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.

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.

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.

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.

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.

Objective

To examine the prevalence of vitamin D insufficiency and the associations of vitamin D concentration with disease status in African Americans with rheumatoid arthritis (RA).

Methods

Study participants (n = 266) were enrolled in the Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) Registry. 25(OH)-D was measured on baseline plasma and associations of 25(OH)-D with disease status (baseline and at 3 years disease duration) were examined using univariate and multivariate regression.

Results

The prevalence of 25(OH)-D insufficiency (≤ 37.5 nmol/L or 15 ng/ml) was 50%, with the highest prevalence in winter. In unadjusted analyses, vitamin D concentrations were inversely associated with baseline pain (p = 0.04), swollen joints (p = 0.04), and Disease Activity Score (DAS-28, p = 0.05) but not with measures at 3 years disease duration. There were no multivariate associations of 25(OH)-D with any disease measures at baseline or at 3 years with the exception of a positive borderline association with rheumatoid factor positivity at enrollment (p = 0.05).

Conclusions

Vitamin D insufficiency is common in African Americans with recent-onset RA. Unadjusted associations of circulating vitamin D with baseline pain, swollen joints, and DAS-28 were explained by differences in season, age, and gender and were not significant in multivariate analyses. In contrast to reports of Northern Europeans with early inflammatory arthritis, there are not strong associations of 25(OH)-D concentration with symptoms or disease severity in African Americans with RA.

The dawn of the biologic era has been an exciting period for clinical research and patient care in rheumatoid arthritis (RA). Targeted biologic therapies have changed the outcome of this disease and made remission a realistic outcome for many patients. Tocilizumab (TCZ, Actemra®), is a humanized monoclonal antibody against the interleukin 6 receptor and has been approved in many countries for the treatment of moderate to severe RA. There have been a number of important clinical trials demonstrating the efficacy of TCZ in active rheumatoid arthritis. This review summarizes the data on efficacy, patient-reported outcomes, adverse events, and safety from some of these trials. Current trends in clinical practice will be discussed. It is difficult to place TCZ and many new medications in the algorithm of treatment at present. However, the next few years will hopefully reveal their role as we better define abnormal immune processes in individuals with RA.

Purpose: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data.

Methods: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site ≥2.5 SD below the young adult mean. Osteopenia was defined as a BMD ≥1 SD and <2.5 SD below this mean.

Results: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic.

Conclusion: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.

PURPOSE: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data. METHODS: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site > or =2.5 SD below the young adult mean. Osteopenia was defined as a BMD > or =1 SD and <2.5 SD below this mean. RESULTS: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic. CONCLUSION: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.

The objective of this study was to evaluate the safety and possible efficacy of IFN-β-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 μg IFN-β-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-β and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-β-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.

Although the predominant mechanism of intra-articular hyaluronan (hyaluronic acid) (HA) and hylans for the treatment of pain associated with knee osteoarthritis (OA) is unknown, in vivo, in vitro, and clinical studies demonstrate various physiological effects of exogenous HA. HA can reduce nerve impulses and nerve sensitivity associated with the pain of OA. In experimental OA, this glycosaminoglycan has protective effects on cartilage, which may be mediated by its molecular and cellular effects observed in vitro. Exogenous HA enhances chondrocyte HA and proteoglycan synthesis, reduces the production and activity of proinflammatory mediators and matrix metalloproteinases, and alters the behavior of immune cells. Many of the physiological effects of exogenous HA may be a function of its molecular weight. Several physiological effects probably contribute to the mechanisms by which HA and hylans exert their clinical effects in knee OA.

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.

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.

Objective

To describe radiographic changes in African-Americans with rheumatoid arthritis (RA) from the CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, a multicenter observational study.

Methods

Self-declared African-American patients, were enrolled in CLEAR I, a longitudinal cohort of early RA (disease duration <2 years) from 2000 to 2005; or in CLEAR II, a cross-sectional cohort (any disease duration), from 2006 to the present. Demographic and clinical data were obtained, and sets of hand/wrist and foot radiographs were scored using the modified Sharp/van der Heijde scoring system.

Results

A total of 357 and 418 patients, respectively, have been enrolled into CLEAR I and CLEAR II. We report here an interim analysis of radiographic severity in these patients. For the CLEAR I cohort, 294 patients had a mean radiographic score of 2.89 at the baseline visit; 32.0% showed either erosions (25.9%) or joint space narrowing (JSN) (19.4%). At the 36-month visit the mean score was 5.65; 44.2% had erosions, 41.5% JSN and 55.4% had either. Among those patients without radiographic damage at baseline, 18.9% had progressed at the 36-month visit, compared to 57.1% of those with baseline damage (p<0.0001). For the CLEAR II cohort, 167 patients with RA of any duration, 65.3% exhibited joint erosions, 65.3% JSN and 74.8% exhibited either. The mean radiographic score was 33.42.

