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Association of HLA-DRB1 Haplotypes With Rheumatoid Arthritis Severity, Mortality, and Treatment Response

Lookup NU author(s): Professor John Isaacs

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Abstract

IMPORTANCE Advances have been made in identifying genetic susceptibility loci for autoimmune diseases, but evidence is needed regarding their association with prognosis and treatment response.OBJECTIVE To assess whether specific HLA-DRB1 haplotypes associated with rheumatoid arthritis (RA) susceptibility are also associated with radiological severity, mortality, and response to tumor necrosis factor (TNF) inhibitor drugs.DESIGN, SETTING, AND PARTICIPANTS The Norfolk Arthritis Register (NOAR; 1691 patients and 2811 radiographs; recruitment: 1989-2008; 2008 as final follow-up) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (421 patients and 3758 radiographs; recruitment: 1986-1999; 2005 as final follow-up) as an independent replication cohort for studies of radiographic outcome. Mortality studies were performed in the NOAR cohort (2432 patients; recruitment: 1990-2007; 2011 as final follow-up) and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006-2010; 2011 as final follow-up). Longitudinal statistical modeling was performed to integrate multiple radiograph records per patient over time. All patients were from the United Kingdom and had self-reported white ancestry.EXPOSURES Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74.MAIN OUTCOMES AND MEASURES Radiological outcome using the Larsen score (range: 0 [none] to 200 [severe joint damage]) and erosions of the hands and feet on radiographs, all-cause mortality, and treatment response measured by change in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response.RESULTS Patients with RA and valine at position 11 of HLA-DRB1 had the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51-2.05], P = 4.6E-13). By year 5, the percentages of patients with erosions of the hands and feet were 48% of noncarriers (150/314) of valine at position 11, 61% of heterozygote carriers (130/213), and 74% of homozygote carriers (43/58). 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) (noncarriers: 319 deaths in 1398 patients over 17 196 person-years, mortality rate of 1.9% per year; carriers: 324 deaths in 1116 patients in 13 208 person-years, mortality rate of 2.5% per year) and with better EULAR response to TNF inhibitor therapy (OR, 1.14 [95% CI, 1.01-1.30], P = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote carriers: 81% [698/866]; and homozygote carriers: 86%[277/322]). The risk hierarchy defined by HLA-DRB1 haplotypes was correlated between disease susceptibility, severity, and mortality, but inversely correlated with TNF inhibitor treatment response.CONCLUSIONS AND RELEVANCE Among patients with RA, the HLA-DRB1 locus, which is associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA.


Publication metadata

Author(s): Viatte S, Plant D, Han B, Fu B, Yarwood A, Thomson W, Symmons DPM, Worthington J, Young A, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD, Raychaudhuri S, Barton A

Publication type: Article

Publication status: Published

Journal: JAMA: The Journal of the American Medical Association

Year: 2015

Volume: 313

Issue: 16

Pages: 1645-1656

Print publication date: 28/04/2015

Online publication date: 28/04/2015

Acceptance date: 01/01/1900

ISSN (print): 0098-7484

ISSN (electronic): 1538-3598

Publisher: American Medical Association

URL: http://dx.doi.org/10.1001/jama.2015.3435

DOI: 10.1001/jama.2015.3435


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