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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Objective

To determine whether the HLA–DRB1 shared epitope (SE) is associated with early mortality and specific causes of death in rheumatoid arthritis (RA).

Methods

HLA–DRB1 genotyping was carried out on blood samples from 767 patients recruited for the Early RA Study (ERAS), a multicenter, inception cohort study with followup over 18 years. Dates and causes of death (n = 186) were obtained from the Office of National Statistics. The association of HLA–DRB1 alleles with risk of mortality was assessed using Cox proportional hazards regression analyses. Multivariate stepwise models were used to assess the predictive value of HLA–DRB1 genotypes compared with other potential baseline risk factors.

Results

The SE was not significantly associated with overall mortality. However, the presence of 2 SE alleles was associated with risk of mortality from ischemic heart disease (hazard ratio [HR] 2.02 [95% confidence interval 1.04–3.94], P = 0.04), and malignancy (HR 2.18 [95% confidence interval 1.17–4.08], P = 0.01). Analysis of specific SE genotypes (corrected for age and sex) revealed that the HLA–DRB1*0101/*0401 and 0404/*0404 genotypes were the strongest predictors of mortality from ischemic heart disease (HR 5.11 and HR 7.55, respectively), and DRB1*0101/*0401 showed a possible interaction with smoking. Male sex, erythrocyte sedimentation rate, and Carstairs Deprivation Index were also predictive, but the Health Assessment Questionnaire score, rheumatoid factor, nodules, and swollen joint counts were not. Mortality due to malignancy was particularly associated with DRB1*0101 genotypes.

Conclusion

The risk of mortality due to ischemic heart disease or cancer in RA is increased in patients carrying HLA–DRB1 genotypes with particular homozygous and compound heterozygous SE combinations.

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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Study population.

Consecutive RA patients were recruited from 9 centers in England. Entry criteria included symptom duration of <2 years and no prior treatment with disease-modifying antirheumatic drugs (DMARDs). Initial and yearly assessments were performed, and standard clinical, laboratory, functional, and socioeconomic data were recorded prospectively, as previously described (24, 25). These assessments included evaluation regarding the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria for RA (26), swollen and tender joint counts (24), functional grade (27), the disability index of the Health Assessment Questionnaire (HAQ) (28), erythrocyte sedimentation rate (ESR), RF, antinuclear antibodies, body mass index (weight [kg]/height [m2]), radiographic involvement of the hands and feet (29), and the Carstairs Deprivation Index (CDI) (30).

The CDI was used to categorize the socioeconomic status of the patients. Scores were obtained from the 1991 census small-area statistics for the UK and assigned to patients based on their district of residence, which was identified from the postal address. The index is based on a composite of 4 variables: male unemployment, the social class of the head of the household, overcrowding, and access to a car. Higher scores are associated with less favorable status.

Clinicians recorded the presence or development of any extraarticular manifestations (including nodules, vasculitis, RA-associated lung disease, RA neuromyopathies, Felty's syndrome, and Sjögren's syndrome) and coexistent medical conditions, all hospital admissions (31), and causes of death if known. Smoking history was not initially recorded but was added later in the study.

Survival followup.

All patients in this study were included in the National Health Service Central Register, a computerized database of the records of all patients registered with a general practitioner in England or Wales. Access to this registry is obtained via the Office for National Statistics (General Register Office, Southport, UK). All patients were tracked using the registry, and notification of patient deaths was obtained from the Office for National Statistics within 1 month of death. The date and main cause of death were obtained from death certificates, which included up to 3 other contributing causes and 3 comorbid conditions. Causes of death were coded by the Office for National Statistics, using the International Classification of Diseases, Ninth Revision (32). Most patients (66%) died in the hospital, while for the remainder, death certificates were signed by general practitioners. Details were cross-referenced with the ERAS database and with medical records of premorbid conditions and hospitalizations, as previously described (12).

Treatment.

All centers followed published UK guidelines for management of RA (33). DMARDs were chosen according to physician preference, using the standard practice of sequential monotherapy, and combination therapy for more severe disease. The majority of patients (83%) received ≥1 DMARD, started at a median of 2 months after the onset of symptoms (68% of patients were receiving DMARDs within 3 months and 87% by 12 months after the onset of symptoms). This was consistent with the group's early treatment practice. The remaining patients (17%) were treated with nonsteroidal antiinflammatory drugs and/or low-dose steroids.

