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2.  Changes in Lipoproteins Associated with Treatment with Methotrexate or Combination Therapy in Early Rheumatoid Arthritis: Results from the TEAR Trial 
Arthritis and rheumatism  2013;65(6):1430-1438.
Objective
To study changes in lipid profiles at 24 weeks among early rheumatoid arthritis (RA) patients participating in the Treatment of Early Rheumatoid Arthritis (TEAR) Trial randomized to initiate methotrexate plus etanercept (MTX+ETA), triple therapy (TT) [MTX plus sulfasalazine plus hydroxychloroquine] or aggressively-titrated MTX monotherapy.
Methods
The TEAR biorepository study had 459 participating patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured in serum plasma at 0 and 24 weeks.
Results
At 24 weeks, there were statistically significant mean increases in cholesterol levels in the MTX + ETA, TT, and MTX monotherapy arms, the observed increases were 31.4, 28.7 and 30 mg/dL in LDL-C; 19.3, 22.3 and 20.6 mg/dL in HDL-C and 56.8, 53 and 57.3 mg/dL values in TC (p < 0.001 all compared to baseline). There was a statistically significant decrease in TC/HDL-C ratio at 24 weeks in all 3 treatment groups from baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein was associated with change in LDL-C (p=0.03), HDL-C (p=0.09), and TC (p=0.01), but disease activity score in 28-joints was not. Baseline glucocorticoid use was associated with changes in HDL-C (p=0.03) and TC (p=0.02).
Conclusion
Levels of TC, LDL-C, and HDL-C increased equivalently shortly after initiation of MTX + ETA, TT and MTX monotherapy among early RA patients with active disease participating in a clinical trial. The clinical relevance of short term changes in traditional lipids on cardiovascular outcomes remains to be determined.
doi:10.1002/art.37916
PMCID: PMC3672346  PMID: 23460074
rheumatoid arthritis; etanercept; methotrexate; cholesterol; lipoprotein; cardiovascular
3.  A Randomized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in Early, Aggressive Rheumatoid Arthritis 
Arthritis and rheumatism  2012;64(9):2824-2835.
Objective
To assess if it is better to intensively treat all early RA patients with drug combinations or reserve this for those who do not appropriately respond to methotrexate monotherapy and assess if the combination therapy of methotrexate plus etanercept is superior to the combination of methotrexate plus sulfasalazine plus hydroxychloroquine.
Methods
The TEAR study is a 2-year, randomized, double-blind trial. Using a 2×2 factorial design, participants were randomized to one of four treatment arms: immediate combination therapy of methotrexate plus etanercept; or oral triple therapy (methotrexate plus sulfasalazine plus hydroxychloroquine); or initial methotrexate monotherapy with a step-up to one of the combination therapies (all arms included matching placebos). The primary outcome was an observed-group analysis of DAS28-ESR scores from weeks 48 to 102.
Results
At the week 24 step-up period, those receiving immediate combination therapy (etanercept plus methotrexate; or triple therapy) demonstrated greater reduction in DAS28-ESR compared to those on initial methotrexate monotherapy (DAS28-ESR: 3.6 vs. 4.6, p<0.0001), with no differences between regimens of combination therapy. For weeks 48 through 102, participants randomized to step-up arms had a DAS28-ESR clinical response that was not different than those who received initial combination therapy, regardless of the treatment arm (3.2 vs. 3.2, p=0.75). There was no significant difference in DAS28-ESR between participants receiving oral triple therapy versus combination methotrexate plus etanercept (3.1 vs. 3.2, p=0.42). By week 102, there was a small, statistically significant difference in change in radiographic measurements from baseline between methotrexate plus etanercept compared to oral triple therapy (0.64 vs. 1.69, p= 0.047). The absolute difference at week 102 was small.
Conclusions
There were no differences in the mean DAS28-ESR during weeks 48-102 between participants randomized to methotrexate plus etanercept or triple therapy, regardless of whether they received immediate combination treatment or step-up from methotrexate monotherapy. At 24 months, immediate combination treatment with either strategy was more effective than methotrexate monotherapy prior to step-up. Initial use of methotrexate monotherapy with the addition of sulfasalazine plus hydroxychloroquine; or etanercept, if necessary after 6 months, is a reasonable therapeutic strategy for early RA. The combination of etanercept plus methotrexate resulted in a statistically significant, but clinically small, radiographic benefit over oral triple therapy.
doi:10.1002/art.34498
PMCID: PMC4036119  PMID: 22508468
4.  The HLA–DRB1 Shared Epitope Is Associated With Susceptibility to Rheumatoid Arthritis in African Americans Through European Genetic Admixture 
Arthritis and rheumatism  2008;58(2):349-358.
