OBJECTIVE: To examine the role of the variants of the PTPN22 and HLA-DRB1 genes 
as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid 
arthritis (RA).
METHODS: Patients were recruited from a primary care-based inception cohort of 
patients with IP and were followed up prospectively. For patients who died, the 
cause and date of death was obtained. Cox proportional hazards regression models 
were used to assess the association of the HLA-DRB1 (including the shared 
epitope [SE]) and PTPN22 genes with the risk of death from all causes and from 
cardiovascular disease (CVD) and to assess the interactions between SE, smoking, 
and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at 
symptom onset and sex.
RESULTS: DNA samples were available from 1,022 IP patients. During followup, 751 
of them (74%) satisfied the American College of Rheumatology 1987 criteria for 
RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted 
death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 
1.1-2.2]) and from CVD (HR 1.68 [95% CI 1.1-2.7]). This effect was most marked 
for individuals with the HLA-DRB1*01/*04 combination. An interaction of smoking, 
SE alleles, and anti-CCP antibodies was observed and was associated with the 
greatest risk of death from CVD (HR 7.81 [95% CI 2.6-23.2]). No association of 
the PTPN22 gene with mortality was detected.
CONCLUSION: SE alleles, particularly compound heterozygotes, are associated with 
death from all causes and from CVD, independently of autoantibody status. 
However, the combination of SE, smoking, and anti-CCP antibodies is associated 
with a high risk of premature death in patients with IP and RA, which raises the 
possibility of a targeted strategy to prevent CVD in these patients.