Overall, 54% of the patients received sulfasalazine at some point during the study period, 18% received methotrexate, 13% received intramuscular gold, 9% received D-penicillamine, 4% received antimalarials, and 2% received various other treatments. Of the patients treated with DMARDs, 55% needed >1 drug. Steroids in doses of ≥7.5 mg daily for ≥12 months were used in 246 patients (17%).

Genotyping.

Full genotyping with HLA–DRB1 allele subtype analysis was not carried out on all patients in the ERAS. In the present study we have included only those patients in whom this allele subtype analysis was ascertained in one department (Centre for Integrated Genomic Medical Research), using the methodology previously described (34).

Statistical analysis.

The association of HLA–DRB1 with mortality risk was assessed using Cox proportional hazards regression analyses adjusted for age and sex. The time intervals for those patients who were alive at the end of the study period, and for those who were lost to followup, were censored using the date of the last hospital visit. It is important to note that, because of the central recording of mortality data in the UK, we collected these data on all patients entered into the study, and no deaths were missed in patients lost to followup.

Univariate analyses (age and sex adjusted) were carried out to determine baseline clinical risk factors for mortality. Multivariate models were used to assess the predictive value of HLA–DRB1 phenotypes or genotypes, compared with other potential baseline risk factors. Separate analyses were carried out on the risk of ischemic heart disease–related mortality and on the risk of malignancy-related mortality. The hazard ratio (HR) and the 95% confidence interval (95% CI) were calculated for each risk factor. For analysis of each specific cause of mortality, data on patients who died of other causes were censored at the time of death, and data on survivors were censored at last followup. All data were analyzed using the Number Cruncher Statistical Software package for Windows (NCSS, Kaysville, UT).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

Demographic characteristics of the ERAS cohort.

Of 1,429 patients recruited between 1986 and 1997, 422 (30%) died, of whom 177 were men (42%) and 245 were women (58%). In the group of patients who had been genotyped for this study (n = 767), 186 died (24%), of whom 80 were men (43%) and 106 were women (57%). Table 1 summarizes the baseline clinical features of the whole cohort and of those whose HLA–DRB1 genotype was known. There were no significant differences between these 2 groups, and their characteristics were similar to patient characteristics in other studies of early RA.

Table 1. Characteristics of the ERAS patients at baseline*
CharacteristicAll patients (n = 1,429)Patients with known HLA–DRB1 genotypes (n = 767)
  • *

    ERAS = Early Rheumatoid Arthritis Study; IQR = interquartile range; HAQ = Health Assessment Questionnaire; ESR = erythrocyte sedimentation rate; SE = shared epitope.

Age at onset, median (IQR) years57 (45–66)56 (45–65)
Sex, % female66.767.4
Disease duration, median (IQR) months6 (4–11)7 (4–12)
% rheumatoid factor positive72.876.1
% with nodules11.013.0
% with erosive disease26.024.2
HAQ score, median (IQR)1.0 (0.5–1.75)1.0 (0.5–1.5)
ESR, median (IQR) mm/hour38 (19–62)36 (19–60)
% with extraarticular RA18.120.5
SE status, no. (%)  
 SE−/SE−210 (27.4)
 SE−/SE+387 (50.4)
 SE+/SE+170 (22.2)
SE+/SE+ genotypes, no. (%)  
 DRB1*0101/*01018 (1.0)
 DRB1*0101/*040137 (4.8)
 DRB1*0101/*040410 (1.3)
 DRB1*0401/*040141 (5.3)
 DRB1*0401/*040436 (4.7)
 DRB1*0401/*040818 (2.3)
 DRB1*0404/*040410 (1.3)
 Other SE+/SE+10 (1.3)

Main causes of death.

Table 2 shows the main causes of death in patients who had been genotyped. These were similar to those previously described for the whole cohort (12), and in general are similar to causes of death in the overall population of England and Wales. The 2 major causes of death were cardiovascular disease (28.5%) and malignancy (24.7%). The most common primary cause of death was ischemic heart disease (23%; n= 43). The most common malignancy-related cause of death was lung cancer, which accounted for 14 of the 46 deaths from cancer (30.4%).