Objective
To determine whether shared epitope (SE)–containing HLA–DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population.
Methods
In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti–cyclic citrullinated peptide (anti-CCP) antibodies and HLA–DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry.
Results
The frequency of SE-containing HLA–DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA–DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody–positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody–negative RA (P = 0.01, by chi-square test).
Conclusion
HLA–DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which ~50–70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.
doi:10.1002/art.23166
PMCID: PMC3726059  PMID: 18240241
5.  ASSOCIATIONS OF ALCOHOL USE WITH RADIOGRAPHIC DISEASE PROGRESSION IN AFRICAN AMERICANS WITH RECENT ONSET RHEUMATOID ARTHRITIS 
The Journal of rheumatology  2013;40(9):1498-1504.
Objective
To investigate the associations of alcohol consumption and radiographic disease progression in African Americans with recently diagnosed rheumatoid arthritis (RA).
Methods
RA patients included in the study were participants in the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) registry. Patients were categorized based on self-reported alcohol consumption; those consuming < 15 beverages per month versus those with ≥ 15 per month. Association of radiographic disease progression over a one to three year period of observation with alcohol consumption was evaluated using multivariate generalized estimating equations.
Results
There were 166 patients included in the study, 39% reported that they had never consumed alcohol. Of the 61% who had consumed alcohol, 73% reported that they on average consumed less than 15 alcoholic beverages per month and 27% reported consuming ≥ 15 per month. In multivariate analysis, consumption of ≥ 15 alcoholic beverages per month was associated with an increased risk of radiographic disease progression (p = 0.017). There was no evidence of a relationship in those consuming < 15 beverages per month (p = 0.802).
Conclusion
There appears to be a dose-dependent relationship between alcohol use and radiographic disease progression in RA. Individuals who consume 15 or more alcoholic beverages per month may have accelerated rates of radiographic joint damage than with lower levels of consumption.
doi:10.3899/jrheum.121325
PMCID: PMC4026220  PMID: 23772080
Rheumatoid Arthritis; alcohol consumption; disease severity; disease activity
6.  Comparison of the Disease Activity Score using Erythrocyte Sedimentation Rate and C-reactive Protein in African-Americans with Rheumatoid Arthritis 
The Journal of rheumatology  2013;40(11):1812-1822.
INTRODUCTION
The Disease Activity Score based on 28 joints (DAS28) has been increasingly used in clinical practice and research studies of rheumatoid arthritis (RA). Studies have reported discordance between DAS28 based on erythrocyte sedimentation rate (ESR) versus C-reactive protein (CRP) in RA patients. However such comparison is lacking in African-Americans with RA.
METHODS
This analysis included participants from the Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry which enrolls self-declared African-Americans with RA. Using tender and swollen joint counts separate ESR-based and CRP-based DAS28 scores (DAS28-ESR3 and DAS28-CRP3) were calculated, as were DAS28-ESR4 and DAS28-CRP4, which included the patient’s assessment of disease activity. The scores were compared using paired t-test, simple agreement and kappa, correlation coefficient and Bland-Altman plots.
RESULTS
Of the 233 included participants, 85% were women, mean age at enrollment was 52.6 years, and median disease duration at enrollment was 21 months. Mean DAS28-ESR3 was significantly higher than DAS28-CRP3 (4.8 vs. 3.9; p<0.001). Similarly, mean DAS28-ESR4 was significantly higher than DAS28-CRP4 (4.7 vs. 3.9; p<0.001). ESR-based DAS28 remained higher than CRP-based DAS28 even when stratified by age, sex, and disease duration. Overall agreement was not high between DAS28-ESR3 and DAS28-CRP3 (50%) or between DAS28-ESR4 and DAS28-CRP4 (59%). DAS28-CRP3 underestimated disease activity in 47% of the participants relative to DAS28-ESR3 and DAS28-CRP4 in 40% of the participants relative to DAS28-ESR4.
CONCLUSION
There was significant discordance between the ESR-based and CRP-based DAS28 which could impact clinical treatment decisions in African-Americans with RA.
doi:10.3899/jrheum.121225
PMCID: PMC3987124  PMID: 23950187
DAS28; Rheumatoid Arthritis; African-Americans
7.  Complementary and Alternative Medicine Use in African Americans With Rheumatoid Arthritis 
Arthritis care & research  2014;66(2):180-189.
