Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response.
OBJECTIVE
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.


METHODS
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.


METHODS
Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74.


METHODS
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
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.
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England.
Sebastien
S
Viatte
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manches.
Darren
D
Plant
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts4Division of Rheumatology and Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
Buhm
B
Han
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England6Centre for Biostatistics, Institute of Population Health, University of M.
Bo
B
Fu
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England.
Annie
A
Yarwood
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manches.
Wendy
W
Thomson
NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, England7Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeleta.
Deborah P M
DP
Symmons
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manches.
Jane
J
Worthington
St Albans City Hospital, St Albans, England9Health and Human Sciences Research Institute, University of Hertfordshire, Hertfordshire, England.
Adam
A
Young
Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England.
Kimme L
KL
Hyrich
NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, England11Leeds Institute of Rheumatic and Musculoskeletal Medicine, School of Medicine, University of Leeds, Wellcome Trust Brenner B.
Ann W
AW
Morgan
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Anthony G
AG
Wilson
National Institute for Health Research, Newcastle Biomedical Research Centre, Newcastle-upon-Tyne Hospitals NHS Foundation Trust and Newcastle University (Institute of Cellular Medicine), Newcastle-upon-Tyne, England.
John D
JD
Isaacs
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England3Program in Medical and Population Genetics, Broad Institute of Massachuse.
Soumya
S
Raychaudhuri
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, University of Manchester, Manchester, England2NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manches.
Anne
A
Barton
D000328:Adult; D000368:Aged; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005528:Foot / Q000473:pathology; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006225:Hand / Q000473:pathology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012042:Registries; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
D018501:Antirheumatic Agents; D059811:HLA-DRB1 Chains; D014409:Tumor Necrosis Factor-alpha