Table 2. Main causes of death in the 186 Early Rheumatoid Arthritis Study patients typed for HLA–DRB1 alleles
Cause of deathNo. (%) of patients
Cardiovascular disease53 (28.5)
Cerebrovascular disease16 (8.6)
Malignancy (solid tumors)42 (22.6)
Malignancy (hematologic)4 (2.1)
Chest infections23 (12.4)
Other infections6 (3.2)
Diseases of the respiratory system25 (13.4)
Diseases of the digestive system8 (4.3)
Diseases of the genitourinary system4 (2.2)
Other5 (2.7)

Clinical, laboratory, and demographic risk factors for mortality.

In this report we have not provided a full description of the analyses of clinical and demographic risk factors for mortality in patients genotyped for HLA–DRB1, since the findings were similar to those previously described for the whole cohort (12). The most significant predictors of mortality from any cause, present at baseline or at 1 year, were older age, male sex, increased ESR, increased HAQ score, extraarticular disease, and increased CDI score. As in the whole cohort (12), the HAQ score at 1 year had improved predictive value compared with the HAQ score at baseline. Independent baseline predictors of death due to ischemic heart disease alone were older age, male sex, increased ESR, and increased CDI score. Factors that were shown to be predictive or close to significant in these analyses were included in multivariate models with SE genotypes, as described below.

Association of the HLA–DRB1 SE with mortality.

Univariate analyses corrected for age and sex showed no association between the SE and mortality overall or particular causes of mortality (Tables 3 and 4). Although not significantly associated with mortality overall, carrying 2 SE alleles was associated with mortality from ischemic heart disease (HR 2.02 [95% CI 1.04–3.94], P = 0.04) (Table 3) and malignancy (HR 2.18 [95% CI 1.17–4.08], P = 0.01) (Table 4). Of the 89 patients who died due to ischemic heart disease or malignancy, 29 (32.6%) carried 2 SE alleles, compared with 141 of the 678 remaining patients (20.8%). Patients who had 2 SE alleles had a significantly younger mean age at death compared with all other patients (71.05 years versus 76.75 years; P = 0.001). This was particularly striking in patients who died of ischemic heart disease; those carrying 2 SE alleles died at a mean age of 67.8 years (P = 0.001).

Table 3. Association of the SE with overall mortality and mortality due to ischemic heart disease in the ERAS patients*
SE statusOverall mortalityIschemic heart disease mortality
Hazard ratio (95% CI)PHazard ratio (95% CI)P
  • *

    Individual analyses for each variable were carried out using Cox proportional hazards regression corrected for age and sex. Individuals with an SE+/SE+ genotype were compared with individuals without an SE+/SE+ genotype (i.e., SE−/SE− and SE−/SE+). Particular SE+/SE+ genotypes (e.g., DRB1*0401/*0401) were also compared with the combined SE−/SE− and SE−/SE+ group. 95% CI = 95% confidence interval (see Table 1 for other definitions).

SE positive1.16 (0.82–1.62)0.390.91 (0.47–2.56)0.77
SE+/SE+1.34 (0.94–1.89)0.12.02 (1.04–3.94)0.04
SE genotype    
 DRB1*0401/*04011.29 (0.74–2.24)0.372.26 (0.87–5.93)0.09
 DRB1*0404/*04041.26 (0.31–5.13)0.757.55 (1.70–33.45)0.008
 DRB1*0101/*04012.04 (1.11–3.75)0.025.11 (1.90–13.87)0.001
 DRB1*0101/*04041.64 (0.60–4.44)0.332.05 (0.28–15.18)0.48
 DRB1*0401/*04041.15 (0.60–2.20)0.68<0.00011.0
 DRB1*0401/*04080.97 (0.35–2.67)0.96<0.00011.0
Table 4. Association of the SE with mortality due to malignancy in ERAS patients*
SE statusAll cancer mortalityLung cancer mortality
Hazard ratio (95% CI)PHazard ratio (95% CI)P
  • *

    Individual analyses for each variable were carried out using Cox proportional hazards regression corrected for age and sex. Individuals with an SE+/SE+ genotype were compared with individuals without an SE+/SE+ genotype (i.e., SE−/SE− and SE−/SE+). Patients positive for DRB1*0101 or a DRB1*04 SE allele (*0401, *0404, *0405, or *0408) were compared with SE-negative patients. For comparison of genotypes, patients with a DRB1*0101 allele were compared with all patients with genotypes lacking a DRB1*0101 allele. 95% CI = 95% confidence interval (see Table 1 for other definitions).

