rheumatoid arthritis and cvd
- From: MarilynMann <mannm@xxxxxxxxxxx>
- Date: 29 Apr 2007 09:30:01 -0700
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 published in Arthritis & Rheumatism, 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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