TY - JOUR
T1 - Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response
AU - Viatte, Sebastien
AU - Plant, Darren
AU - Han, Buhm
AU - Fu, Bo
AU - Yarwood, Annie
AU - Thomson, Wendy
AU - Symmons, Deborah P.M.
AU - Worthington, Jane
AU - Young, Adam
AU - Hyrich, Kimme L.
AU - Morgan, Ann W.
AU - Wilson, Anthony G.
AU - Isaacs, John D.
AU - Raychaudhuri, Soumya
AU - Barton, Anne
PY - 2015/4/28
Y1 - 2015/4/28
N2 - 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 feetwere 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 alsowas 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 haplotypeswas 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.
AB - 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 feetwere 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 alsowas 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 haplotypeswas 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.
UR - http://www.scopus.com/inward/record.url?scp=84928731411&partnerID=8YFLogxK
U2 - 10.1001/jama.2015.3435
DO - 10.1001/jama.2015.3435
M3 - Article
C2 - 25919528
AN - SCOPUS:84928731411
SN - 0098-7484
VL - 313
SP - 1645
EP - 1656
JO - Journal of the American Medical Association (JAMA)
JF - Journal of the American Medical Association (JAMA)
IS - 16
ER -