SE positive1.65 (0.76–3.56)0.20.76 (0.23–2.51)0.65
SE+/SE+2.18 (1.17–4.08)0.011.09 (0.29–4.05)0.89
Phenotype    
 DRB1*01012.91 (1.62–5.23)0.00031.92 (0.62–5.87)0.25
 DRB1*04 (SE alleles)1.46 (0.65–3.32)0.360.43 (0.13–1.46)0.18
DRB1*01/SE status    
 DRB1*0101+/SE−2.03 (0.99–4.18)0.0542.23 (0.67–7.46)0.19
 DRB1*0101+/SE+5.82 (2.77–12.55)<0.00011.38 (0.17–11.25)0.76
Genotype    
 DRB1*0101/*04016.49 (2.61–16.12)<0.00011.82 (0.22–15.03)0.58
 DRB1*0101/*04046.14 (1.83–20.50)0.003<0.00011.0

Impact of specific HLA–DRB1 genotypes.

It has been demonstrated that different SE genotypes may vary in their association with specific disease outcomes. We therefore analyzed the association of individual SE+/SE+ genotypes with mortality. These analyses revealed an increased risk of mortality from any cause in patients with the DRB1*0101/*0401 genotype (Table 3). The same genotype was strongly associated with ischemic heart disease mortality, as was DRB1*0404/*0404, and the association of the DRB1*0401/*0401 genotype with mortality from ischemic heart disease approached significance (Table 3).

In a separate analysis, we investigated whether the DRB1*0101/*0401 and DRB1*0404/*0404 genotypes were associated with ischemic heart disease mortality in patients without a previous history of ischemic heart disease. Due to the yearly nature of data collection, the ischemic heart disease status could only be established to within 1 year of death. Evidence of previous ischemic heart disease was present in 67 of the 767 genotyped patients (8.7%), but of the 43 patients who died of ischemic heart disease, 26 had no history of the disease. Cox regression analysis of patients with no history of ischemic heart disease revealed a strong association between DRB1*0101/*0401 or DRB1*0404/*0404 and ischemic heart disease mortality (HR 7.07 [95% CI 2.69–18.35], P < 0.0001).

Investigation of markers of disease activity and severity revealed that patients with the DRB1*0101/*0401 genotype had significantly higher mean ESRs at baseline than patients with all other genotypes (54.2 mm/hour versus 41.0 mm/hour; P = 0.01). There was no significant difference in radiographic damage at baseline, but patients with the DRB1*0101/*0401 genotype had developed significantly higher Larsen scores (35) by the second yearly assessment, compared with all patients with genotypes other than DRB1*0401/*0401 (mean score 15.5 versus 8.8; P = 0.002), and continued to show significantly higher scores over each of the following 8 years (data not shown).

In the case of malignancy-related mortality, a highly significant association was found with the DRB1*0101 allele. The strongest association was found for genotypes with DRB1*0101 and another SE allele (Table 4), although the combination of DRB1*0101 with an SE-negative allele showed close to significant association. Patients carrying the HLA–DRB1*0101/*0401 or DRB1*0101/*0404 genotypes demonstrated the strongest association.

Interestingly, there were differences in the association of particular DRB1*0101 genotypes with different cancer-related mortalities. Thus, the risk of death from gastrointestinal-related cancer was significantly greater in individuals with an HLA–DRB1*0101/SE+ genotype compared with patients lacking a DRB1*0101 allele (HR 8.0 [95% CI 2.09–30.3], P = 0.002). In contrast, the risk of death from lung cancer was not significantly associated with DRB1*0101 or any DRB1*0101 genotype (Table 4).

Multivariate determinants of mortality.