Objective.
Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking.
Methods.
Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon’s rank sum test, chi-square test, and logistic regression analyses.
Results.
Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA.
Conclusion.
CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care.
doi:10.1002/acr.22148
PMCID: PMC3977347  PMID: 23983105
8.  Gene-body mass index interactions are associated with methotrexate toxicity in rheumatoid arthritis 
Annals of the rheumatic diseases  2013;73(4):785-786.
doi:10.1136/annrheumdis-2013-204263
PMCID: PMC3970399  PMID: 24291656
Gene polymorphism; methotrexate; rheumatoid arthritis
9.  Certolizumab pegol: a new biologic targeting rheumatoid arthritis 
The past decade has been an exciting period for clinical research and patient care in rheumatoid arthritis. This is mostly due to targeted biologic agents that have changed the outcome of this disease. Certolizumab pegol (Cimzia®, UCB Inc., GA, USA), which targets TNF-α with a different mechanism of action than widely used biologics, was initially investigated for Crohn's disease but has now been shown to be effective for rheumatoid arthritis. There have been three significant clinical trials demonstrating the efficacy of certolizumab pegol in active rheumatoid arthritis; two with combination methotrexate and one with monotherapy. This article will summarize the data from those trials and compare some of the characteristics of certolizumab pegol to conventional disease-modifying antirheumatic drugs and other biologic agents. Treatment recommendations are beyond the scope of this review; however, with many options available, there will be annotations on current trends in the care of this chronic disease.
doi:10.1586/eci.10.69
PMCID: PMC3971417  PMID: 20979550
anti-TNF-α therapy; biologics; certolizumab pegol; rheumatoid arthritis
10.  Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene 
PLoS ONE  2014;9(2):e87645.
Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10−6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted.
doi:10.1371/journal.pone.0087645
PMCID: PMC3919745  PMID: 24520335
11.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
12.  Serum cotinine as a biomarker of tobacco exposure is not associated with treatment response in early rheumatoid arthritis 
Arthritis care & research  2012;64(12):10.1002/acr.21758.
Objective
Cigarette smoking has emerged as a risk factor for development of rheumatoid arthritis (RA). Recent studies have suggested that cigarette smoking may lead to lower treatment response rates with methotrexate (MTX) and some biologic agents in RA. Knowledge of whether tobacco exposure reduces treatment efficacy is important as smoking could represent a modifiable factor in optimizing RA treatment.
Methods
Study participants included patients with early RA (<3 years duration) enrolled in the Treatment of Early Aggressive RA (TEAR) trial, a randomized, blinded, placebo-controlled clinical trial (RCT) comparing early intensive therapy (MTX + etanercept or MTX + hydroxychloroquine + sulfasalazine [triple therapy]) versus initial treatment with MTX with step-up to MTX + etanercept or to triple therapy if still active at 24 weeks. Serum cotinine was measured using a commercially available ELISA at baseline and 48 weeks with detectable concentrations at both visits serving as indicator of smoking status. Mean Disease Activity Score (DAS-28) was compared by smoking status, adjusting for baseline disease activity.
Results
Of 412 subjects included in the analysis, 293 (71%) were categorized as ‘non-smokers’ and 119 (29%) as ‘current smokers’. There were no differences in the mean DAS-28 between 48 and 102 weeks based on smoking status for the overall group (p=0.881) or by specific treatment assignment.
Conclusion
Among patients enrolled in a large RCT of early RA with poor prognostic factors, smoking status did not impact treatment responses for those receiving early combination or initial MTX with step-up therapy at 24 weeks if still active.
doi:10.1002/acr.21758
PMCID: PMC3467327  PMID: 22730343
16.  A Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Relaxin in the Treatment of Systemic Sclerosis with Diffuse Scleroderma 
Arthritis and rheumatism  2009;60(4):1102-1111.
Background/Purpose
A phase II randomized controlled trial of recombinant human relaxin suggested that 25 ug/kg/day was safe and clinically effective in improving skin disease and functional disability in scleroderma. We report the results of a large randomized, double-blind, placebo-controlled clinical trial comparing placebo with recombinant human relaxin, 10 ug/kg of body weight per day and 25 ug/kg per day, given for 24 weeks in patients with stable, diffuse, moderate to severe scleroderma (SSc).
