Specific haplotypes of the of the HLA-DRB1 gene – well known to confer increased risk for rheumatoid arthritis – proved to be strong, independent predictors of radiological disease severity, risk of death, and response to tumor necrosis factor inhibitor therapy in a three-cohort study involving more than 6,000 patients.

The report represents the first analysis to find significant predictors for those outcomes based on 16 haplotypes that are derived from three amino acid positions of the HLA-DRB1 gene. Two of those amino acid positions, 71 and 74, are within the classic shared epitope, which has been “associated with the development of anticitrullinated protein antibodies and has been consistently associated with markers of severe disease, such as radiological joint damage and mortality in patients with RA,” wrote Dr. Sebastien Viatte of the University of Manchester (England) and his coauthors (JAMA 2015;313:1645-56).

Dr. Sebastien Viatte

Dr. Sebastien Viatte

The third amino acid position examined in the study, position 11, which lies outside the shared epitope, was associated with increased risk for radiological damage, mortality, and response to tumor necrosis factor (TNF) inhibitor treatment, the latter of which neither position 71 or 74 was associated with.

To find these significant predictors of prognosis, the investigators examined the three amino acid positions in a large prospective cohort of patients with inflammatory polyarthritis or RA who were recruited at disease onset in the Norfolk Arthritis Register. They then independently validated the results for mortality and radiological damage in a replication cohort of patients from the Early Rheumatoid Arthritis Study study and for treatment response in patients from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort. All the patients were from the United Kingdom and had self-reported white ancestry.

Overall, radiographic outcome was associated with amino acid positions 11, 71, and 74 independently of each other and “completely superseded the shared epitope model.” Analyses of the effects of the three amino acid positions on all-cause mortality showed similar results. Change in the 28-joint Disease Activity Score or European League Against Rheumatism response was not associated with anticitrullinated protein antibodies or the shared epitope, but was significantly associated with valine at position 11.

Valine at position 11 consistently had the strongest effects on increasing risk for radiographic damage, mortality, and better TNF inhibitor treatment response. Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (odds ratio, 1.75; 95% confidence interval, 1.51-2.05) as measured by Larsen score. “Valine at [position 11] represents what we believe is the strongest single genetic association with radiographic damage identified to date,” they wrote.

Valine at position 11 also was associated with higher all-cause mortality in patients with inflammatory polyarthritis (hazard ratio, 1.16; 95% CI, 1.03-1.31; P = .01) and with better EULAR response to TNF inhibitor therapy (OR, 1.14; 95% CI, 1.01-1.30; P = .04).

The investigators found that the 16 haplotypes that existed in the cohorts based on the amino acid positions at 11, 71, and 74 of HLA-DRB1 could be used to construct a hierarchy of risk for the three outcome measures. For instance, they noted that the valine-containing VKA haplotype was associated with RA susceptibility (OR, 4.44; 95% CI, 4.02-4.91), joint erosions in patients with RA (OR, 1.82; 95% CI, 1.35-2.46), and a better response to TNF inhibitor drugs (OR, 1.23; 95% CI, 1.06-1.43). Although a 23% increase in the odds of good response to TNF inhibitors is “modest,” the researchers wrote, “it refers to the likelihood of moving from the EULAR [European League Against Rheumatism] category of none to a moderate response, or from a moderate to a good response for every copy of the VKA haplotype carried by the patient, compared with noncarriers.

“Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRBl haplotype analysis for management of RA,” the authors concluded.

The study was funded by a grant from Arthritis Research UK. Several authors reported receiving fees or grant support from companies that market drugs for RA.