Many studies have shown that the mortality rate is increased in rheumatoid arthritis (RA) compared with the general population, and that this is associated with disease severity (1–12). Causes of death in RA are similar to those in the general population, although in RA there are excess deaths due to cardiovascular disease (1, 5, 6, 8, 10–12). Most cardiovascular deaths in RA are due to congestive heart failure or myocardial infarction, implicating ischemic heart disease. As in the general population, classic risk factors such as age, sex, hypertension, diabetes mellitus, smoking, and socioeconomic status have been associated with mortality. In addition, comorbid conditions and clinical manifestations of RA, including markers of inflammation, rheumatoid factor (RF), nodular disease, joint counts, and functional disability, have all been shown to be significant risk factors. Increased systemic inflammation, in particular, appears to confer additional risk of development of atherosclerosis and cardiovascular mortality in RA (6, 11, 13–16).
There is little information on the possible influence of genetic factors on mortality in RA. However, it seems reasonable to postulate that genes important in the development and progression of RA may also play a role in comorbidity and mortality. Such genetic factors include HLA–DRB1 alleles encoding the shared epitope (SE). This is a conserved region with similar amino acid sequences (QKRAA, QRRAA, or RRRAA) encoded by DRB1 alleles associated with RA susceptibility and/or severity (17).
The association with the risk of developing severe disease appears to vary among SE alleles, with particular combinations of these (e.g., HLA–DRB1*0401/*0404) being associated with worse disease (18, 19). Homozygosity for the HLA–DRB1*0401 allele has been associated with major organ involvement (19), while both homozygosity and heterozygosity for 2 HLA–DRB1 SE alleles have been associated with rheumatoid nodules and vasculitis (19–22). There is also preliminary evidence that increased cardiovascular risk in RA patients may, at least in part, be associated with polymorphism at the HLA–DRB1 locus. A previous study of Spanish patients with RA demonstrated that HLA–DRB1*04 SE alleles were associated with endothelial dysfunction, and may thus predict increased cardiovascular risk (23).
The current study was carried out on a subgroup of patients recruited for the Early RA Study (ERAS). This is a UK multicenter, inception cohort study with the primary aims of recording various dimensions of outcome over time and examining predictive features in patients receiving conventional therapies (24). We have recently reported that in the whole cohort (n = 1,429) mortality was increased, especially in the early stages of RA, and particularly from ischemic heart disease (12). Risk factors present within the first year included older age, measures of functional decline and disease severity, socioeconomic status, extraarticular RA, and comorbidity. More than half of the patients (n = 767) have been genotyped for HLA–DRB1. The size of the cohort and length of followup have provided the opportunity to investigate the association of the SE with overall mortality and with cause-specific mortality in patients who have been treated with optimal therapies accepted as part of standard practice in the 1990s.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
We found evidence that RA patients carrying particular HLA–DRB1 SE genotypes are at increased risk of mortality from cardiovascular disease and malignancy. In particular, the DRB1*0101/*0401 and *0404/*0404 genotypes were associated with an increased risk of ischemic heart disease mortality, and there was an increased risk of mortality due to malignancy in patients carrying genotypes with a DRB1*0101 allele.
The DRB1*0101/*0401 genotype was the strongest predictor of mortality overall and was a significant risk factor for both ischemic heart disease–related and malignancy-related mortality. Interestingly, patients with the DRB1*0101/*0401 genotype had higher ESRs at baseline than did other patients, and, along with patients carrying DRB1*0401/*0401, showed a greater rate of radiographic progression. These data suggest that certain HLA–DRB1 genotypes that are associated with more severe RA are also associated with poor survival in RA, and may confer an increased risk of death due to ischemic heart disease or malignancy. This did not apply to all genotypes previously associated with severe disease (18). For example, the DRB1*0401/*0404 genotype was not predictive of overall mortality or death due to ischemic heart disease or malignancy. However, in this study the DRB1*0401/*0404 genotype was also not associated with more active or severe disease (Mattey DL, et al: unpublished observations).
There is considerable evidence to suggest that systemic inflammation plays an important role in the development of atherosclerosis, and the extent of inflammation in RA patients has been shown to be predictive of cardiovascular disease and overall mortality (6, 11, 14–16). One possible explanation for the association of the DRB1*0101/*0401 genotype with ischemic heart disease mortality was the higher ESR at baseline in patients with this genotype. However, in models which contained ESR and the DRB1*0101/*0401 genotype, only the latter was predictive of mortality due to ischemic heart disease. There was no evidence of interaction between this genotype and ESR or other clinical variables.
These data suggest that this particular genotype is predictive of ischemic heart disease mortality independently of the level of inflammation. The association also appears to be independent of other clinical features such as RF status, nodules, HAQ score, swollen joint count, and extraarticular disease. Similarly, DRB1*0101/*0401 and other genotypes with the DRB1*0101 allele were predictive of death due to malignancy, independent of other clinical features of RA.