Methods
Men and women 18 to 70 years of age with diffuse SSc, disease duration ≤ 5 years since the onset of the first non-Raynaud sign or symptom, a baseline modified Rodnan skin score (MRSS) of 20 or greater, or at least 16 if truncal involvement was present. Recombinant human relaxin (10 or 25 ug/kg/day), or placebo was administered for 24 weeks as a continuous subcutaneous infusion and there was a follow-up safety visit at week 28.
Results
The primary outcome measure, the MRSS, was similar between the 3 groups at baseline and at weeks 4, 12, and 24 (P=NS). Secondary outcomes such as functional disability were similar in all 3 groups and the forced vital capacity significantly decreased in the relaxin groups (p< 0.04). The discontinuation of relaxin (both doses) at week 24 led to statistically significant declines in creatinine clearance and serious renal adverse events (defined as either doubling of baseline serum creatinine, renal crisis, or grade 3 or 4 hypertension) in 7 patients who had received relaxin therapy but in none who had received placebo (p=0.04).
Conclusion
Recombinant relaxin was not significantly better than placebo in improving total skin score, pulmonary function, or functional disability in patients with diffuse SSc. In addition, relaxin was associated with serious renal adverse events, the majority of which occurred after stopping the infusion. If relaxin is used therapeutically for any conditions other than scleroderma, close monitoring of blood pressure and renal function must be performed.
doi:10.1002/art.24380
PMCID: PMC3711466  PMID: 19333948
17.  Clinical Response within 12 Weeks as a Predictor of Future Low Disease Activity in Early RA Patients: Results from the TEAR Trial 
The Journal of rheumatology  2013;40(5):572-578.
Background
Rapidly predicting future outcomes based upon short-term clinical response would be helpful to optimize RA management in early disease.
Objective
To derive and validate a clinical prediction rule to predict low disease activity (LDA) at 1 year among patients participating in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial escalating RA therapy by adding either etanercept (E) or sulfasalazine + hydroxychloroquine [triple therapy (TT)] after 6 months of methotrexate (MTX) therapy.
Methods
Eligible subjects included in the derivation cohort (used for model building, n=186) were participants with moderate or higher disease activity (DAS28ESR>3.2) despite 24 weeks of MTX monotherapy who added either etanercept or sulfasalazine+hydroxychloroquine. Clinical characteristics measured within the next 12 weeks were used to predict LDA 1 year later using multivariable logistic regression. Validation was performed in the cohort of TEAR patients randomized to initially receive either MTX+E or TT.
Results
The derivation cohort yielded three prediction models of varying complexity that included age, DAS28 at various time points, body mass index, and ESR (AUROC up to 0.83). Accuracy of the prediction models ranged between 80 and 95% in both derivation and validation cohorts, depending on the complexity of the model and the cutpoints chosen for response and non-response. Approximately 80% of patients could be predicted to be responders or non-responders at week 12.
Conclusion
Clinical data collected early after starting or escalating DMARD/biologic treatment could accurately predict LDA at 1 year in early RA patients. For patients predicted to be non-responders, treatment could be changed at 12 weeks to optimize outcomes.
doi:10.3899/jrheum.120715
PMCID: PMC3694569  PMID: 23588939
rheumatoid arthritis; prediction; anti-TNF; triple therapy
18.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
19.  Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis 
PLoS Genetics  2013;9(3):e1003394.
Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10−8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10−11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry.
Author Summary
There are no genetic predictors of response to one of the most widely used classes of drugs in the treatment of rheumatoid arthritis—biological modifiers of the inflammatory cytokine tumor necrosis factor-alpha (or anti-TNF therapy). To identify genetic predictors, we performed the largest genome-wide association study (GWAS) to date as part of an international collaboration. In our study, which included 2,706 RA patients treated with one of three anti-TNF drugs, the most significant finding was restricted to RA patients treated with etanercept (P = 8×10−8), a drug that acts as a soluble receptor to bind circulating cytokine and prevents TNF from binding to its cell surface receptor. The associated variant influences expression of a nearby immune-related gene, CD84, whose expression is correlated with disease activity in RA patients. Together, our data support a model in which genomic factors related to CD84 expression serve as a predictor of disease activity and response to etanercept therapy among RA patients of European ancestry, but not anti-TNF therapies that act through different biological mechanisms or potentially in RA patients of other genetic ancestries.
doi:10.1371/journal.pgen.1003394
PMCID: PMC3610685  PMID: 23555300
20.  Interactions of Cigarette Smoking with NAT2 Polymorphisms Impact Rheumatoid Arthritis Risk in African Americans 
Arthritis and Rheumatism  2012;64(3):655-664.
