These were subsequently included as covariates in the study of genetic factors. of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort Monomethyl auristatin F (MMAF) (1846 patients enrolled at initiation of TNF inhibitor; recruitment: 2006C2010; 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 experienced self-reported white ancestry. EXPOSURES Sixteen HLA-DRB1 haplotypes defined by amino acids at positions 11, 71, and 74. MAIN OUTCOMES AND Steps Radiological end result 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 switch in Disease Activity Score based on 28 joint counts and European League Against Rheumatism (EULAR) response. RESULTS Monomethyl auristatin F (MMAF) Patients with RA and valine at position 11 of HLA-DRB1 experienced the strongest association with radiological damage (OR, 1.75 [95% CI, 1.51C2.05], = 4.6E-13). By 12 months 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 service providers (130/213), and 74% of homozygote service providers (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, 1.03C1.31], = .01) (noncarriers: 319 deaths in 1398 patients over 17 196 person-years, mortality rate of 1 1.9% per year; service providers: 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, 1.01C1.30], = .04) (noncarriers: 78% [439/561 patients] with moderate or good EULAR response; heterozygote service providers: 81% [698/866]; and homozygote service providers: 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 usually associated with disease susceptibility, was also associated with radiological severity, mortality, and treatment response. Replication of Monomethyl auristatin F (MMAF) these findings in other cohorts is needed as a next step in evaluating the role of HLA-DRB1 haplotype analysis for management of RA. Like many autoimmune diseases, the success in identifying genetic loci associated with rheumatoid arthritis (RA) susceptibility has not informed clinical practice. The largest RA genetic susceptibility effect is usually conferred by the HLA locus,1 and studies conducted in the 1980s recognized multiple RA risk alleles within the gene, encoding a similar amino acid motif at positions 70 through 74, leading to the shared epitope hypothesis.2 The shared epitope is associated with the development of anticitrullinated protein antibodies and has been consistently associated with markers of severe disease, such Monomethyl auristatin F (MMAF) as radiological joint damage3,4 and mortality in patients with RA.5,6 However, the epitope has not shown a consistent association with treatment response.7C10 Amino acid positions 11, 71, and 74 within HLA-DRB1 are the major determinants of the association with RA susceptibility11 because no residual association at other HLA-DRB1 amino acid positions was observed after conditioning on these 3 positions. These 3 positions define 16 HLA-DRB1 haplotypes that can be ranked in a hierarchy based on the risk they confer and better model the association at HLA-DRB1 than the shared epitope alone. We hypothesized that these markers of disease susceptibility are also markers of disease severity and treatment FIGF response to tumor necrosis factor (TNF) inhibitor drugs. In this study, we tested their association with multiple steps of RA severity (radiological damage and mortality) and with response to TNF inhibitor drugs. Methods Patients and Cohorts The Norfolk Arthritis Register (NOAR) was used as a discovery cohort and the Early Rheumatoid Arthritis Study (ERAS) as an independent replication cohort for studies of radiographic end result. Mortality studies were performed in the NOAR cohort and studies of treatment response in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort. All patients were from the United Kingdom and experienced self-reported white ancestry thus avoiding spurious associations caused by populace stratification. To compare the odds ratios (ORs) for disease severity with susceptibility and the ORs for treatment response with susceptibility, we recalculated the ORs for susceptibility using 9585 cases and 33 742 controls (explained in eMethods in Product 1). Radiographic End result: NOAR and ERAS Cohorts We used the NOAR and ERAS cohorts to test association with radiographic end result. NOAR is a primary careCbased inception cohort of patients recruited since 1989 presenting with at least 2 swollen joints for at least 4 weeks (inflammatory polyarthritis) and followed up prospectively for 20 years or less.12,13 Patients with inflammatory polyarthritis who satisfied the 1987 American College of.