We carried out stepwise Cox proportional hazards regression in models containing HLA–DRB1 genotypes and demographic and clinical variables, in order to determine the best predictors of ischemic heart disease–related and malignancy-related mortality (Table 5). For the analysis of ischemic heart disease mortality, patients with the DRB1*0101/*0401 or *0404/*0404 genotypes were combined into one group and compared with patients negative for these genotypes.

Table 5. Independent baseline predictors of mortality due to ischemic heart disease and malignancy in ERAS patients*
Step and variableHazard ratio (95% CI)P
  • *

    Analyses were carried out using a stepwise Cox proportional hazards regression model. Baseline variables included in the analyses but excluded during the stepwise procedure because they were not statistically significant were rheumatoid factor (+/−), nodular disease (+/−), ESR (mm/hour), HAQ score (0–3), hemoglobin (gm/dl), extraarticular disease (+/−), swollen joint count, number of disease-modifying antirheumatic drugs taken, and number of steroids taken. 95% CI = 95% confidence interval; CDI = Carstairs Deprivation Index (see Table 1 for other definitions).

  • Hazard ratios for age are per year.

Ischemic heart disease  
 Age1.11 (1.08–1.15)<0.0001
 DRB1*0101/*0401 or DRB1*0404/*04045.13 (2.04–12.8)0.0005
 CDI score (per unit)1.30 (1.03–1.64)0.04
 Male sex2.01 (1.07–3.80)0.03
Malignancy  
 Age1.07 (1.04–1.10)<0.0001
 DRB1*0101/*0401 or DRB1*0101/*04044.68 (2.10–10.49)0.0001
 Male sex2.14 (1.13–4.10)0.03

Carrying either of these genotypes was found to provide the highest risk of ischemic heart disease mortality, after older age (HR for the DRB1 *0101/*0401 or *0404/*0404 genotype 5.13 [95% CI 2.04–12.8], P = 0.0005). Increased CDI score and male sex were also predictive. We found no significant association with RF status, nodular disease, ESR, HAQ score, extraarticular disease, swollen joint count, or number of DMARDs or steroids taken in the first year. No evidence of interaction between DRB1 genotypes and clinical or demographic variables was found.

Of the 46 deaths due to malignancy, 10 patients (21.7%) carried either the DRB1*0101/*0401 or the *0101/*0404 genotype, while only 37 of the remaining 721 patients (5.1%) carried either of these genotypes. In a stepwise regression model, these genotypes were associated with the highest risk of malignancy-related death, after older age (HR for the DRB1*0101/*0401 or *0101/*0404 genotype 4.68 [95% CI 2.10–10.49], P = 0.0001). In this model, male sex was also predictive, but other clinical variables were not. No interactions between DRB1 genotypes and clinical or demographic variables were found.

Impact of cigarette smoking.

It was not possible to control for smoking status in all genotyped patients, since information on smoking was collected retrospectively and available only on 586 patients (76.4%). In this subset there were 147 deaths, 36 (24.5%) due to malignancy and 34 (23.1%) due to ischemic heart disease. No significant associations were found between ever smoking and overall mortality (HR 1.35, P = 0.09), mortality due to ischemic heart disease (HR 1.34, P = 0.4), or mortality due to malignancy (HR 1.69, P = 0.13). In all cases, HLA–DRB1*0101/*0401 was a significant predictor of mortality, independent of smoking status (data not shown).

Cox regression models, which included interaction terms between ever smoking and DRB1 genotypes, as well as the main effects, indicated that overall mortality and mortality due to ischemic heart disease were associated with a possible interaction between ever smoking and carrying the DRB1*0101/*0401 genotype (HR for interaction 4.41, 95% CI 1.14–16.28 and 7.71, 95% CI 1.01–54.6, respectively). However, the wide confidence intervals indicate that these results should be treated with caution. No interaction was seen for malignancy-related mortality. Lung cancer mortality was primarily associated with smoking (HR 8.97 [95% CI 1.71–36.97], P = 0.005), and no interaction between SE phenotypes or genotypes and smoking was found (data not shown).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

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.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES

The authors would like to thank Cathy Mayes, Annie Seymour, Terry McCourt, Lynn Hill, Linda Waterhouse, Hazel Tait, Dora White, Sue Stafford, Helen Dart, Cathy Boys, and Alison Kent for their invaluable metrology work.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. Acknowledgements
  8. REFERENCES
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