Objective
To examine whether polymorphisms in genes coding for drug metabolizing enzymes (DMEs) impact rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans.
Methods
Smoking status was evaluated in African American RA cases and non-RA controls categorized as heavy (≥ 10 pack-years) vs. other. Individuals were genotyped for a homozygous deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) in addition to tagging single nucleotide polymorphisms (SNPs) in N-acetyltransferase (NAT)1, NAT2, and epoxide hydrolase (EPXH1). Associations of genotypes with RA were examined using logistic regression and gene-smoking interactions were assessed.
Results
There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and NAT2 SNPs rs9987109 (Padd = 0.000003) and rs1208 (Padd = 0.00001); attributable proportions (APs) due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant after adjustment for multiple testing in overall disease risk. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to anti-citrullinated protein antibody (ACPA) positive individuals.
Conclusion
Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA with relative risks that are at least two-fold higher compared to non-smokers lacking these risk alleles.
doi:10.1002/art.33408
PMCID: PMC3272109  PMID: 21989592
rheumatoid arthritis; African Americans; cigarette smoking; anti-CCP antibody; drug metabolizing enzyme; N-acetyltransferase; epoxide hydrolase; glutathione S-transferase
21.  Herpes Simplex Encephalitis during Treatment with Tumor Necrosis Factor-α Inhibitors 
We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-α) inhibitors for rheumatologic disorders. Although TNF-α inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti–TNF-α drugs and herpes simplex virus encephalitis has not been previously described.
doi:10.1086/605498
PMCID: PMC3315107  PMID: 19681709
22.  Most Common SNPs Associated with Rheumatoid Arthritis in Subjects of European Ancestry Confer Risk of Rheumatoid Arthritis in African-Americans 
Arthritis and Rheumatism  2010;62(12):3547-3553.
Objective
Large-scale genetic association studies have identified over 20 rheumatoid arthritis (RA) risk alleles among individuals of European ancestry. The influence of these risk alleles has not been comprehensively studied in African-Americans. We therefore sought to examine whether these validated RA risk alleles are associated with RA in an African-American population.
Methods
27 candidate SNPs were genotyped in 556 autoantibody-positive African-Americans with RA and 791 healthy African-American controls. Odds ratios (OR) and 95% confidence intervals (CI) for each SNP were compared to previously published ORs of RA patients of European ancestry. We then calculated a composite Genetic Risk Score (GRS) for each individual based on the sum of all risk alleles.
Results
There was overlap in the OR and 95% CI between the European and African-American populations in 24 of the 27 candidate SNPs. Conversely, 3 of the 27 SNPs (CCR6 rs3093023, TAGAP rs394581, TNFAIP3 rs6920220) demonstrated an OR in the opposite direction from those reported in RA patients of European ancestry. The GRS analysis indicated a small but highly significant probability that African-American cases were enriched for the European RA risk alleles relative to controls (p=0.00005).
Conclusion
The majority of RA risk alleles previously validated among European ancestry RA patients showed similar ORs in our population of African-Americans with RA. Furthermore, the aggregate GRS supports the hypothesis that these SNPs are risk alleles for RA in the African-American population. Future large-scale genetic studies are needed to validate these risk alleles and identify novel risk alleles for RA in African-Americans.
doi:10.1002/art.27732
PMCID: PMC3030622  PMID: 21120996
23.  Associations of cigarette smoking with rheumatoid arthritis in African Americans 
Arthritis and rheumatism  2010;62(12):3560-3568.
Objective
To examine the associations of cigarette smoking with rheumatoid arthritis (RA) in African Americans and to determine to whether this association is impacted by HLA-DRB1 shared epitope (SE).
Methods
Smoking status, cumulative smoking exposure, and SE status were measured in African American patients with RA and in healthy controls. Associations of smoking with RA were examined using age- and gender-adjusted logistic regression. Additive and multiplicative SE-smoking interactions were examined.