Conclusion

This is the largest radiographic study of African American RA patients. Damage occurs early in the disease and is associated with radiographic progression at 3 years of disease duration. The CLEAR Registry will provide a valuable resource for future analyses of genetic, clinical, and environmental factors associated with radiographic severity of RA in African-Americans.

Introduction

To determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.

Methods

Two IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.

Results

Of the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score >0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj = 8.08 (95% confidence interval (CI): 1.60-40.89), P = 0.01 and ORadj = 2.97 (95% CI, 1.08 to 8.17), P = 0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj = 8.45 (95% CI, 1.57 to 45.44), P = 0.01, and ORadj = 3.57 (95% CI, 1.18 to 10.76), P = 0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj = 4.52 (95% CI, 1.20 to 17.03), P = 0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.

Conclusions

We found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.

Objective

To examine the association of smoking with clinical and serologic features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE).

Methods

In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current vs. past vs. never and pack-years of exposure) with anti-CCP antibody, rheumatoid factor (RF) (-IgM and -IgA), rheumatoid nodules, and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes.

Results

Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05–2.88) and nodules (OR = 2.43; 95% CI 1.13–5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-CCP antibody, IgM-RF, or radiographic erosions. There was also no evidence of a biologic or statistical SE-smoking interaction for any of the outcomes examined.

Conclusion

This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.

Cytotoxic T-lymphocyte associated protein 4 (CTLA4) is a negative regulator of T-cell proliferation. Polymorphisms in CTLA4 have been inconsistently associated with susceptibility to rheumatoid arthritis (RA) in populations of European ancestry but have not been examined in African Americans. The prevalence of RA in most populations of European and Asian ancestry is ∼1.0%; RA is purportedly less common in black Africans, with little known about its prevalence in African Americans. We sought to determine if CTLA4 polymorphisms are associated with RA in African Americans. We performed a 2-stage analysis of 12 haplotype tagging single nucleotide polymorphisms (SNPs) across CTLA4 in a total of 505 African American RA patients and 712 African American controls using Illumina and TaqMan platforms. The minor allele (G) of the rs231778 SNP was 0.054 in RA patients, compared to 0.209 in controls (4.462×10−26, Fisher's exact). The presence of the G allele was associated with a substantially reduced odds ratio (OR) of having RA (AG+GG genotypes vs. AA genotype, OR 0.19, 95% CI: 0.13–0.26, p = 2.4×10−28, Fisher's exact), suggesting a protective effect. This SNP is polymorphic in the African population (minor allele frequency [MAF] 0.09 in the Yoruba population), but is very rare in other groups (MAF = 0.002 in 530 Caucasians genotyped for this study). Markers associated with RA in populations of European ancestry (rs3087243 [+60C/T] and rs231775 [+49A/G]) were not replicated in African Americans. We found no confounding of association for rs231778 after stratifying for the HLA-DRB1 shared epitope, presence of anti-cyclic citrullinated peptide antibody, or degree of admixture from the European population. An African ancestry-specific genetic variant of CTLA4 appears to be associated with protection from RA in African Americans. This finding may explain, in part, the relatively low prevalence of RA in black African populations.

Author Summary

Rheumatoid arthritis (RA) is a systemic autoimmune condition affecting the synovial membranes of diarthrodial joints. The etiology of RA is unclear but is thought to result from an environmental trigger in the context of genetic predisposition. We report that a single nucleotide polymorphism (SNP) (rs231778) in CTLA4, which encodes a negative regulator of T cell activation, is associated (p = 2.4×10−28) with protection from developing RA among African Americans. rs231778 is only polymorphic in populations of African ancestry. Protective alleles such as this one may contribute to the purported lower prevalence of RA in African Americans. Our finding appears to be independent from confounding by linkage with the HLA-DRB1 shared epitope or by genetic admixture. Furthermore, we did not replicate associations of CTLA4 SNPs with RA or other autoimmune diseases previously reported in Asians and Caucasians, such as rs3087243 (+60C/T) and rs231775 (+49A/G). The associations of different SNPs with RA susceptibility specific to different populations highlight the importance of CTLA4 in the pathogenesis of RA and demonstrate the ethnic-specific genetic background that contributes to its susceptibility.