study's limitations, including the relatively small and racially homogenous sample (all subjects were Caucasian), the incomplete information on patients' smoking status, and the inability to assess the effects of different therapies on mortality. "Treatment recommendations have changed substantially since the ERAS was first initiated," they observe. "Thus, further studies are necessary to determine the impact of DRB1 genotypes on mortality under current treatment regimens. It has been suggested that methotrexate and TNF inhibitors reduce the risk of cardiovascular death in RA, so the association between specific DRB1 genotypes and mortality may be modified by more aggressive treatment in those patients with genotypes that predispose to more severe disease."
Article: "Association of DRB1 Shared Epitope Genotypes With Early Mortality in Rheumatoid Arthritis: Results of Eighteen Years of Follow Up From the Early Rheumatoid Arthritis Study," D.L. Mattey, W. Thomson, W.E.R. Ollier, M. Batley, P.G. Davies, A.K. Gough, J. Devlin, P. Prouse, D.W. James, P.L. Williams, J. Dixey, J. Winfield, N.L. Cox, G. Koduri, and A. Young, Arthritis & Rheumatism, May 2007; (DOI: 10.1002/art.22527).


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