Results
After adjusting for age and gender, ever (OR = 1.45; 95% CI 1.07 to 1.97) and current smoking (OR = 1.56; 95% CI 1.07 to 2.26) were more common in African American RA cases (n = 605) than in controls (n = 255). The association of smoking with RA was limited to those with a cumulative exposure exceeding 10 pack-years, associations that were evident in both autoantibody positive and negative disease. There was evidence of a significant additive interaction between SE status and heavy smoking (≥ 10 pack-years) in RA risk (attributable proportion due to interaction [AP] of 0.58, p = 0.007) with an AP of 0.47 (p = 0.006) between SE status and ever smoking. There was no evidence of multiplicative interactions.
Conclusion
Among African Americans, cigarette smoking is associated not only with the risk of autoantibody positive RA but also with the risk of autoantibody negative disease. RA risk attributable to smoking is limited to African Americans with more than 10 pack-years of exposure and is more pronounced among individuals positive for HLA-DRB1 SE.
doi:10.1002/art.27716
PMCID: PMC2995845  PMID: 20722010
rheumatoid arthritis; African Americans; cigarette smoking; rheumatoid factor; anti-CCP antibody; HLA-DRB1 shared epitope
24.  A Functional RANKL Polymorphism Associated with Younger Age at Onset of Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(10):2864-2875.
Objective
We previously reported association of co-occurrence of HLA-DRB1 shared epitope (SE) and RANKL SNPs with younger age of RA onset in 182 rheumatoid factor positive (RF) European American (EA) early RA patients. Here, we fine-mapped the 48 kb RANKL region in the extended 210 EA RF-positive early RA cohort, sought replication of RA-associated SNPs in additional 501 EA and 298 African-Americans (AA) RA cohorts, and explored functional consequences of RA-associated SNPs.
Methods
SNP genotyping was conducted using pyrosequencing or TaqMan PCR assays. Associations of rs7984870 with RANKL expression in plasma, PBMC and isolated T cells were quantified using ELISA and RT-PCR. Site-directed mutagenesis of rs7984870 within the 2kb RANKL promoter was performed to drive the luciferase reporter gene in osteoblast and stromal cell lines. Interaction of DNA and protein was determined by electrophoretic mobility shift assay.
Results
A single promoter SNP rs7984870 was consistently significantly associated with earlier age of RA onset in 3 independent seropositive (RF or anti-cyclic citrullinated peptide antibody positive) RA cohorts but not in seronegative RA patients. The risk C allele of rs7984870 conferred 2-fold higher plasma RANKL levels in RF-positive RA patients, significantly elevated RANKL mRNA expression in activated normal T cells, and increased promoter activity after stimulation in vitro via differential binding to transcription factor SOX5.
Conclusion
The RANKL promoter allele that increased transcriptional levels upon stimulation might promote interaction between activated T cells and dendritic cells, predisposing to younger RA onset in seropositive EA and/or AA individuals.
doi:10.1002/art.27589
PMCID: PMC2944013  PMID: 20533289
25.  Generalized Bone Loss as a Predictor of 3-Year Radiographic Damage in African American Patients with Recent-Onset Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(8):2219-2226.
Objective
To examine the association between baseline bone mineral density (BMD) and radiographic damage at 3-year disease duration in a longitudinal cohort of African Americans (AAs) with recent-onset RA.
Methods
Participants (n=141) included AAs with < 2 years of disease duration. All patients underwent baseline BMD measurement (femoral neck and/or lumbar spine) using DXA. T-scores were calculated using AAs normative data. Patients were categorized as having osteopenia/osteoporosis (T score ≤ −1) or healthy. Hand/wrist radiographs, obtained at baseline and at 3-year disease duration, were scored using modified Sharp/van der Heijde method. The association between baseline BMD and total radiographic score at 3-year disease duration was examined using multivariable negative binomial regression.
Results
At baseline, the mean age and disease duration were 52.4 years and 14.8 months respectively (85.1% women). Average total radiographic scores at baseline and 3-year disease duration were 2.4 and 5.7. In the final reduced multivariable model adjusting for age, gender, anti-cyclic citrullinated peptide antibody positivity, and the presence of radiographic damage at baseline, the total radiographic score at 3-years of disease duration in patients with osteopenia/osteoporosis at the femoral neck was twice that in patients with healthy bone density and the difference was statistically significant (p=0.0084). No association between lumbar spine osteopenia/osteoporosis and radiographic score was found.
Conclusion
These findings suggest that reduced generalized BMD may be a predictor of future radiographic damage and support the hypothesis that radiographic damage and reduced generalized BMD in RA patients may share a common pathogenic mechanism.
doi:10.1002/art.27510
PMCID: PMC2922001  PMID: 20506234

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