Of particular interest was the finding that the DRB1*0101/*0401 and *0404/*0404 genotypes were risk factors for ischemic heart disease–related mortality in patients who had no clinical evidence of ischemic heart disease up to 1 year before death. There is evidence that the presentation of coronary heart disease is different in RA patients compared with individuals without RA (36). Ischemic heart disease may be clinically silent in many RA patients, and there appears to be a higher risk of unrecognized myocardial infarction and sudden cardiac death. RA patients also have a lower likelihood of demonstrating angina symptoms. Furthermore, the increased risk of coronary heart disease in RA precedes the ACR criteria–based diagnosis of RA, and is not due to an increased incidence of traditional risk factors (36).
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. 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.
We do not currently have an explanation for the association of particular HLA–DRB1 genotypes with ischemic heart disease–related or malignancy-related mortality in RA. Similarities between RA and atherosclerosis are evident, including T cell activation in the synovium and accumulation of T cells in atherosclerotic plaques. It is tempting to speculate that immune responses associated with particular HLA–DRB1 genotypes may be common to the pathogenesis of both conditions. However, investigations of the relationship between HLA–DRB1 alleles and atherosclerosis/coronary heart disease have produced contradictory findings, and no clear consensus about a relationship has emerged (37–39).
Since HLA–DRB1 genes are in strong linkage disequilibrium with other genes in the major histocompatibility complex, some of these studies have also included investigations of polymorphisms in HLA–DQB1, HLA class I alleles, tumor necrosis factor α (TNFα), and TNFβ (lymphotoxin). A previous study in a Japanese population has implicated variants in the lymphotoxin α gene as risk factors for myocardial infarction (40). In the present study it is possible that gene polymorphisms in linkage disequilibrium with DRB1*0101, *0401, or *0404, or particular DRB1–DQB1–TNFα–TNFβ haplotypes may explain the observed associations with ischemic heart disease–related mortality. However, further genotyping for other HLA class II and class III gene polymorphisms is needed to investigate this possibility.
Associations of various HLA class II and TNF polymorphisms with a variety of cancers have been found in different populations (41–43), although no particular associations with the HLA–DRB1*0101/*0401 or DRB1*0101/*0404 genotypes have been reported. A recent study of Chinese patients showed that the DRB1*01 allele was associated with the development of gastric cancer in Helicobacter pylori–infected individuals, but not in uninfected individuals (43). Such studies suggest that the host HLA genotype may play an important role in the risk of cancers that are associated with particular types of infection. However, there is no evidence that SE alleles or SE genotypes are associated with such cancers in RA, although a number of cancers have been shown to be increased in RA. These include non-Hodgkin's lymphoma, lung cancer, and non-melanoma skin cancers (44, 45).
One of the limitations of the present study was the incomplete information on smoking status at the start of the study. Retrospective data on smoking was collected on a significant number of patients, but it was not possible to obtain data on many of the patients, due to death or loss to followup. However, it is worth noting that in those patients for whom information on smoking status was available, HLA–DRB1*0101/*0401 remained a predictor of ischemic heart disease–related and malignancy-related mortality (apart from lung cancer), independent of smoking status.
A previous study has suggested that the development of RA may involve an interaction between smoking and the SE (46), although another study has shown an interaction in SE-negative patients (47). In the present investigation there was evidence of a possible interaction between ever having smoked and carrying DRB1*0101/*0401 with respect to overall mortality and ischemic heart disease mortality. However, the wide confidence intervals and relatively small number of patients with this combination who had smoked indicate that these results need to be treated with caution.
A detailed assessment of the effects of treatment was beyond the scope of this study, and, because of the time period of the investigation, it was not possible to assess the impact of anti-TNF or other biologic agents on mortality. Treatment recommendations have changed substantially since the ERAS was first initiated. 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 (48, 49), so the association between specific DRB1 genotypes and mortality may be modified by more aggressive treatment in patients with genotypes that predispose to more severe disease.
In conclusion, our data suggest that the increased risk of mortality in RA patients may be, at least in part, genetically determined, and is associated with particular HLA–DRB1 SE genotypes which also influence the severity of rheumatic disease. Some caution in the interpretation of results is required, since multiple comparisons of SE genotypes were performed, and confirmation of associations in another population is needed. Due to differences in allele frequencies among ethnic groups, consideration should also be given to possible variations in the association of specific DRB1 genotypes with RA mortality in different populations. Therefore, in addition to confirmatory studies in Caucasians, studies to explore whether specific DRB1 genotypes are important in mortality in other ethnic groups are needed.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Mattey had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Davies, Prouse, James, Williams, Dixey, Winfield, Cox, Young.
Acquisition of data. Thomson, Ollier, Batley, Davies, Gough, Devlin, Prouse, James, Williams, Dixey, Winfield, Cox, Koduri, Young.
Analysis and interpretation of data. Mattey, Ollier, Young.
Manuscript preparation. Mattey, Ollier, Gough, Devlin, Dixey, Young.
Statistical analysis. Mattey, Young.