The Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry is a National Institute of Arthritis and Musculoskeletal and Skin Diseases-funded program enrolling self-identified African Americans with RA, as defined by the revised American College of Rheumatology (ACR) classification criteria 23 . Patients with disease duration of <2 years were enrolled in CLEAR I, a longitudinal cohort, from 2000 to 2005. Patients with any disease duration were enrolled in CLEAR II, a cross-sectional arm of the registry, beginning in 2006. Enrollment in CLEAR II is ongoing. Comprehensive demographic, clinical, and radiographic data were obtained from CLEAR I participants at the baseline visit and at 36 and 60 months from disease onset, and at one time point in CLEAR II participants. Data on current and previous drug treatments, including disease-modifying antirheumatic drugs (DMARDs), biologic agents, and glucocorticoids were collected. Participants were recruited, informed consents were obtained from study participants by study coordinators, and studies were conducted under approval by the Institutional Review Boards of the participating institutions: The University of Alabama at Birmingham (UAB) (Coordinating Center), Emory University (Atlanta, GA); The Medical University of South Carolina (Charleston), The University of North Carolina at Chapel Hill, and Washington University (St. Louis, MO). A group of 282 healthy African Americans matched for age and gender without RA, recruited as part of the CLEAR Registry, were used as a control group.

Variables ascertained included age, ethnicity, education, poverty (as defined by the United States Federal Government and adjusted for the number of subjects in the household 24 ), history of RA in a first-degree relative, smoking history (self-reported ever or never), disease duration, the ACR core set of variables (number of swollen joints, number of painful joints, pain scale (assessed with a 0 to 10 Visual Analog Scale)) 25 , functional status assessed with the Health Assessment Questionnaire 26 , and presence of extraarticular manifestation (pulmonary fibrosis, Sjögren syndrome, pericarditis, vasculitis, skin ulcers, or scleritis). The following laboratory variables were recorded at enrollment: serum CRP measured with a high-sensitivity immunometric assay (hsCRP; Immulite 2000 Diagnostic Products, Los Angeles, CA), anti-CCP antibody (IgG) detected with a second-generation enzyme-linked immunosorbent assay (ELISA; Diastat, Axis-Shield Diagnostics, Dundee, Scotland), and rheumatoid factor measured with ELISA (INOVA Diagnostics, San Diego, CA, USA) 27 .

The presence of rheumatoid nodules was defined by history and physical examination at enrollment. Participants who reported a history of rheumatoid nodules on chest imaging were also considered to have rheumatoid nodules. All RA participants underwent radiographic evaluations of their hands/wrists (posteroanterior views) and feet (anteroposterior views). Study radiographs were read by an experienced reader blinded to all clinical and demographic data, who scored the radiograph for erosions and joint-space narrowing (JSN) by using the van der Heijde modified Sharp method 28 29 . The presence of erosions and JSN for each patient was defined by scores greater than zero; only the baseline evaluations were included in these analyses because of the limited number of follow-up radiographs in this ongoing study 30 .

Genotypes for rs1805010 and rs1801275 were determined by TaqMan (Applied Biosystems (ABI), Foster City, CA) on an ABI 7900 HT Sequence Detection System. HLA-DRB1 shared epitope (SE) status was determined as previously described 31 .

The analyses were performed by using SAS 9.1 (Cary, NC). Separate comparisons between socioeconomic, demographic, clinical, and laboratory characteristics as a function of the presence of rheumatoid nodules and erosions were performed. Categoric variables were compared by using the Pearson χ² test, whereas continuous variables were compared with independent t tests and the nonparametric Wilcoxon rank-sum test, where appropriate. A two-tailed P value of <0.05 was chosen as the statistically significant level. We analyzed potential associations between the IL4R SNPs and the presence of rheumatoid nodules and radiographic erosions, by using univariate and multivariate analyses. Logistic regression models were used to analyze the odds of having rheumatoid nodules and erosions as a function of the presence of IL4R SNPs, adjusted by nodules or erosions (according to the outcome analyzed), age at RA onset, gender, disease duration (≥2 years versus <2 years), smoking, and methotrexate use. The patients were stratified by the presence of autoantibodies (anti-CCP or RF positive, as one or separate), and HLA-DRB1 SE. Hardy-Weinberg equilibrium for the distribution of genotypes was examined with Fisher's Exact test.

In total, 749 African-American RA patients from CLEAR I and II were analyzed. The mean age at RA onset was 47.0 years, and 84.6% of patients were women. Median disease duration was 1.9 years; 86% of the patients had either anti-CCP antibodies or RF.

Of the 749 RA participants, 156 (20.8%) had rheumatoid nodules; these patients had more comparable ages at disease onset than did those without nodules but were more likely to have longer disease duration, a smoking history, higher HAQ scores, increased presence of joint-space narrowing and of autoantibodies, and higher levels of CRP (Table 1).

Radiographic scores at enrollment were available in 461 CLEAR I and CLEAR II RA participants. Of these 461 patients, 185 (40.1%) patients had at least one radiographic erosion. RA participants with erosions were younger at RA onset, had longer disease duration, were more likely to have joint-space narrowing and autoantibodies, and to have been treated with methotrexate (Table 1).

The distribution of patients with other extraarticular manifestations was as follows: 16 (2.2%) pulmonary fibrosis, 21 (2.9%) Sjögren syndrome, six (0.8%) pericarditis, three (0.4%) vasculitis, 11 (1.5%) skin ulcers, and 16 (2.2%) scleritis.

Each SNP was in Hardy-Weinberg equilibrium, and the frequencies were similar to those reported in other studies for rs1805010 but different for rs1801275 8 32 33 . No significant differences were found in the genotype and allele frequencies between controls and RA patients. For rs1805010, frequencies were 23.7% and 26.5% for homozygous AA and GG genotypes, respectively, and 49.8% for the heterozygous AG genotype. Likewise, rs1801275 frequencies were 9.9% and 46.6% for homozygous AA and GG genotypes, respectively, and 43.5% for the heterozygous AG genotype.

No significant association between the rs1801275 and rs1805010 alleles and rheumatoid nodules were found in the unadjusted and adjusted analyses (data not shown). After stratification for the presence of HLA-DRB1 SE and autoantibody status (RF or anti-CCP) in multivariable models, the rs1801275 AA genotype (OR_adj = 8.08 (95% CI, 1.60 to 40.89); P = 0.01] and AG genotype (OR_adj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04)] were found to be associated with rheumatoid nodules (Table 2). Similarly, stratifying separately by the presence of HLA-DRB1 SE and anti-CCP antibodies, the AA and AG genotypes of rs1801275 were associated with rheumatoid nodules (OR_adj = 8.12 (95% CI, 1.59 to 41.44), P = 0.01; and OR_adj = 2.96 (95% CI, 1.15 to 7.62), P = 0.02; respectively) in the multivariable model (data not shown). Likewise, stratifying separately by the presence of HLA-DRB1 SE and RF, the rs1801275 AA and AG genotypes (OR_adj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01; and OR_adj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively] and the rs1805010 AA genotype (OR_adj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03) were associated with rheumatoid nodules (data not shown).

No significant association between the presence of radiographic erosions and the SNPs examined was found in any of the unadjusted and adjusted analyses performed. Specifically, statistical significance was not reached after stratification by the presence or absence of HLA-DRB1 SE and anti-CCP or RF status (alone or combination). These data are shown in Table 3.